Dydrogesterone and Bed Rest vs. Bed Rest Alone in the

Transcription

Dydrogesterone and Bed Rest vs. Bed Rest Alone in the
Management of Hemorrhage
RAMON M. G ONZALEZ, MD, FPOGS
Department of Obstetrics and Gynecology, University of Santo Tomas Hospital
Subchorionic hemorrhage is a common sonographic
feature during early pregnancy. It appears as a hypoechoic
area (half moon or rocket shape) between the chorion and
uterine wall. It can be seen as early as 9 weeks until 20
weeks AOG. The most common presenting feature of
subchorionic hemorrhage is vaginal bleeding. Some
however, are asymptomatic. Clinical significance of
subchorionic hemorrhage remains controversial. Some
studies conducted showed association of subchorionic
hemorrhage with spontaneous abortion, preterm delivery,
pre-eclampsia, pregnancy-induced hypertension and
placental abnormalities. Recent management options for
subchorionic hemorrhage are bed rest and progesterone
supplementation. Data on bed rest are limited. Studies on
the use of progesterone in subchorionic hemorrhage is
also limited. But because of the risk of spontaneous
abortion, most clinicians opt to give progesterone to
prevent abortion. A total of 210 patients were included in
the study. Subjects were randomly assigned to either the
bed rest group or dydrogesterone plus bed rest group.
Results showed that after two weeks of treatment, 44
patients (41.5%) had resolution of subchorionic
hemorrhage after receiving dydrogesterone while 48
patients (46.2%) resolved in the bed rest group. A total of
2 early fetal demise were noted on each arm. For patients
treated with dydrogesterone and bed rest, 62 still had
subchorionic hemorrhage and 56 of the patients with bed
rest alone, still had subchorionic hemorrhage. There is no
significant difference in the mean measurement of
subchorionic hemorrhage of patients under the two groups
who still have it, after two weeks of treatment. Management
of subchorionic hemorrhage with dydrogesterone plus bed
rest and bed rest alone in patients does not resolve the
hemorrhage and does not reduce the incidence of abortion.
Key words: Subchorionic hemorrhage, dydrogesterone, bed
rest
S
ubchorionic hemorrhage is a commonly observed feature in ultrasonographic examinations
during the first trimester of pregnancy in women
presenting with vaginal bleeding . However, some
can be asymptomatic. The clinical significance of
subchorionic
hemorrhage
detected
on
ultrasonography remains controversial. Some
investigators consider this a benign finding 1,12 ,
whereas others suggest an increase risk for adverse
pregnancy outcomes. 8-11
In a study conducted by Pederson and
Mantoni, detection of subchorionic hemorrhage
during early trimester of pregnancy (9-20 weeks) has
a prevalence of 18% and overall spontaneous
abortion rate of 10%.1 A certain level of progesterone
produced by the corpus luteum and later on, by the
placenta must be achieved to support pregnancy.
Perkins demonstrated that ser um progesterone
concentration of < 45 mmol/L was highly predictive
of non-viable pregnancy in spontaneously pregnant
patients.2
With the 10% association of spontaneous
abortion with subchorionic hemorrhage, clinicians
have been prescribing progesterone and advising bed
rest to prevent abortion. The preliminary results of
this study will focus on the effect of dydrogesterone
in subchorionic hemorrhage as compared to bed
rest.
Objectives
The aims of this study were:
1. To compare the rate of spontaneous abortion in
patients diagnosed with subchorionic hemorrhage
and managed with or without dydrogesterone
therapy.
September, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 3) 117
Dydrogesterone and Bed Rest in the Management of Hemorrhage / Gonzalez
2. To compare the resolution of subchorionic
hemorrhage treated with dydrogesterone and bed
rest in comparison to bed rest alone.
MATERIALS AND METHODS
In this single-blind randomized controlled trial,
a total of 210 obstetric patients who presented at the
OB-OPD from May 2007 to May 2009, during early
trimester of pregnancy (4 weeks to 20 weeks) and
diagnosed with subchorionic hemorrhage
sonographically were included in the study. Patients
with a non-viable fetus, multifetal pregnancy or fetal
abnormality diagnosed by ultrasound were excluded
in the study.
Subjects were randomly assigned to either the
bed rest group or dydrogesterone plus bed rest group
using a pre-sealed envelope containing numbers. Per
subject, a number was withdrawn by an OB resident.
All patients under even numbers consist the
experimental group while those under odd numbers
consist the control group.
The experimental group received dydrogesterone
10mg three times a day for two weeks and the control
group did not receive any medication. Both groups
were advised to stay at home with light physical
activities (bed rest) and to avoid sexual intercourse.
Repeat ultrasound was done by a sonographer
blinded to the treatment received by the subjects after
two weeks to detect resolution of subchorionic
hemorrhage. The subjects were followed-up until
20 weeks AOG.
Relevant data were gathered from each case
regarding maternal age, previous abortions, age of
gestation detected with subchorionic hemorrhage and
2-dimensional measurement of subchorionic
hemorrhage by the standard gray scale ultrasound
and presence and/or absence of spontaneous
abortion.
(on all patients) and after two weeks (on patients
still with subchorionic hemorrhage),
Descriptive statistics were generated for all
variables. For nominal data frequencies and
percentages were computed. For numerical data,
mean ± SEM were generated. Comparison of the
different variables under study was done using the
following test statistics:
T test was used to compare two groups with
numerical data (compares means), chi-square test used to compare/associate nominal data and Fisher
exact test - was used to compare/associate nominal
data in a 2 x 2 contingency table.
The number of subjects to be included in this
study was computed based from a 95% confidence
level and 80% power of the study. With an estimated
prevalence of subchorionic hemorrhage to be 18%,
a total of 52 patients per arm will be included.
Flowchart of Activities
Statistical Analysis
The age of gestation and measurement of
subchorionic hemorrhage at diagnosis is reported as
mean and standard error. To measure the resolution
of subchorionic hemorrhage, the difference between
measurements at time of diagnosis and after two
weeks was reported as mean difference and standard
error.
Independent-samples t-test was used in the
comparison of the mean age, AOG (in weeks),
measurement of the subchorionic hemorrhage before
Review of Related Literature
Subchorionic hemorrhage is a common
sonographic feature during early pregnancy. It
appears as a hypoechoic area (half moon or rocket
shape) between the chorion and uterine wall. It can
be seen as early as 9 weeks until 20 weeks AOG. The
most common presenting feature of subchorionic
hemorrhage is vaginal bleeding. Some are
asymptomatic.
118 September, 2013 Philippine Journal of Obstetrics & Gynecology Volume 37 (No. 3)
Detection of subchorionic hemorrhage in
patients who have vaginal bleeding during early
pregnancy can be as high as 18% (62 of 342 patients
who had symptoms of threatened abortion in weeks
9-20). 1 Similar studies were conducted on patients
with symptoms of threatened abortion and showed
incidences varying from 4-22% (Table 1). 3
The discrepancy between the repeated incidences
can be due to variable patient populations, wide range
of gestational ages and lack of a standard definition
of intrauterine hematoma. 3 In contrast to the study
conducted by Ball, et al. in 1996, 4 the cases of
subchorionic hemorrhage were recruited from general
patient population, thus an incidence of 1.3%
(representing a more accurate reflection of true
incidence). However, it was noted that the
population of Ball et al were mostly high-risk because
of high mean maternal age and high frequency of
invasive procedures.
In the past, the etiology and epidemiologic
factors of subchorionic hemorrhage remain unclear.5
Baxi and Pearlstone however, demonstrated that the
presence of autoantibodies may cause subchorionic
hemorrhage. This was because antibodies may
increase the tendency of platelets to aggregate which
leads to thrombus and/or vasculitis and thereby to
an increase likelihood of subchorionic hematoma.5
They, therefore, recommend that patient with
subchorionic hemorrhage with symptoms of
threatened abortion be tested for presence of
autoantibodies regardless of obstetric history.
In a recent study of Coulam, the mechanism
implicated in subchorionic hemorrhage is under T
helper type 1 (Th1) cytokine control.6 Endothelial
cells activated by interleukin (IL)-1, tumor necrosis
factor-alpha (TNF alpha) and interferon-gamma
(INF gamma) release prothrombinase, which
conver ts prothrombin to activated thrombin.
Activated thrombin stimulates endothelial cells to
secrete IL-8, which recruits polymorphonuclear
(PMN) cells. These PMN cells destroy the decidual
endothelial cells activated by IL-1, TNF alpha and
INF gamma, and this leads to coagulation in the
decidual vessels. Under normal conditions, this
coagulation is prevented by IL-4 and IL-10, which
inhibit the activity of endothelial prothrombinase
stimulated by cytokines.7
Clinical significance of subchorionic
hemorrhage remains controversial. Some studies
conducted showed association of subchorionic
hemorrhage with spontaneous abortion, preterm
delivery and other pregnancy outcome.3 In the study
by Pederson, et al. the overall spontaneous abortion
rate was 10%, but the presence of subchorionic
hemorrhage did not alter this rate. 1 Other authors
have found abortion rates of two of 108, six of 33 9,
three of 29 10 , seven of 16 11, and none of 22 12 in
patients who had subchorionic hemorrhage before
week 20. This wide variation in abortion rates
ranging from 0% 12 to 44% 11 can be due to small
number of patients studied, and involving different
populations.
Other studies have reported that the size and
situation of the hematoma have prognostic value.
Amongst 516 women with bleeding and
subchorionic hematoma in the first trimester, the
Table 1. Review of the literature on intrauterine hematoma.
Author (year)
Mantoni (1981)
Goldstein (1983)
Jouppila (1985)
Saurbei (1986)
Abu-Youssef (1987)
Nyberg (1987)
Borlum (1989)
Mandruzzato (1989)
Pedersen (1990)
Baxi (1991)
Ball (1996)
Seki (1998)
Tower (2001)
No. of Patients
12
10
33
30
21
65
86
62
23
5
317
22
41
Hematoma
Frequency
(%)
Spontaneous
Abortion Rate
(%)
Preterm
Delivery Rate
(%)
NA
20
NA
NA
NA
NA
22.1
11
4
NA
1.3
0.46
12
2 (17)
2 (20)
6 (19)
3 (10)
12 (57)
6 (9)
13 (16)
8 (13)
1 (4)
0 (0)
16 (7)
3 (14)
6 (15)
1 (8)
0 (0)
3 (11)
7 (23)
3 (33)
15 (25)
6 (15)
7 (13)
2 (9)
1 (20)
27 (11)
17 (77)
8 (32)
miscarriage rate was about twice as high in those
with a large hematoma (18.8%) compared with small
and medium hematomas (7.7% and 9.2%,
respectively).29
The size of hemorrhage was studied in relation
to pregnancy outcome by Ball et al in 1996. The
size of subchorionic hemorrhage only appeared to
be related to the outcome in certain cases. A "large"
(at least 25% of the size of the gestational sac)
subchorionic hemorrhage appears to carry a worse
prognosis with respect to total adverse outcome than
a "small" (≥5%) one. A "medium" (<25%)
subchorionic hemorrhage did not influence
prognosis compared with the "small" or "large" ones.
(Table 2). It was concluded that there was no
correlation between the size of hemorrhage and
pregnancy outcome.4 Nagy, et al. also showed no
correlation between estimated volume of hematoma
with outcome of pregnancy and commented that
perhaps it is the presence or absence of hematoma as
a marker of the integrity of placentation and not its
size that is important.3
Another pregnancy outcome studied in relation
to subchorionic hemorrhage is preterm delivery.
Nagy, et al. showed 16% rate of preterm delivery in
a general obstetric population, 3 which was similar
to 12% reported by Pearlstone13 but lower that the
32% rate re por ted by Tower 14 in a high-risk
population. Pedersen, et al. showed 11% overall rate
of preterm delivery but the presence of subchorionic
hemorrhage did not alter this rate.1 Other studies
showed premature delivery rates of none of 108, three
of 339, seven of 29 10, and three of 1611 in patients
who had subchorionic hemorrhage before week 20.
These variations can be due to small number of
patients and different populations.
In the study of Tower and Regan, premature
delivery happens because a localized accumulation
of blood causes mechanical uterine irritation leading
to contractions.14 Another possible mechanism is
bacterial colonization of the hematoma and
endotoxin release with subsequent prostaglandin
synthesis.3 This was seen in the study of Seki, et al.
where 77% of pregnancies with a persistent
subchorionic hematoma had delivery before 37
weeks, and six of their 22 cases (27.3%) had
chorioamnionitis. 15
Other pregnancy outcomes related to
subchorionic hemorrhage are pre-eclampsia,
pregnancy-induced hypertension and placental
abnormalities. 3
Recent management options for subchorionic
hemorrhage are bed rest and progesterone
supplementation.
Data on bed rest are limited. There was only
one randomized controlled trial which study the
impact of bed rest on threatened abortion.16 This
study included 61 women with viable pregnancies
at less than 8 gestational weeks and vaginal bleeding
who were randomly allocated into either injections
of hCG, injections of placebo, or bed rest. The
abortion rates in the three groups were 30%, 48%,
and 75% - significant differences between hCG and
bed rest groups but not between hCG and placebo
groups or between placebo and bed rest groups.
A retrospective study was also done on the impact
of bed rest on abortion.17 This study showed that
16% of 146 women who had bed rest eventually had
abortion as compared to a fifth of women who did
not follow this option. However, this was not
significant (P=0.41). This was in contrast to a recent
observational cohort study 18 of 230 women with
threatened miscarriage who were recommended bed
rest had abortion rate of 9.9% as compared with
23.3% of women who continued their usual activities
(P=0.03). The duration of vaginal bleeding,
Table 2. Pregnancy outcomes in patients in relation to subchorionic hemorrhage size.
Outcome
Small Subchorionic
Hemorrhage
(n = 103, 44%)
Medium Subchorionic
Hemorrhage
(n = 66, 28%)
Large Subchorionic
Hemorrhage
(n = 64, 28%)
Spontaneous abortion
3 (3%)
4 (6%)
7 (11%)
Stillbirth
1 (%)
2 (3%)
5 (8%)
Neonatal death
2 (2%)
0 (0%)
0 (0%)
Total adverse outcome
6 (6%)
6 (9%)
12 (19%)
hematoma size and gestational age at diagnosis did
not influence abortion rate. Although there is no
definite evidence that bed rest can affect the course
of pregnancy, abstinence from active environment
for a couple of days may help women feel safer, thus
providing emotional relief.
The other management option for subchorionic
hemorrhage is progesterone supplementation.
Progesterone is prescribed in 13-40% of women with
threatened miscarriage, according to published
series. 19 Progesterone is needed to maintain
pregnancy. Initially, it is produced by the corpus
luteum and later by the placenta. Mishell and
coworkers (1973) 20 demonstrated that there is an
increase of progesterone after implantation. Later
on between the 6th and 10th week of gestation, there
is not only a plateau but even a decrease which can
be farely steep and longlasting in individual case.
Thereafter, there is a continuous rise of progesterone
till term.
The turnaround of these events is due to the
limited life span of the corpus luteum which is
reflected initially by the rise of 17 α-hydroxyprogesterone after implantation then gradually
decreasing around 7th to 8th week of gestation.21 It
must be noted that 17 α-hydroxyprogesterone is
produced by the corpus luteum and not by the
placenta. Thus, first trimester pregnancy is
endocrinologically determined by the luteo-placental
shift.22
Therefore, abortion happens if there is corpus
luteum insufficiency, defective luteo-placental
progesterone or placental delay of progesterone
synthesis and secretion.22
Like bed rest, studies on progesterone
supplementation on miscarriage are limited.
Recently, a meta-analysis assessed the impact of
progesterone supplementation on miscarriage rate in
various clinical settings23; however it did not provide
a separate analysis for progesterone in threatened
miscarriage. There are only four old randomized
controlled trials on progestogens, and their
cumulative results show that they do not improve
outcome.24
Dydrogesterone is an orally active, highly
selective progestogen that is similar to endogenous
progesterone, but which has a better bioavailability
and hence allows administration of lower doses and
avoidance of progestogenic side-effects.2
In the study conducted by Omar, et al. 25
administration of dydrogesterone to women with
threatened miscarriage in first trimester can be
beneficial in the maintenance of pregnancy beyond
20 weeks gestation. The pregnancy success rate (in
terms of viable pregnancies at 20 weeks) was 95.9%
in women treated with dydrogesterone and 86.3%
in women treated conservatively (P = 0.037,
statistically significant).
The use of progesterone in subchorionic
hemorrhage is still limited. Because of the risk of
spontaneous abortion, most clinicians opt to give
progesterone to prevent abortion.
A total of 210 patients were included in the study.
Table 3 shows the comparison of the different
demographic characteristics between the two groups.
The results showed that there was no significant
difference noted as proven by all P-values > 0.05.
Table 3. Comparison of the demographic characteristics between the two groups.
Bed Rest Alone
(n = 104)
Dydrogesterone and Bed Rest
(n = 106)
Age (in years)
Mean ± SEM
27.42 ± 0.46
27.55 ± 0.54
Gravidity
Primigravid
Multigravid
56 (53.8%)
48 (46.2%)
55 (51.9%)
51 (48.1%)
Mean ± SD
0.78 (NS)
AOG (in weeks)
Mean ± SEM
2±1
2±1
8.88 ± 0.20
9.05 ± -0.19
P-value
0.91 (NS)
0.55 (NS)
Table 4 shows the comparison of the mean
measurement of the subchorionic hemorrhage
between the two groups. The results shows that
the mean measurement of the subchorionic
hemorrhage of the dydrogesterone and bed rest
group was significantly higher (P=0.0006) than the
bed rest alone group with mean of 1.26 and 0.99
respectively.
Table 5 shows the comparison of the different
outcomes between the two groups. The results
showed that there was no significant difference noted
in the proportion of subjects with or without
resolution of subchorionic hemorrhage as shown by
the P value of 0.49 as well as the proportion of
subjects with or without spontaneous abortion with
P value of 1.00. Almost 42% had resolution of
subchorionic hemorrhage after receiving
dydrogesterone for 2 weeks while almost 46.2%
resolved in the bed rest group. A total of 2 early
fetal demise (1.9%, respectively) were noted on each
arm after 2 weeks of treatment.
After two weeks of treatment, 56 of the patients
with bed rest alone, are still with subchorionic
hemorrhage with mean measurement of 1.10 ± 0.06.
For patients treated with dydrogesterone and had
bedrest, 62 were still with subchorionic hemorrhage
with mean measurement of 1.19 ± 0.07. Independent
t-test's p-value of 0.32 indicates that there is no
significant difference in the mean measurement of
subchorionic hemorrhage of patients under the two
groups who still have it, after two weeks of treatment.
Table 6 shows the association of the subchorionic
hemorrhage measurement with spontaneous
abortion. With P-value of 0.006, results show that
the mean measurement of the subchorionic
hemorrhage with spontaneous absorption is
significantly higher than the mean measurement of
the subchorionic hemorrhage without spontaneous
absorption.
Table 4. Comparison of the mean measurement of the subchorionic hemorrhage measurements between the two
groups.
Bed Rest Alone
(n = 104)
Mean measurement
Mean ± SEM
(n = 106)
0.99 ± 0.51
1.26 ± 0.56
P-value
0.0006 (S)
Table 5. Comparison of the outcome between the two groups.
Bed Rest Alone
(n = 104)
(n = 106)
P-value
Resolution of Subchorionic Hemorrhage
With
Without
Mean ± SEM
48 (46.2%)
56 (53.8%)
1.10 ± 0.06
44 (41.5%)
62 (58.5%)
1.20 ± 0.07
0.498 (NS)
Difference in Measurement of SCH After
2 Weeks of Treatment, n
Mean ± SD
Median
1.10 ± 0.06, 56
1.03
1.19 ± 0.07, 62
1.10
0.32 (NS)
Spontaneous Abortion
With
Without
2 (1.9%)
102 (98.1%)
2 (1.9%)
104 (98.1%)
1.00 (NS)
0.295 (NS)
Table 6. Association of the baseline measurement of subchorionic hemorrhage with spontaneous abortion.
With Spontaneous Abortion
(n = 4)
SCH measurement
Mean ± SD
Without Spontaneous Abortion
(n = 206 )
1.83 ± 0.44
1.11 ± 0.04
P value
0.006 (S)
After two weeks, the output above (P = 0.794)
shows that the outcome is not dependent on the
treatment.
DISCUSSION
Early trimester of pregnancy is sometimes
complicated with sonographically detected
subchorionic hemorrhage in 18% of population,
clinically presenting with vaginal bleeding. However,
some are asymptomatic.
In the study of Goldstein, sonographic detection
of subchorionic hemorrhage can be as early as 9
weeks. 8 This is comparable in our study wherein
the mean age of gestation of detection of
subchorionic hemorrhage in both group is 8-9 weeks,
however, no significant differences were noted
between the two groups.
Majority of these subchorionic hemorrhages will
resolve spontaneously. However, 10% of these
hemorrhages may result to abortion.1 In our study,
1.9% ended in abortion in both groups but with no
significant difference. Other authors have found
abortion rates ranging from 0%12 to 44%.11 This wide
variation in abortion rates can be explained by the
small number of patients studied, and involving
different populations.
Correlation between the size of subchorionic
hemorrhage and spontaneous abortion rate was
statistically significant in our study (p = 0.006). This
is in contrast with the study of Ball, et al. wherein
there was no significant difference between the size
of subchorionic hemorrhage and abortion rate.4
With the associated abortion in subchorionic
hemor rhage,
clinicians
often
prescribe
Dydrogesterone to prevent such complication. In
the study of Pelinescu-Onciul, the marked
immunomodulatory effect of dydrogesterone in
maintaining a T helper-2 cytokine balance means a
good choice for preventing abortion in women with
subchorionic hemorrhage. 27 In contrast with this
study, our study showed no significant difference in
patients prescribed with dydrogesterone and bed rest
vs. bed rest alone (P = 1.00). There was also no
significant difference in resolution of size of
subchorionic hemorrhage in both groups (P = 0.49).
subchorionic hemorrhage using dydrogesterone plus
bed rest will not resolve the hemorrhage and will
not reduce the incidence of abortion. Bed rest alone
is not also statistically significant in decreasing
occurrence of hemorrhages in the first trimester of
pregnancy. However, large size subchorionic
hemorrhage may result to spontaneous abortion.
RECOMMENDATION
It is recommended to follow-up these patients to
determine other adverse pregnancy outcome
previously mentioned associated with subchorionic
hemorrhage.
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A Simple Osteoporosis Risk Assessment Tool for
Postmenopausal Filipino Women with Bone Densitometry
Testing from January to December 2010 in St. Luke's
Medical Center
EMICIEL ALTA F. CAJUCOM, MD
AND
GRACE B. CARAS, MD
Department of Obstetrics and Gynecology, St. Luke's Medical Center, Quezon City
Screening all postmenopausal women for low bone mineral
density by dual-energy x-ray absorptiometry (DXA) is
currently not recommended and not cost-effective. Risk
factors for osteoporosis are evaluated to develop a simple
tool for identifying those at increased risk and therefore
should undergo further bone mineral density testing by
DXA.
Materials and Methods: Records of postmenopausal Filipino
women, who had BMD measurements by DXA in the
Department of Nuclear Medicine in a tertiary hospital from
January 2010 to December 2010, were reviewed. Scores
computed based on each of the three clinical prediction
rules (ABONE, OST, NOF) were compared with their
corresponding T-scores obtained from DXA machine.
Validity of the osteoporosis risk indices was evaluated.
Logistic regression analysis and receiver operating
characteristic analysis were used to identify the simplest
tool that would classify subjects at increased risk for low
BMD.
Results: The study population composed of 514
postmenopausal Filipino women with a mean age of 60
years, with DXA data for the femoral neck. The following
were the results obtained regarding the validity of each of
the clinical prediction rule: ABONE 92.9% specific, 20.9%
sensitive, positive predictive value of 80.8%; OST 31.6%
specific, 88.7% sensitive, positive predictive value of 64.9%;
NOF 49.5% specific, 79.1% sensitive, positive predictive
value of 69.1%. A simple algorithm based on the age and
body mass index (BMI) was developed. Age, BMI
osteoporosis scoring tool 59.4% specific, 67.2% sensitive,
positive predictive value of 70.2%. Based on the newly
developed age, BMI osteoporosis scoring tool, patients
with score of 3 or more is likely three times at risk of low
bone mineral density.
Conclusion: Based on the data gathered and analyzed, a
higher percentage of osteopenia/osteoporosis was seen
in the elderly (aged 66-84yrs) and in those with low BMI.
These two variables performed fairly well in identifying
postmenopausal Filipino women at risk for osteoporosis,
hence the development of age, BMI osteoporosis scoring
tool. Other clinical prediction rules including (ABONE,
OST and NOF) evaluated in Caucasians and other Asian
women also performed well in postmenopausal Filipino
women.
Key words: Bone mineral density (BMD); Dual-energy X-ray
Absorptiometry (DXA); Age, Body size, No Estrogen
(ABONE); Osteoporosis Self-Assessment Tool (OST);
National Osteoporosis Foundation (NOF)
steoporosis is a rising problem and currently
a public health concern. This disease entity is
associated with increase in fragility which leads to
pain, deformity and especially disability. Hence, this
results to socioeconomic losses due to the substantial
costs in relation to its outcome, fracture.
Several reasons are available to warrant screening
for this condition. It is one of those diseases in which
screening is beneficial. Even though the concept of
management for postmenopausal osteoporosis is still
the same since many decades ago, emphasis is on
the prevention of fractures in osteoporotic
postmenopausal women. The primary goal of the
clinician is to diminish fracture rates in elderly
women.
O
Simple Osteoporosis Risk Assessment Tool for Postmenopausal Filipino Women / Cajucom and Caras
Since osteoporosis has a long preclinical course
before fracture occurs and with the availability of
bone densitometry to establish its diagnosis as well
as pharmaceuticals that have been shown to reduce
fracture risk, with its early diagnosis, preventive
measures can be implemented to avoid decrease in
the quality of life and socioeconomic losses in
women with fracture resulting from osteoporosis.
Several selection criteria are available for use by
clinicians as screening tools for referring women for
bone densitometry. Bone mineral density is measured
by means of Dual-Energy X-ray Absorptiometry
(DXA). At present, still there is no clear cut method
for recommending women who should undergo
DXA testing and eventually be recommended for
treatment because available guidelines are not
sufficiently precise to allow clinicians to decide who
warrants further DXA testing. Due to this, clinicians
are left with the option to test all women for DXA
at the time menopause. However, mass screening of
women for DXA is still not recommended and is
not cost-effective. This study aimed to develop and
validate a simple screening tool in the local setting
to assist physicians in selecting patients for bone
densitometry. These decision rules include: 1. Age,
Body size, No Estrogen (ABONE); 2. Osteoporosis
Self-Assessment Tool for Asians (OST); 3. National
Osteoporosis Foundation (NOF) practice guideline,
and 4. Age, body mass index (BMI) osteoporosis
scoring tool.
Age, Body size, No Estrogen (ABONE) score of
≥ 2 is high risk for osteoporosis. Factors being
evaluated in the ABONE scoring tool includes: Age
(score of 1 if >65yrs), Weight (score of 1 if <63.5kg),
Estrogen use (score of 1 if did not use for at least 6
months). Osteoporosis Self-Assessment Tool (OST)
score of <2 is high risk. OST score is computed by
subtracting age in years from weight in kg, then
multiplying the difference by 0.2. National
Osteoporosis Foundation (NOF) includes one point
for each: Age ≥ 65yrs, weight <57.6kg, Personal
history of fracture or minimal trauma >40yrs,
Family history of fracture and current cigarette
smoking. NOF score of ≥ 1 is high risk. The new
scoring index in this study, age and body mass index
are graded; 2 for age ≥ 60yrs and 3 for BMI
<25kg/m 2 . A score of ≥ 3 is high risk for
osteoporosis. (Appendix A)
Dual-energy X-ray Absorptiometry (DXA) is
accepted as the most accurate clinical method for
identifying those with low BMD. However,
measurement of bone mineral density (BMD) is not
widely available in some communities. Also, the
cost of BMD determination and lack of
reimbursement may limit its widespread use. This is
where a simple questionnaire would be useful if it
can identify the population at risk for osteoporosis.
Upon identification of the population at risk for
osteoporosis based on a simple risk assessment tool,
these individuals can be subjected to bone mineral
density measurement by DXA. Hence, clinicians can
do away with recommending all their patients to
undergo and pay for BMD testing by DXA, and
instead recommend it to those who are at risk.
Several risk assessment tools for osteoporosis are
available as mentioned earlier, but it is not known
how well they perform in Asian populations,
specifically in Filipinos. Suggestions concerning
who should be tested are quite broad. The National
Osteoporosis Foundation 1998 Practice Guidelines
(revised in 1999) recommend bone mineral density
testing in women considering treatment and who are
aged 65 years or older, and in younger
postmenopausal women considering treatment who
have one or more risk factors for osteoporotic fracture
other than menopause. The recommendation to select
perimenopausal women on the basis of "other risk
factors" is echoed in a number of other guidelines.1
According to the study by Karen F. Mauck, et
al. clinical prediction rules are designed to stratify
patients into risk subgroups by summarizing risk
factors with a point system. The quality of most of
these decision rules has been rated fair or poor, most
often because of methodological limitations. 2
The primary purpose of risk assessment tool for
osteoporosis is to identify most patients at risk, in
whom BMD can then be measured to obtain a
definite diagnosis.6 Although effective treatments
can reduce fracture risk by about half, it is probably
not possible to restore bone strength fully once the
patient has developed osteoporosis, because much
of the structural loss of bone microarchitecture has
become irreversible. Therefore, treatment should
ideally be started when BMD is in the lower range
of normal before it falls into the range of
osteoporosis. 7
Study Design and Sample Population
The database of patients with DXA bone mineral
density measurements at the Department of Nuclear
Medicine St. Luke’s Medical Center was reviewed.
This database included a risk factor survey on
osteoporosis filled up by the patients before
undergoing DXA testing. Weight and height
measurements were taken and recorded in this
database. Patients seen here either consulted
spontaneously or were referred by the clinicians for
bone mineral density measurement from January to
December 2010. The following were the outcomes
recorded in the database: personal data, race, age,
weight, height, age at menopause, medications for
osteoporosis, hormone replacement therapy, personal
and family history of fracture, smoking, alcohol
intake, presence of rheumatoid arthritis and medical
history (comorbids). Inclusion criteria would be ≥6
months since menopause, and hip anatomy suitable
for evaluation by DXA of the hip. Exclusion criteria
included women of any race other than Filipino,
with history or evidence of metabolic bone disease
other than postmenopausal bone loss (including
hyper- or hypoparathyroidism, Paget's disease,
osteomalacia, renal osteodystrophy, or osteogenesis
imperfect), presence of cancer with known bone
metastasis, evidence of significant renal impairment,
oophorectomy, previous bilateral hip fracture or
replacement, and prior use of bisphosphonates,
fluoride, or calcitonin. Sample size was adequate,
as computed from the formula shown in Appendix
F.
Appendix A shows the descriptions of the
different clinical prediction rules as well as their
scoring system assigned by their respective developers.
The number of points was used to identify women
at risk for osteoporosis or low bone mineral density:
ABONE points of 2 or more, OST points of less than
2, NOF points of 1 or more and age, BMI
osteoporosis scoring tool points of 3 or more. Age,
BMI osteoporosis scoring tool gives two points for
those aged ≥ 60 yrs and a score of three points for
BMI <25kg/m2.
BMD of the femur was measured by dualenergy x-ray absorptiometry using one machine,
the IDXA-GE Lunar. T-scores were calculated
using the peak reference ranges for young healthy
Asian women provided by the manufacturer to
standardize measurements. T scores were classified
into normal, osteopenia and osteoporosis
(Appendix B). During the statistical analysis, the
osteopenia and osteoporosis were put together
under the "high risk" group, while those with
normal T score values were classified under the
"low risk" group.
Statistical Analysis
Descriptive statistics, which included the mean
and percentages, were computed to describe the
demographic characteristics as well as the presence
of risk factors of the study population (Table 1).
Bone mineral density results of the subjects were also
tabulated into three outcomes: normal, osteopenia
and osteoporosis based on T score values by dual
energy X-ray absorptiometry (Appendix B).
The internal validity of each clinical prediction
rule was evaluated by computing for the sensitivity
and specificity. Sensitivity was defined as the
proportion of the study population with low bone
mineral density correctly identified by the risk index,
and specificity as the fraction of the population who
truly has normal BMD. To evaluate the external
validity of the scoring system, the positive and
negative predictive values for each tool were also
calculated. Positive predictive value (true-positive
findings) comprised of the fraction of the population
identified by the clinical prediction rule as at risk for
osteoporosis and confirmed by low BMD results by
DXA; while negative predictive value (true-negative
findings) included the proportion of study population
with low risk for osteoporosis and truly had normal
BMD results by DXA.
The next step in the statistical analysis was the
development of a simple risk assessment tool
applicable to the postmenopausal Filipino women
included in the study population. A simple
osteoporosis scoring index was made based on the
full regression model then variables were dropped
one at a time from the final model to determine
whether the scoring index can be simplified without
compromising its validity (Appendix C).
Sensitivity, specificity and area under the curve were
examined at each step. Analyses resulted to a final
scoring index based on age and BMI only. This
simple osteoporosis risk assessment tool was referred
to as "Age, BMI osteoporosis scoring index" in this
study.
RESULTS
The total number of study population was 514.
Table 3 shows the demographic characteristics of the
study population. Ages ranged from 42 to 84 years,
but the mean age of the population was 60.18 years.
BMI ranged from 13.1 to 61.6 kg/m2, while the mean
BMI was 25.49kg.m 2 . Overall prevalence of
osteoporosis among the study population was 8.5%.
Prevalence of osteoporosis/osteopenia was also
tabulated according to age group and BMI as shown
is Tables 2 and 3. Elderly age group 66-84yrs had
the highest prevalence of osteoporosis/osteopenia at
Table 1. Demographic characteristic, risk factors for osteoporosis,
bone mineral density status of the study population.
Demographic Characteristic
Mean
Age
BMI
60.18 yrs
25.49 kg/m 2
Risk factors
n (%)
Fracture after age 40 years
Mother or father with history of fracture
Rheumatoid arthritis
Steroid use
Smoking
Alcoholic beverage drinker
Bone mineral density status
42 (8.2 %)
28 (5.4%)
1 (0.2%)
2 (0.4%)
16 (3.1%)
8 (1.6%)
n (%)
Normal
Osteopenia
Osteoporosis
212 (41.25%)
257 (50%)
45 (8.75%)
Total Population: (n = 514)
71.6%, while those in the lowest BMI group (≤13.1
kg/m2) had the highest proportion of osteoporosis/
osteopenia at 75%.
Three risk indices were evaluated in this study.
Sensitivity, specificity and predictive values of each
osteoporosis scoring tool are shown in Table 4.
ABONE had the lowest sensitivity (20.9%), but with
the highest specificity (92.9%). Its positive predictive
value was 80.8%. OST and NOF practice guidelines
had comparable results, having sensitivity of 88.7%
and 79.1 %, specificity of 31.6% and 49.5%
respectively. Positive predictive values of the OST
and NOF practice guideline were 64.9% and 69.1%
respectively.
Table 5 shows the performance of the simple Age,
BMI osteoporosis scoring index on postmenopausal
Filipino women with BMD results at SLMC by
DXA. This risk assessment tool yielded fair values
of sensitivity at 67.2%, specificity at 56%, positive
predictive value at 70.2%. On further analysis of
this index based on age and BMI only, risk estimate
value was 3.004 (Table 6).
Comparing the four clinical prediction rules for
osteoporosis included in this study, accuracy of each
risk assessment tool was computed as shown in Table
7. NOF had the highest accuracy at 67% and
ABONE had the lowest accuracy at 51% in Filipino
postmenopausal women with bone densitometry
Table 2. Prevalence of osteopenia/osteoporosis according to age group.
BMD Status
42-55yrs
n=157
56-59yrs
n=108
60-65yrs
n=140
66-84yrs
n=109
Normal
83 (52.9%)
49 (45.4%)
49 (35%)
31 (28.4%)
Osteopenia/Osteoporosis "high risk"
74 (47.1%)
59 (54.6%)
91 (65%)
78 (71.6%)
BMD = bone mineral density
Table 3. Prevalence of osteopenia/osteoporosis according to BMI (kg/m 2)
BMD Status
≤13.1 kg/m2
n = 128
Normal
32 (25%)
42 (33.9%)
55 (43.3%)
75 (60%)
Osteopenia/Osteoporosis
96 (75%)
82 (66.1%)
72 (56.7%)
50 (40%)
13.2 to 21.9kg/m2
n = 124
BMD = bone mineral density
22 to 24.2kg/m2
n = 127
24.3 to 27.5 kg/m2
n = 125
Table 4. Performance of the different clinical prediction rules for osteoporosis in postmenopausal Filipino women with BMD
measurement at SLMC, 2010.
Index
Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
ABONE
20.9
92.9
80.8
45.2
OST
88.7
31.6
64.9
66.3
NOF
79.1
49.5
69.1
62.5
ABONE = age, body size, no estrogen; OST = osteoporosis self-assessment tool; NOF = National Osteoporosis Foundation;
PPV = positive predictive value; NPV = negative predictive value
Table 5. Distribution of results for age, BMI osteoporosis scoring index.
Screening result
T score ≤ -1.0 (osteopenia/osteoporosis)
T score >-1.0 (normal)
Total
High risk
203 (67.2%)
86 (40.6%)
289
Low risk
99 (32.8%)
126 (59.4%)
225
212
514
Total
302
Performance of the Age, BMI scoring tool for osteoporosis in postmenopausal Filipino women with BMD measurement at
SLMC, 2010.
Sensitivity (%)
67.2
Specificity (%)
PPV (%)
59.4
NPV (%)
70.2
56
PPV = positive predictive value; NPV = negative predictive value
measurements in SLMC in the year 2010. The new
osteoporosis scoring index fared well in terms of the
accuracy. It had a relatively high percentage of
accuracy at 64%.
Table 6. Risk estimate* for Age, BMI osteoporosis scoring index
DISCUSSION
*95% Confidence Interval
Since 1994, osteoporosis was based on bone
mineral density measurement by dual-energy X-ray
absorptiometry of the spine, hip or forearm, expressed
in SD units known as T scores. 3 The goal for
determining individuals at high risk for osteoporosis
is the early initiation of treatment enough to prevent
fractures from occurring. However, the use of dualenergy X-ray absortpiometry is limited by the cost
and lack of the equipment in many communities
worldwide, including in the Philippines, where only
four machines are available to cater our population.
At risk/ Low risk
Value
Lower
Upper
3.004
2.087
4.326
Table 7. Accuracy of each clinical prediction rule.
Clinical Prediction Rule
Accuracy (%)
ABONE
51
OST
65
NOF
67
Age, BMI osteoporosis scoring index
64
Hence, this study was conducted to offer to clinicians
a simple, and probably a cost-effective screening tool
for Filipino postmenopausal women.
From the results tabulated above, it was noted
that age and risk of osteoporosis had a direct
relationship, while BMI and risk of osteoporosis
had an inverse relationship. As shown in the
prevalence of osteoporosis based on age, 71.6% of
those aged 66 to 84 years had low bone mineral
density (osteopenic or osteoporotic). In those with
low BMI (<13kg/m 2), 75% had a low bone mineral
density status. Most studies evaluated body weight
as a risk factor. In this study, body mass index was
assessed.
Body mass index is one of the few methods used
to estimate a person's body fat percentage. It is a
simple weight-for-height measurement that is
commonly used to classify underweight, overweight
and obesity in adults. BMI may not correspond to
the same degree of fatness in different populations
due, in part, to different body proportions. The health
risks associated with increasing BMI are continuous
and the interpretation of BMI grading in relation to
risk may differ for different populations. Although
it is an indirect measurement, it has been found to
be a fairly reliable indicator of body fat proportion
in most populations. If the weight alone is used, it
should be taken into consideration that ideal weight
varies considerably for men and women and by age
also, but with estimation of the fat percentage thru
BMI, a minimum percentage difference is considered
safe for good health.
Different diagnostic tests for the same disease
often trade sensitivity for specificity or vice versa. In
general, the more sensitive a test is for a disease, the
higher its false-positive rate, lowering its specificity.
A test with a higher specificity will usually sacrifice
sensitivity by increasing its false-negative rate. This
makes a highly sensitive test ideal for a screening
examination. While highly specific tests are best in
a confirmatory role.10 These statements were evident
in the results of a study by Saeko Fujiwara in
Japanese population.6 This was also the same with
the results of this study shown in table 4 which
compared the sensitivities and specificities of the
different existing prediction rules. In contrast to the
findings of a study by Lorraine Silver Wallace on
postmenopausal African-American women, ABONE
had a high sensitivity and fairly good specificity. In
this study, ABONE also perfor med well in a
population of postmenopausal Filipino women. It
had a specificity of 92.9%, but had a low sensitivity
(20.9%). Hence, ABONE in this study population is
a highly specific screening test meaning a positive
test result is good in ruling in the disease. OST and
NOF performed well also in postmenopausal Filipino
women, having high sensitivity values shown in Table
4, but with relatively low specificity values. With
high sensitivity values, a negative screening test result
based on OST and NOF rules out an increased risk
for osteoporosis.
After statistical analysis, these two risk factors
for osteoporosis were the ones determined to also
perform well in identifying postmenopausal
Filipino women compared with the other risk factors
assessed by the existing clinical prediction rules. A
scoring tool having only two variables may seem
unusual, since most risk assessment tools include
several variables. However, increased age and
decreased BMI were found out to be associated with
a low bone mineral density status, hence an
increased risk for fracture. In fact, in a study of
osteoporotic fractures by Margolis it was reported
that body weight is a useful predictor of hip and
other non-spine fractures when BMD has not been
measured. 11 Other researches supporting the results
of this study include the one done in a population
of almost 7000 women in France. The said study
concluded that scoring tool assessing only body
weight performed as good as a scoring tool with 6
risk factors for classifying women with very low
femoral neck BMD. 12 However, the study was
limited to body weight only since they found out
that age had no contribution to the risk for low
bone mineral density. Another scoring tool known
as the osteoporosis risk assessment index (ORAI)
which was developed in Canadian postmenopausal
women also evaluated age, body weight and use of
estrogen. The researcher noted that ORAI had a
sensitivity of 90-93%. 13
Age, BMI osteoporosis scoring tool performed
fairly well compared with the other risk assessment
tools, in terms of both the sensitivity (67.2) and
specificity (59.4%). On further analysis of the data,
risk estimate value was determined in the population
using this scoring tool. It means that if the subject
was found to be at risk for osteoporosis based on
the Age, BMI osteoporosis scoring tool, then the
subject has an estimate of three times higher risk for
low bone mineral density. This tool, hence, can be
of use to clinicians to determine those at risk for
low bone mineral density and then subject these
individuals for bone densitometry to confirm
osteopenia or osteoporosis. This will probably result
to lower costs for the patients and therefore they may
allocate their budget to other health-related expenses,
without compromising their bone mineral density
status.
CONCLUSION
In conclusion, the Age, BMI osteoporosis
scoring tool based on the said two variables
performed fairly well in identifying patients among
postmenopausal Filipino women who are at risk
for low BMD and would warrant a bone
densitometry. Hence, giving this gives clinician an
option to do away with subjecting all
postmenopausal Filipino women to bone
densitometry. Other clinical prediction rules tested
in Caucasian and Asian populations also had good
performance in screening postmenopausal Filipino
women. Osteoporosis self-assessment tool and
National Osteoporosis Foundation guidelines can
be used to identify those Filipino postmenopausal
women at risk for osteoporosis. However, Age,
body weight, no estrogen (ABONE) screening tool
with positive results in postmenopausal Filipino
women is more significant than those with negative
results, hence ruling in the disease.
Like in most other researches, the result of this
study has its own limitations. There can be
inaccurate reporting of the variables evaluated in
the different clinical prediction rules reducing the
ability of predicting BMD status of the individual.
But as mentioned earlier in the discussion, this
scoring index based on age and BMI had a
comparable performance with the other scoring
tools since age and BMI are information available
in all women and can be measured accurately/
objectively, and not only based on reporting of the
subjects. Hence, as part of the recommendation of
this study, we are encouraging researchers to do a
more analytical study (cohort) in postmenopausal
Filipino women for a more conclusive outcome and
stronger relationships between the risk factors and
osteoporosis.
Appendix A. Description and scoring system of the clinical prediction rules used to identify postmenopausal Filipino women
at risk for low bone density/osteoporosis.
Clinical Prediction Rules6
Criteria
Age, Body size, No Estrogen (ABONE)
Age: 1 if >65yrs
Score ≥2
Weight: 1 if <63.5kg
Estrogen use: 1 if never used oral contraceptive or estrogen therapy for
at least 6 months
Osteoporosis Self-Assessment Tool (OST)
Body weight in kg and Age in years
Score <2
0.2 (body weight - age)
National Osteoporosis
Foundation (NOF)
One point each for:
Age ≥65 yrs
Score ≥1
Weight <57.6 kg
Personal history of fracture: minimal trauma fracture >40 y
Family history of fracture
Current cigarette smoking
Age, BMI Osteoporosis Scoring Tool
2 if ≥ 60 yrs
Score ≥3 Age:
BMI: 3 if <25kg/m2
Appendix B. T score classification based on WHO criteria.
Bone Mineral Density
Appendix F. Sample size determination.
T Score
Normal
-1 SD or higher
Osteopenia
>-1.0 to -2.5
Osteoporosis
-2.5 or lower
Appendix C. Univariate analysis of the risk factors for osteoporosis.
Risk factor
Pearson Chi square
(p value*)
Personal history of fracture
Family history of fracture
Cigarette smoking
Alcohol beverage drinker
Use of steroids
Rhematoid arthritis
Use of HRT
Age >60yrs
BMI <25kg/m2
0.277
0.541
0.757
0.607
0.801
0.402
0.063
0.000
0.000
Significance
insignificant
insignificant
insignificant
insignificant
insignificant
insignificant
insignificant
significant
significant
Multivariate analysis of risk factors for osteoporosis
Age >60yrs
BMI <25kg/m2
0.000
0.000
significant
significant
*p value ≤ 0.05 = significant, otherwise it is insignificant
Appendix D. Logistic regression analysis variables in the equation.
B
Step 7a
a.
Age grp2 (1)
BMI 3 (1)
Constant
.839
1.160
-.656
S.E.
.193
.192
.170
Sig.
Exp (B)
.000
.000
.000
2.315
3.190
.519
95.0% C.I. for EXP (B)
Lower
Upper
1.587
2.190
3.375
4.645
Variables entered on step 1: Personal history of fracture at age ≥40yrs, Family history of fracture, Smoking, Alcoholic
beverage drinking, Age group, BMI, Use of steroids
Appendix E. Area under the curve (AUC)
Test result variables for Age, BMI osteoporosis scoring tool
Asymptotic 95% Confidence interval
Area
Std. Errora
.682
.024
Asymptotic Sig.b
.000
Lower bound
.635
Upper Bound
.728
The test result variable(s) has at least one tie between the positive actual state group and the negative actual state group. Statistics
may be biased.
a. Under the non-parametric assumption
b. Null hypothesis: true area = 0.5
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Acute Pancreatitis in Pregnancy
RAQUEL P. ADOLFO, MD
AND
ANALYN F. FALLARME, MD, FPOGS
Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines Manila
Acute pancreatitis during pregnancy is rarely encountered.
It may range from mild pancreatitis to serious pancreatitis
complicated by necrosis, abscesses, pseudocysts and
multiple organ dysfunction syndromes. As in any other
disease occurring concomitantly with pregnancy, acute
pancreatitis is associated with greater concerns as it deals
with two lives rather than just one as in non-pregnant
population. We report here a case of a 38-year old
multigravida at 27 weeks of gestation presenting with
recurrent epigastric pain and vomiting. Physical
examinations showed abdominal tenderness and decreased
bowel sounds. Laboratory results showed hyperamylasemia
and hyperlipasemia. The patient was managed medically
and discharged improved after stabilization in the maternal
intensive care unit. When properly managed, worse
outcomes of acute pancreatitis in pregnancy can be
avoided.
Key words: acute pancreatitis, pregnancy, pancreatitis in
pregnancy
cute pancreatitis is the sudden inflammation of
the pancreas and peripancreatic tissues triggered
by activation of pancreatic trypsinogen followed by
autodigestion. 1 It is manifested clinically by
abdominal pain, nausea and vomiting that is usually
self limiting but occasionally can progress to severe
disease and even death. Its variable presentations,
ranging from benign to classic to catastrophic, make
diagnosis possible only with a high index of
suspicion. For tunately, acute pancreatitis in
pregnancy is uncommon. For a favorable outcome,
correct and early treatment is essential. A review of
literature by Langmade and Edmondson in 1951 2
mentions symptomatology of this disease entity as
first described in 1818 by Schmitt in a 30 year old
A
multigravida and later on in 1838 by Lawrence. In
our institution, this is the first case of acute
pancreatitis in pregnancy during the last five years.
THE CASE
This is the case of E.T., a 38-year old G4P3
(2102) married from Las Pinas City who was
admitted in our institution for the second time last
January 14, 2012 for abdominal pain.
Patient was diagnosed with Hepatitis B infection
during this pregnancy. She also has bronchial asthma
since childhood, but the last attack was at 18 years
old. In 2004, she intentionally self inflicted an
abdominal stab wound due to a marital quarrel, and
underwent an exploratory laparotomy with ligation
of bleeders at our institution. She has no
hypertension, diabetes, cancer, heart disease, lung
disease, thyroid disease or any food and drug
allergies.
Patient has history of hypertension in both
paternal and maternal sides. Her father was also
previously diagnosed with pulmonary tuberculosis
and was treated with anti-Koch's medications for six
months. She has no family history of diabetes
mellitus, cancer, heart disease or thyroid disease.
Patient is a high school g raduate, cur rently
unemployed, with no vices. Her first coitus was at
25 years old with one non-promiscuous sexual
partner. She used combined oral contraceptive pills
for seven years. She does not have any sexually
transmitted infections.
Her menarche was at 13 years old with
subsequent menses occuring in regular monthly
intervals, 3 to 5 days duration, consuming 2 pads
per day at its heaviest. She has no episodes of
dysmenorrhea. Her last normal menstrual period was
in July 3 to 8, 2011 and her past menstrual period
Acute Pancreatitis in Pregnancy / Adolfo and Fallarme
was in June 1 to 6, 2011, giving her an amenorrhea
of 27 weeks and 6 days.
She had four pregnancies. The first pregnancy
was carried to term and delivered vaginally with no
complications. The second pregnancy was a preterm
delivery around 32 weeks age of gestation and also
delivered vaginally, but had a neonatal sepsis which
led to an early neonatal death. The third pregnancy
was also carried to term and delivered vaginally at a
lying in clinic assisted by a midwife with no
complications. This is her fourth pregnancy. She was
seen twice by an obstetrician for prenatal consult.
Three weeks before her admission (at around
24 weeks age of gestation), she noted sudden onset
of crampy epigastric pain radiating to her back with
VAS 10/10, associated with nausea. There was no
jaundice, abdominal distention, edema, fever or
hypotension. She experienced good fetal movement
with no vaginal bleeding, uterine contractions or
watery vaginal discharge. She sought consult at a
private institution where she was admitted and
managed medically as a case of acute pancreatitis
based on 20 times elevated value of serum amylase
and 25 times elevated value of serum lipase. She
was placed on bowel rest, was carefully hydrated,
and was given adequate pain control. She was
subsequently discharged improved after four days.
Four hours prior to her admission, she had
recurrence of the sudden onset of epigastric pain,
steady and boring in character, radiating to her
periumbilical region and back with VAS 10/10,
associated with nausea and vomiting. Her abdominal
pain is more intense when in supine, and is partially
relieved when sitting. She still experienced good fetal
movement without vaginal bleeding, watery vaginal
discharge or uterine contractions. Due to persistent
abdominal pain, she subsequently sought consult at
the OB Admitting Section of our institution.
On review of systems, there was no fever,
dyspnea, chest pain, dysuria, hematuria, jaundice,
edema and bowel movement changes.
At the OB Admitting Section, she was received
with a blood pressure of 110/60mmHg, heart rate
of 88 beats per minute, respiratory rate of 22 cycles
per minute and was afebrile at 37.5ºC. She was
conscious, coher ent, ambulator y, and not in
cardiorespiratory distress.
She had pink palpebral conjunctivae, anicteric
sclerae, without cervical lymphadenopathies.
She had equal chest expansion, clear breath
sounds with no crackles or wheezes noted. Her
precordium was adynamic with distinct heart sounds,
normal rate and regular rhythm. There were no
murmurs appreciated. She had full and equal pulses,
with pink nail beds and had no edema, cyanosis or
clubbing.
The abdomen was globular, soft, and with
decreased bowel sounds. There is a 20cm midline,
infraumbilical, vertical surgical scar. There is direct
tenderness on light and deep palpation on the left
upper abdominal quadrant and epigastric area
radiating to the back. She has a fundic height of
25cm, estimated fetal weight of 1.2-1.4kg with the
fetus in cephalic presentation and with good heart
tones at the left lower abdominal quadrant.
On internal examination, patient had normal
external genitalia, smooth parous vagina, cervix was
closed, uneffaced, with intact bag of waters, corpus
was enlarged to age of gestation without adnexal
masses and tenderness.
The admitting impression was pregnancy uterine
27 weeks and 6 days age of gestation by amenorrhea,
cephalic not in labor; acute pancreatitis in pregnancy;
hepatitis B infection; bronchial asthma, in remission;
poor obstetric history for one preterm early neonatal
death; status post exploratory laparotomy for an
abdominal stab wound (2004); gravida 4 parity 3
(2102).
She was immediately transferred to the maternal
intensive care unit and baseline laboratory tests
showed a hemoglobin of 119 g/l, a white blood
count of 16400/cumm, a hematocrit of 34 and a
platelet count of 278000. Urine analysis, random
blood sugar, serum electrolytes, liver function tests
and renal function tests were within normal limits.
Serum amylase was 2259 U/l (ref. 16-73 U/l) (30
times elevated), and lipase was 5057 U/l (ref. 10-160
U/l) (31 times elevated).
Biometry, biophysical studies and congenital
anomaly scan were also done. This revealed a single
live intrauterine pregnancy in cephalic presentation
with good cardiac and somatic activities. The fetus
was 29 weeks and 5 days by biparietal diameter and
27 weeks by femoral length. The placenta was
posterior, high-lying, grade II. Biophysical profile
score was 10/10 with adequate amniotic fluid
volume. Sonographic estimated fetal weight at 1146
grams by Hadlock and at 1338 grams by Warsof was
appropriate for gestational age. The congenital
anomaly scan was negative.
She was placed on nil orally and was carefully
hydrated. Work up was done to look for the causes
and complications of pancreatitis. These included a
holoabdominal ultrasonography, serial monitoring
of serum amylase and lipase, and blood tests for
possible dyslipidemia. She was also started on
meperidine 50mg intravenously every 12 hours as
needed for pain control. Fetal surveillance in the form
of fetal well being studies (biometry every 10 to 14
days, biophysical profile weekly, and daily non-stress
test) was continued. She was also started on once
daily dosing of multivitamins and ferrous sulfate.
Intravenous ranitidine was given twice a day for
gastric protection. Urine output, hemodynamics, and
fetal heart tones were monitored hourly. Capillary
blood glucose level was monitored every 4 hours.
She was r efer red to General Medicine,
Gastroenterology, and Perinatology for evaluation
and co-management.
On the second hospital day, patient noted
decrease in abdominal pain from VAS 10/10 to VAS
4/10. There was no recurrence of vomiting. Repeat
laboratory tests showed a hemoglobin of 97 g/l, a
white blood count of 10900/cumm, a hematocrit of
30 and a platelet count of 257000. Serum amylase
was 1029 U/l (ref. 16-73 U/l) (14 times elevated),
lipase was 1284 U/l (ref. 10-160 U/l) (8 times
elevated) and calcium was 1.93 mmol/l (ref. 2.132.75 mmol/l).
Holoabdominal ultrasonography showed normal
ultrasound of the liver, spleen and pancreas. The
intrahepatic ducts and common bile duct (4.3 mm)
are not dilated. The portal vein (1.0 cm), inferior
vena cava and intrahepatic veins are unremarkable.
The gall bladder was suboptimally distended
precluding its adequate assessment.
Initial
management
was
continued.
Hypocalcemia was corrected by giving calcium
gluconate intravenously and adding oral calcium
supplements to her daily medications. Her anemia
(hemoglobin of 97 g/l) was also addressed by
increasing her ferrous sulfate to twice daily dosing.
On the third hospital day, she has no more
abdominal pain. However, she had 3 episodes of
hypoglycemia with capillary blood glucose level
ranging from 63 to 71 mg/dl which was corrected
by giving 50 ml of D50 solution. Her diet was
progressed to general liquids. Other management was
continued. Repeat serum amylase was 198 U/l (ref.
16-73 U/l) (2.7 times elevated), and lipase was 640
U/l (ref. 10-160 U/l) (4 times elevated). Fetal wellbeing studies showed adequate fetal growth and good
fetal activity.
On the fourth hospital day, there was no more
recurrence of the abdominal pain. She was started
on soft diet. Repeat laboratory tests showed normal
levels of serum amylase (50 U/L) and lipase
(156 U/L).
On the fifth hospital day, she was cleared for
discharge by all the co-managing services and was
sent home on low fat diet and prenatal medications.
The discharge diagnosis was pregnancy uterine 28
weeks and 4 days age of gestation by amenorrhea,
cephalic not in labor; acute pancreatitis in pregnancy,
resolving; hepatitis B infection; bronchial asthma,
in remission; poor obstetric history for one preterm
early neonatal death; status post exploratory
laparotomy for an abdominal stab wound (2004);
gravida 4 parity 3 (2102).
DISCUSSION
The incidence of acute pancreatitis in pregnancy
varies and is approximately 1 in 1000 to 1 in 10000
births. 3 The wide variation in the incidence is
influenced by the prevalence of its most important
etiologic factors, that is, gallstone disease and
hypertriglyceridemia. Acute pancreatitis can occur
both in nulliparous and multiparous women. It can
also occur during any trimester and even in the
postpartum period. 2,4,5 Acute pancreatitis following
medical abortion is also reported.6
Acute pancreatitis develops due to mechanical
obstruction at the ampulla of Vater due to passage
of stones or sludge.7 It is also proposed to be due to
reflux of gastrointestinal contents into the ampulla
of Vater, or may be due to the immunologic
interactions between mother and child.5 Genetically,
a mutation in the lipoprotein lipase gene causing
hypertriglyceridemia-induced pancreatitis in
pregnancy has also been reported.8 Acute necrotizing
pancreatitis is also reported in preeclampsia due to
pancreatic microvascular alterations. 9 It also occurs
in 5-20% of patients following endoscopic retrograde
cholangiopancreatography. Non-biliary pancreatitis
may also occasionally develop resulting from
abdominal trauma, viral infections, ethanol
ingestion, hypercalcemia, or drugs such as
tetracycline, sulfonamides, estrogen, valproic acid
and thiazides.
Clinical presentations include mild to
incapacitating pain in the epigastrium or left
hypochondrium with or without radiation to the
back. The pain is steady and boring in character,
frequently more intense when in supine, but relieved
when in sitting position with trunk flexed and knees
drawn up. Associated symptoms include anorexia,
nausea, vomiting, abdominal distension and
jaundice. Signs include low grade fever, tachycardia,
hypotension, and abdominal tenderness with
decreased or absent bowel sounds. In 10% of cases,
pulmonary findings such as basilar rales, atelectasis,
pleural effusion, and pneumonia may be associated
which may lead to full blown adult respiratory
distress syndrome. Generalized anasarca may also
be associated with preeclampsia-associated
pancreatitis.9
Our patient presented with recurrent epigastric
pain radiating to her back and periumbilicus. The
pain is crampy, steady and boring in character,
described as being more intense when in supine, and
is partially relieved when sitting. It was associated
with
nausea and vomiting. On physical
examination, tenderness was elicited on light and
deep palpation on the left upper quadrant and
epigastrium. Decreased bowel sounds were also
noted indicating gastric and intestinal hypomotility.
Given this clinical picture, acute pancreatitis was
suspected and confirmatory laboratory tests were
done.
Diagnostic work up includes complete blood
count, serum triglycerides, serum electrolytes, and
liver function tests in the form of serum bilirubin,
transaminases and alkaline phosphatase. Laboratory
confirmation is from serum amylase levels three
times over the upper normal values. An elevated
serum amylase level has a diagnostic sensitivity of
81% and adding serum lipase increases the
sensitivity to 94%. The mean amylase value in such
patients was found to be 1400 U/l, and the mean
lipase value was found to be 7000 U/l. However,
amylase levels do not correlate with disease
severity.10,11 In severe cases, marked leukocytosis and
bacteremia may be present.
Laboratory tests done on our patient included
complete blood count, urine analysis, liver functions
tests in the form of serum albumin and
transaminases, lipid profile which includes serum
cholesterol, triglycerides, high density lipoprotein
and low density lipoprotein, and serum electrolytes
such as sodium, potassium, chloride, calcium and
magnesium. Serial monitoring of serum amylase
and lipase was also done. In her previous
hospitalization for acute pancreatitis, her serum
amylase was 20 times elevated and her serum lipase
was 25 times elevated. However, her condition was
worse when she presented in our institution with
her serum amylase being 30 times elevated and
serum lipase being 31 times elevated. Monitoring
of her serum electrolytes also showed hypocalcemia
which is one of the metabolic complications of acute
pancreatitis.
Imaging of the pancreas can be performed by
using ultrasonography and computed tomography.
Due to hazards of radiation to the fetus, sonography
is preferred which can detect gallstones with 90%
sensitivity. However, the sensitivity for biliary sludge
that appears as low level echoes within the
gallbladder which shifts with positioning is lower.7
In our patient who had a recurrent bout of acute
pancreatitis without an obvious etiology, possible
cause could be occult disease of the gallbladder,
biliary tree or pancreatic duct such as microlithiasis
or biliary sludge. This is likely, especially that her
holoabdominal ultrasound failed to visualize the
pancreatic ducts and the gall bladder was
suboptimally distended precluding its adequate
assessment.
Severity of pancreatitis in pregnancy can be
graded using scales such as Ranson's criteria, Imrie's
criteria or APACHE II score similar to non-pregnant
patients. 7 The differential diagnoses of acute
pancreatitis include biliary colic, acute cholecystitis,
and acute fatty liver of pregnancy.7 Uncomplicated
biliary colic, due to transient obstruction of the cystic
duct by gallbladder sludge or stones is characterized
by right upper abdominal quadrant pain. Its episodes
usually last less than 3 hours and serum laboratory
tests are usually normal. Thus, biliary colic can be
excluded in our patient. Acute cholecystitis,
characterized by right upper abdominal quadrant
pain lasting for more than 3 hours, is associated with
mild elevations in serum transaminases, alkaline
phosphatase, and bilirubin levels. These laboratory
findings are absent in our patient, as well as the
Murphy's sign which is almost always present in cases
of acute cholecystitis. Acute fatty liver of pregnancy,
characterized by microvesicular fatty infiltration of
the liver, presents with nausea, vomiting, right upper
abdominal quadrant pain, and malaise, followed in
3 to 4 days by jaundice and changes in mental status
including confusion, lethargy, or coma. Serum
transaminase levels are elevated and management is
through prompt delivery of the fetus. In our patient,
the normal levels of serum transaminases and the
subsequent improvement in her condition within 72
hours of hospitalization led to the exclusion of this
diagnosis.
The treatment of acute pancreatitis in pregnancy
should be conservative as much as possible with
delaying the surgical intervention until after delivery,
especially if the patient develops uncomplicated
pancreatitis in the third trimester of pregnancy.
Management includes bowel rest, nasogastric
aspiration, careful volume repletion with intravenous
fluids, adequate pain control in the form of narcotic
analgesics, antibiotics and total parenteral nutrition.
Serum electrolytes, calcium, and glucose levels
should also be monitored and supplemented as
necessary. Acid suppression may be necessary,
especially in severely ill patients with risk factors for
stress ulcer bleeding. Endoscopic retrograde
cholangiopancreatography for removal of common
duct stones and papillotomy has also been used
successfully.12,13 Pregnant patients with pancreatitis,
especially those with hemodynamic instability,
should also be managed in a maternal intensive care
unit setting. Complications such as pseudocysts
should be surgically managed in the post partum
period.5,7
Our patient was admitted in the maternal
intensive care unit, placed on bowel rest, carefully
hydrated, and given meperidine for pain control.
Ranitidine was also given for gastric protection since
she is at risk for stress gastritis. Correction of
hypocalcemia was also done. She was allowed clear
liquid diet on the third hospital day, general liquid
diet on the fourth hospital day, and a low fat diet
on the fifth hospital day. The decision to reintroduce
oral intake was based on the following criteria: 1) a
decrease in and subsequent resolution of abdominal
pain; 2) patient is hungry; 3) a consistently decreasing
trend in levels of serum amylase and lipase; and
4) patient had episodes of hypoglycemia which could
also be detrimental to the fetus in her womb.
Nasogastric aspiration is not done because it is
reserved for those with ileus or protracted emesis.
Broad spectrum antibiotics appropriate for bowel
flora are reserved for severe cases with complications
such as infected necrosis and abscess. Prophylactic
antimicrobial therapy was not given since it has no
proven clear role in acute pancreatitis. Total
parenteral nutrition may be necessary when the
pancreatic inflammation is slow to resolve. In this
case, acute pancreatitis started to resolve immediately
as evidenced by the decreasing values of serum
amylase and lipase within 48 hours of
hospitalization.
Reviews of acute pancreatitis in pregnancy
reported maternal and fetal mortality rates as high
as 20% - 50%. 14,15 However, the rate of preterm
delivery is about 30%, with 11% delivered before 35
weeks.16 In our patient, measures taken to prevent
preterm delivery included complete bed rest, careful
hydration, adequate pain control, controlling
psychological factors through emotional support, and
providing more frequent antenatal surveillance tests
to monitor fetal well-being. Single course of
corticosteroids in the form of dexamethasone was
also given to enhance fetal lung maturity. In patients
with non-gallstone pancreatitis, the rate of preterm
delivery appears to be somewhat higher. Therefore,
it is very important that pregnant patients present as
soon as possible to the emergency room for
evaluation should they develop any abnormal
abdominal pain symptoms.
CONCLUSION
While a rare event, acute pancreatitis does occur
in pregnanc y. However, sometimes, after a
conventional work up, a specific cause may not be
identified. In patients with recurrent acute pancreatitis
without an obvious cause, consider occult gallstone,
biliary tree, or pancreatic duct diseases. Though
associated with significant fetal and maternal
mortality, if treated early, unwanted poor maternal
and fetal outcomes as well as severe disease and
complications can be avoided.
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Langmade CF, Edmondson HA. Acute pancreatitis during pregnancy
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McKay AJ, O'Neill J, Imrie CW. Pancreatitis, pregnancy and gallstones.
Br J Obstet Gynaecol 1980; 87(1): 47-50.
Ko CW. Risk factors for gallstone-related hospitalization during
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Pai PR, Shah HK, Samsi AB. Postpartum pancreatitis. J Postgrad
Med 1993; 39(2): 93-4.
Hallberg P, Hallberg E, Amini H. Acute pancreatitis following medical
abortion: case report. BMC Women's Health 2004; 4(1): 1-4.
Ko C. Biliary sludge and acute pancreatitis during pregnancy. Nature
Clin Pract Gastroenterol Hepatol 2006; 3: 53-7.
Keilson LM, Vary CPH, Sprecher DL, Roger R. Hyperlipidemia and
pancreatitis during pregnancy in two sisters with a mutation in the
lipoprotein lipase gene. Ann Intern Med 1996; 124(4): 425-8.
Parmar MS. Pancreatic necrosis associated with preeclampsiaeclampsia. JOP J Pancreas (Online) 2004; 5(2): 101-4.
Ramin K, Ramin S, Richey S, Cunningham FG. Acute pancreatitis in
pregnancy. Am J Obstet Gynecol 1995; 173: 187-91.
Legro R, Laifer S. First trimester pancreatitis: maternal and neonatal
outcome. J Reprod Med 1995; 40: 689-95.
Simmons DC, Tarnasky PR, Rivera-Alsina ME. Endoscopic retrograde
cholangiopancreatography in pregnancy without the use of radiation.
Am J Obstet Gynecol 2004; 190: 1467-70.
Tang S, Mayo MJ, Rodriguez-Frias E. Safety and utility of endoscopic
retrograde cholangiopancreatography during pregnancy. Gastrointest
Endosc 2009; 69: 453-5.
14. Ramin KD, Ramsey PS. Disease of the gallbladder and pancreas in
pregnancy. Obstet Gynecol Clin North Am 2001 Sep; 28(3): 571-80.
15. Wilkinson EJ. Acute pancreatitis in pregnancy: a review of 98 cases
and a report of 8 new cases. Obstet Gynecol Surv 1973 May; 28(5):
281-303.
16. Eddy JJ, Gideonsen MD, Song JY. Pancreatitis in pregnancy. Obstet
Gynecol 2008; 112: 1075-7.
Arteriovenous Malformation of the Uterus: Case Reports
and Review of Literature
MARIA AURORA FATIMA C. ICASAS, MD
Department of Obstetrics and Gynecology, Cardinal Santos Medical Center
Uterine arteriovenous malformation, rare as it may seem,
must be considered whenever there is unexpected,
excessive, intermittent vaginal bleeding, particularly after
delivery or surgical procedures done on the uterus.
Two cases of AVM were presented in addition to the 2
cases published in the local literature. A diagnostic and
treatment flow chart was created based on how the 4 cases
were managed.
A high index of suspicion and timely diagnosis of the
condition are essential to provide appropriate patient care.
1. In women with completed family, a hysterectomy can
be done.
2. Conservative management options are recommended
in women where preservation of fertility is desired. In
a government hospital where there is limited access to
medical facilities, bilateral hypogastric artery ligation
followed by excision of the uterine mass can be
performed.
3. With the advent of minimally invasive treatment
options, selective catheterization and percutaneous
embolization procedure can be done. This expensive
procedure is done in tertiary medical centers where
the facilities and training to perform this interventional
technique are available
With the awareness of the existence of this disease
and its variable clinical presentations and correlating them
with diagnostic modalities, treatment can be optimized for
each individual patient.
malformation was reported in 1926 by Dubreuil and
Loubat.1
The first case report of uterine AVM in our
country by Dr. JE Sy was published in 2003. A young
patient, 27 years old, G4P3 (2112) was diagnosed
to have uterine AVM and was managed with total
abdominal hysterectomy.2
The second published report was made by Cacha
and Moran in 2012. A 31 year old G1P1 (1001) had
CT angiography which showed AV malformation.
The patient subsequently underwent pelvic
angiogram with transcatheter embolization of the
left uterine artery.3
In our institution, 2 cases were seen in 2006 and
recently in 2012. Both patients underwent
conservative treatment since both were still desirous
of pregnancy. Fertility sparing procedure done in the
first case was bilateral hypogastric artery ligation
followed by excision of the uterine mass while
transcatheter embolization of the right uterine artery
was done in the second case.
This report aims to review the local literature on
the 2 cases published and to add the 2 cases we have
seen in our institution. We intend to make a
diagnostic and treatment flowchart based on the 4
cases of AVM seen in our country.
Key words: uterine arteriovenous malformation, internal
iliac artery ligation, embolization of uterine artery
A.C., a 28-year old G2P1 (1011), was admitted
in July 2006, due to vaginal bleeding. She delivered
her first term pregnancy in 2004 via cesarean section
for cephalopelvic disproportion.
Three months prior to admission, she had an
abortion at 16 weeks age of gestation. She underwent
completion curettage and had an uneventful hospital
stay.
Two months prior to admission, patient had
vaginal bleeding amounting to 4 pads per day,
rteriovenous malformation (AVM) of the uterus
is an abnormal connection between uterine
arteries and veins. The classical clinical features are
intermittent heavy vaginal bleeding, which can be
life-threatening. The first case of arteriovenous
A
CASE 1
Arteriovenous Malformation of the Uterus / Icasas
occurring every 14 days and lasting for 5 days. This
was accompanied by intermittent, non-radiating,
crampy hypogastric pain. The bleeding persisted
increasing in amount and duration. No consult was
done.
One day prior to admission, the patient noted
vaginal bleeding, this time with passage of blood
clots. She consulted a gynecologist and was
subsequently admitted. Systemic physical
examination findings were essentially normal. Pelvic
inspection revealed normal external genitalia.
Speculum examination showed smooth vaginal
walls, a pink and smooth cervix, with minimal
bleeding per os and moderate pooling of blood at
the posterior fornix. On internal examination, the
cervix was firm, short and closed. The corpus was
not enlarged and there was neither adnexal mass nor
tenderness noted.
The patient was admitted with a primary working
impression of Abnormal Uterine Bleeding, Rule Out
Endometrial Pathology; Rule Out Gestational
Trophoblastic Disease.
On admission, complete blood count revealed
hemoglobin of 11.2 mg/dl, and hematocrit of 0.34;
Prothrombin and Partial Thromboplastin times were
within normal limits. Qualitative serum β-hCG was
negative.
A transvaginal ultrasound with doppler studies
demonstrated an anteverted uterus measuring 5.47cm
x 4.09cm x 3.9cm, homogenous with a complex
vascular mass at the fundal portion with extension
to the uterine cavity measuring 1.22cm x 0.88cm
showing extensive color aliasing or inversing and
apparent flow reversal (Figures 1 & 2). Endometrial
stripe was 0.44cm, hyperechoic, and the
subendometrial halo appears intact except at the
fundal portion where the complex vessels were noted.
Doppler studies showed the endometrial mass to have
a Resistance Index of 0.46 and a Pulsatility Index of
0.61 (Figure 3). The sonographic impression was:
normal sized anteverted uterus with thin
endometrium; vascular intrauterine mass to
consider arteriovenous malformation, rule out
endometrial pathology.
The patient was then scheduled for pelvic
laparotomy with an intention to perform conservative
surgery. However, before the operation, she had an
episode of profuse vaginal bleeding with passage of
blood clots. She was noted to be hypotensive, with a
blood pressure of 60 palpatory, and tachycardic with
a heart rate of 130 bpm. She was stabilized with
intravenous fluids and colloids and transfused 1 unit
Figure 1. Transvaginal ultrasound showing a complex vascular
mass at the fundal portion with extension to the uterine cavity
measuring 1.22cm x 0.88cm.
Figure 2. On color doppler ultrasound, the mass shows intense
color with extensive color aliasing and apparent flow reversal.
Figure 3. Spectral doppler studies of endometrial mass showing
low impedance and high velocity flow.
of fresh whole blood and an emergency exploration
was undertaken.
Intraoperatively, the uterus was normal in size
measuring 5cm x 4cm x 4cm with smooth serosa.
Bilateral ovaries and fallopian tubes were grossly
normal. A bilateral hypogastric artery ligation was
performed followed by excision of the endometrial
mass including the overlying myometrium.
A vertical incision from the uterine fundus to
the mid-anterior wall was made to expose the
endometrial cavity and the mass (Figure 4). There
was a yellowish, ill-defined, firm, exophytic,
irregularly shaped endometrial mass measuring
approximately 3cm x 2cm x 2cm located at the fundal
area (Figure 5). Multiple cystic spaces, blood vessels,
and purplish-black cystic structures were noted within
the mass. The overlying myometrium and the rest
of the endometrium were grossly normal. Minimal
intraoperative bleeding was observed and the
endometrial mass was excised using electro
coagulation (Figure 6). The hysterotomy incision
was repaired in layers.
An intrauterine catheter
was inserted with the balloon inflated. Estimated
blood loss was 100cc. A total of three units of fresh
whole blood were transfused. The procedure was
well tolerated by the patient and routine postoperative care was rendered. She was then given
medroxyprogesterone acetate 150mg intramuscularly
on the 5th post-operative day and was discharged
on the 6th hospital day.
The specimen consisted of a creamy, sessile mass
with irregular surface measuring approximately 3 cm
showing multiple cystic spaces, blood vessels and
purplish black cystic structure (Figure 7).
Histopathology of the specimen revealed:
arteriovenous malformation of the endometrium;
simple endometrial hyperplasia without atypia
(Figure 8).
She was given Depo-medroxyprogesterone acetate
150mg intramuscularly once a month for 3 doses
with no recurrence of the abnormal uterine bleeding.
A year after the operation, a repeat transvaginal
ultrasound was done which showed a slightly
retrover ted uter us, without any intramural or
endometrial masses noted. Color doppler studies of
uterine arcuate arteries were within normal limits
(Resistance index: 0.65; Pulsatility index: 1.16 cm).
Figure 4. The uterus was normal in size measuring 5cm x 4cm x
4cm with smooth serosa. A vertical incision from the fundus to the
mid-anterior uterine wall was done to expose the endometrial cavity
and mass
Figure 5. A yellowish, ill-defined, firm, exophytic, irregularly
shaped endometrial mass approximately 3cm x 2cm x 2cm at the
fundal area.
CASE 2
J.A., a 24 year old, G1P0 (0010), was admitted
in July 2012 due to vaginal bleeding.
Figure 6. Excision of the endometrial mass and overlying
myometrium using electrocauterization.
Figure 7. A creamy, sessile mass with irregular surface measuring
approximately 3cm showing multiple cystic spaces, blood vessels
and purplish black cystic structures was obtained.
rich color flow occupying the lower one third of the
uterus to the fundal area measuring 4.5cm x 3.4cm
x 2.7cm. Sonographic impression was "Cannot
totally r ule out an invasive mole versus an
arteriovenous malformation". β-hCG done was
normal at 1.46 mIU/mL. CBC done revealed
hemoglobin of 8.4 g/dL. She was then transfused
with 2 units of packed RBC. Repeat β-hCG done
after 2 days was still within normal limits at 1.46 g/
dL. Impression at this time was to consider an
invasive mole rule out arteriovenous malformation.
She was discharged stable with resolution of vaginal
bleeding, given ferrous fumarate and tranexamic
acid, and subsequently advised to transfer to a
tertiary institution for further work-up.
One week prior to admission, patient had
recurrence of vaginal bleeding now consuming 1
maternity pad, fully soaked with passage of blood
clots, warranting consult. On examination, patient
had pale palpebral conjunctivae and nail beds,
abdomen was soft and non-tender, no palpable
masses noted. Internal examination revealed a closed
cervix and a slightly enlarged uterus. Patient
underwent correction of anemia with transfusion of
2 units of packed RBC.
Repeat transvaginal ultrasound done (Figures 9,
10 & 11) revealed a myometrial multicystic
hypervascular mass, to consider an arteriovenous
malformation. CT angiography was performed
which showed a conglomeration of tortuous
vascular structures predominantly involving the
anterior myometrium, supplied by a branch of the
anterior division of the right internal iliac artery
(Figures 12 & 13).
Figure 8. Histopathology of the specimen showing lack of
distinction between the arteries and veins, thickened intimal layer
and absence of capillaries.
Three months prior to admission, patient had
an abortion at 8 weeks gestation for which she
underwent completion curettage which showed
decidual tissues and endometritis on histopath.
Two weeks prior to admission, the patient noted
sudden onset of vaginal bleeding amounting to 4 to
5 pads per day with blood clots. Patient consulted
with an obstetrician where a transvaginal ultrasound
revealed an irregular, ill-defined complex mass with
Figure 9. Gray scale image of the arteriovenous malformation
with a multicystic hypervascular area in the anterior myometrium.
Figure 10. Color doppler image of the arteriovenous malformation
showing hypervascularity and increased blood flow.
Figure 13. 3D reconstruction of the hypervascular mass showing
conglomeration of tortuous vascular structures predominantly
involving the anterior myometrium.
Figure 11. Pulsed doppler image showing broad spectral waveform
with continuous flow throughout systole and diastole.
Patient subsequently underwent embolization of
the right uterine artery using gel foam, with complete
occlusion of the uterine artery on post injection and
confirmatory angiography. (Figures 14 & 15). She
was discharged improved on the 2nd post-operative
day.
Figure 12. CT angiogram showed conglomeration of tortuous
vascular structures predominantly involving the anterior
myometrium, supplied by a branch of the anterior division of the
right internal iliac artery.
Figure 14. Pre-embolization of the right uterine arteries, showing
the hypervascular mass.
Figure 17. Color doppler image 1 month following uterine artery
embolization showing markedly reduced blood flow.
Figure 15. Post-embolization of the right uterine arteries with
note of complete occlusion of the uterine artery on post injection
and confirmatory angiography.
One month after embolization, on repeat
ultrasound, there was a significant change in the
appearance of the arteriovenous malformation on
gray scale imaging (Figure 16) and markedly reduced
blood flow pattern on color doppler (Figure 17). On
follow-up scan two months after the embolization,
the anterior myometrium was noted to be
homogenous, with no demonstrable arteriovenous
malformation on gray scale imaging (Figure 18) and
consequently showing flow only within the periphery
of the myometrium on color doppler application
(Figure 19).
Figure 16. Gray scale image of the arteriovenous malformation 1
month following uterine artery embolization.
Figure 18. Gray scale image of the arteriovenous malformation 2
month following uterine artery embolization showing no
demonstrable uterine AVM.
Figure 19. Color doppler image 2 months following uterine artery
embolization showing flow only within the periphery of the
myometrium.
The patient is presently maintained on combined
oral contraceptive pills with no recurrence of vaginal
bleeding.
DISCUSSION
Uterine AVMs are uncommon, and their true
incidence is unknown.1 To date, only case reports or
small case series exist, making it impossible to
estimate a true incidence. It is known that AVMs are
more common in females and have a predilection
for pelvic blood vessels, although they rarely involve
the uterus.4
AVM may be congenital or acquired. Congenital
AVM results from failure of embryological vascular
differentiation leading to multiple vascular
connections. The mesenchyme forms large flexiform
structures that differentiate into mature vessels with
the primitive components disappearing or they may
develop partially with primitive vascular
communications persisting. Therefore these AVMs
are focal areas of inadequate vascular development.
The lesions grow by recruitment of collateral vascular
channels. However, due to the hormonal stimulation
within the uter us during menstr ual cycles,
disproportional growths may occur explaining the
majority of subclinical AVMs occurring in women
in their 20's. In contrast, causes of acquired uterine
AVM include previous uterine surgery, curettage,
cesarean section, pelvic trauma, gestational
trophoblastic diseases, exposure to diethylstilbestrol,
endometriosis, fibroids and endometrial or cervical
cancers. It is suggested that acquired AVMs are an
"unmasking" of a congenital type. A traumatic
connection or fistula between an artery and a vein
may occur following uterine surgeries.
The two cases presented are examples of acquired
uterine AVM, with both having history of surgical
interventions such as cesarean section and completion
curettage in Case 1 and completion curettage in Case
2. In the report of JE Sy, the patient, underwent
curettage for menorrhagia.2
Congenital uterine AVMs tend to have multiple
feeding arteries, draining veins and intervening
nidus, whereas acquired uterine AVMs tend to have
a single or bilateral feeding arteries, are not supplied
by extrauterine arteries, and do not have a nidus.1
They more commonly involve the corpus, but are
also found in the cervix.6
AVM consists of proliferation of arterial and
venous channels with fistula formation and an
admixture of small capillary like channels. In many
cases, distinction between artery and vein becomes
blurred due to secondary intimal thickening in the
latter as a result of increased intraluminal pressure.2
The vessels are ambiguous with thickened intima and
some elastin in the walls making the distinction
between artery and vein difficult.4 The incorporation
of necrotic villi in the venous sinuses of scar tissue
is thought to cause acquired uterine AVM.7
The classical presentation of uterine AVM is often
one of severe uterine bleeding with no obvious cause.
The pattern of bleeding is usually intermittent and
torrential, and sometimes significant enough to
require multiple blood transfusions.1 The onset and
cessation of bleeding are abrupt, comparable to the
opening and closing of a faucet.
Uterine bleeding is thought to occur when the
vessels of the AVM are exposed from iatrogenic
sloughing of the endometrium during a curettage or
during menses. 1 For patients who almost have
moderate to severe vaginal bleeding, procedure such
as D&C should be considered with caution or even
contraindicated because fatal hemorrhage after this,
procedure would occur in patients with true AVM.
Consequently, prompt, accurate diagnosis is crucial
for good patient outcome.8
The patient in Case 1 presented with vaginal
bleeding approximately 20 days after she underwent
completion curettage while the patient in Case 2 had
vaginal bleeding 59 days after undergoing
completion curettage. The patient in JE Sy's report
had bleeding 4 months after curettage.
How soon can AVM occur after uterine trauma?
The masses usually develop over a long period of
time before becoming symptomatic; however, rapid
growth may occur, often in response to a hormonal
influence such as in puberty or during pregnancy, or
trauma. Eling, et al. in their review of literature
noted the length of time between the occurrence of
uterine trauma and diagnosis of AVM. The average
time since uterine trauma was 44.9 days (range 7 1,095 days).
Diagnosis
Ultrasonography provides a valuable noninvasive method of diagnosing uterine AVM. A
transvaginal ultrasound is the initial imaging
modality that is frequently employed for investigation
of an abnormal uterine bleeding, as it is most
accessible and cost effective in our setting.4
The addition of color doppler improves the
diagnostic ability of ultrasonography because
findings are more consistent.10 A localized area of
increased vascularity within the myometrium itself
typifies these lesions. In Cases 1 and 2, ultrasound
showed hypervascular uterine mass. In the 2
published report, uterine mass with dilated blood
vessels were noted.3,4
Pulsed Doppler evaluation of the identified area
will normally reveal a low resistance blood flow with
high peak velocities and evidence of turbulence.11 The
waveform is usually broad with an irregular spectral
envelope, indicating a turbulent flow resulting from
the many direct arteriovenous connections that are
present.8 In cases 1 and 2, color doppler showed low
resistance and increased velocities (Appendix A).
Three-dimensional power Doppler sonography
provides additional assistance in the evaluation of
uterine vascular AVMs by depicting a clearer view
of the orientation of its tortuous vessels. Doppler
ultrasound is also used to monitor AVMs for response
to treatment or recurrence after embolizaiton.4
Magnetic Resonance Imaging provides an
accurate definition of uterine AVMs and effectively
delineates the invasion of adjacent organs. The
characteristic features include a bulky uterus with a
focal mass, disruption of the junctional zones,
multiple serpiginous flow-related signal voids within
the lesion, and prominent parametrial vessels.11,12
Similar to MRI, computed tomography may be used
to determine the size, extent, vascularity and
involvement of the adjacent organs.9
Currently, angiography is the gold standard for
diagnosis. Angiography, an invasive technique,
allows the confirmation of the diagnosis and helps
identify the leading feeder vessels where embolization
may be indicated as a conservative treatment option.8
In angiographs, the affected arteries appear thicker
and more circuitous than normal ones. AVMs appear
as a complex tangle of vessels supplied by enlarged
feeding arteries and show early venous drainage
during the arterial phase.
Uterine AVMs can be difficult to diagnose not
only because they are rare, but because they may
present similarly to other pregnancy related
pathologies such as subinvolution of the placental
bed, retained products of conception, and gestational
trophoblastic diseases.
Uterine AVM, subinvolution of the placental bed,
retained products of conception and gestational
trophoblastic disease can present with vaginal
bleeding. Subinvolution of the placental bed, retained
products of conception occur exclusively post
pregnancy, while gestational trophoblastic disease
and uterine AVM can be discovered ante or post
partum.7 Both of our cases presented with vaginal
bleeding after undergoing D & C for miscarriage.
Gray scale ultrasonography itself may play a role
in the diagnosis but the characteristics are nonspecific6 and the features of AVM may be similar to
other pelvic structures or pathologies.9 Findings may
vary from subtle myometrial inhomogeneity to
multicystic or tubular spaces within the myometrium.
These sonographic features can also be seen in cases
of or retained products of conception or gestational
trophoblastic diseases.
Sonographically, in cases of retained products
of conception, small amounts of fluid and echogenic
material, which likely represents blood clots, is seen.
The endometrial thickness varies. Color doppler may
be employed which may reveal low resistance flow
within a focal intracavitary mass.
Gestational trophoblastic diseases on the other
hand may have the typical snow-storm appearance central heterogeneous mass with anechoic spaces of
different sizes and shapes, without associated fetal
development. Doppler study will almost always
show high velocities and low resistance to flow in
the uterine arterial circulation and low resistance
flow from the trophoblastic tissue.13
Uterine AVM will likewise show multiple cystic
spaces within the endometrium with vascular tangle
of blood vessels appreciated in gray scale, which on
color Doppler, will manifest avid f low and
demonstrate high velocity and low resistance flow
similar to retained products of conception and
gestational trophoblastic pathologies.
Indeed there can be considerable overlap in the
presentation and appearance of AVM and other
pathologies related to pregnancy even with the use
of ultrasound and color Doppler. Given the
similarities in the presentations, a serum β-hCG will
be helpful in determining the correct diagnosis.
Uterine AVMs are characterized by a negative
β-hCG which is usually weakly elevated in retained
products of conception and grossly elevated with
gestational trophoblastic diseases. In the 2 index cases
presented, the β-hCG was within normal limit which
rules out retained products of conception and
gestational trophoblastic disease. The β-hCG
determination was not done in the 2 published reports
but pregnancy tests done were negative.2,3
It is important to make an accurate diagnosis of
uterine AVM as the treatment of subinvolution of
the placental bed, retained products of conception
and gestational trophoblastic diseases may include
endometrial curettage which is contraindicated in
uterine AVM as there is risk of causing massive
hemorrhage.
Another disease entity that may present with
vaginal bleeding, and a normal β-hCG is a
hyperplastic endometrium, or malignancy. In Case
1, simple hyperplasia without atypia of the
endometrium was noted on histopathology of the
excised mass. Given the suspicion of an endometrial
pathology, there is a need to get a tissue sample
through an endometrial curettage. However, if a
diagnosis of arteriovenous malformation is also
entertained, performing the aforementioned
procedure is contraindicated thereby encouraging the
gynecologist to consider other diagnostic modalities.
While uterine AVM can be suspected with the
use of ultrasound, only angiography can differentiate
true uterine AVM from potentially more benign
lesions. Angiography can easily delineate feeding
arteries and draining veins in an AVM and thereby
confirm the diagnosis, define the extent of the lesion
and offer a more accurate characterization given an
unequivocal sonographic finding. Angiography
remains the gold standard in diagnosing uterine
AVM.
Angiography, an invasive technique, helps
identify the leading feeder vessels where embolization
may be indicated as a conservative treatment option.8
In angiographs, the affected arteries appear thicker
and more circuitous than normal ones. AVMs appear
as a complex tangle of vessels supplied by enlarged
feeding arteries and show early venous drainage
during the arterial phase. In Case 2, angiography
showed a conglomeration of tortuous vascular
structures predominantly involving the anterior
myometrium. A diagnosis of AVM was then singled
out. In the report of Cacha and Moran, CT
angiography showed a hypervascular lesion in the
uterine fundus. A vascular malformation was
primarily considered.3
Treatment
Immediate treatment of uterine AVM consists of
stabilization and management of active bleeding. A
Foley balloon inser ted into the uter us may
tamponade the site of active bleeding. Intravenous
estrogens have been suggested and may provide an
endometrial covering over the AVM. 4 Blood
transfusion can be given while preparing the patient
for operation.
The definitive management of uterine AVM
depends on several factors: the site and size of the
lesion, the severity of the vaginal bleeding, the age
of the woman and her desire to maintain her
reproductive capacity.
The choice of management is probably dictated
by the site and size of the lesion. Large lesions that
involve the subendometrial tissue, usually require
surgical intervention while others respond to
conservative management.1
Long-term medical management may be used if
the bleeding is not severe. The treatment includes
estrogens and progestins, methylergonovine,
danazol, 15-methyl-prostaglandin F2-alpha, oral
contraceptives, and intramuscular followed by oral
methylergonovine maleate. 8 However, given the
propensity of these patients to bleed excessively,
medical therapy should be limited to
hemodynamically stable patients, with close clinical
follow up.
In the past, ultimate treatment of uterine AVM
has been contingent on whether the patient desires
fertility. Hysterectomy is the treatment of choice for
a symptomatic AVM if the patient no longer desires
fertility.4 In some areas, as may be the case in resourcepoor countries, where there is limited access to
medical facilities or in whom embolization therapy
fails, hysterectomy is also indicated.8
The first reported case in our country was a 27
year old, G4P3 (2112), presenting with heavy
menstrual bleeding and anemia. Since she no longer
desires future pregnancy, a total abdominal
hysterectomy was done.2 Hysterectomy is the most
definitive treatment option that is readily available
that could offer symptomatic resolution. However,
in cases where future childbearing is desired, a more
conservative approach can be performed.
The two patients in this report desire fertility
preservation. In Case 1, conservative management
consists of bilateral hypogastric artery ligation
followed by excision of the uterine mass. This was
done based on the ultrasonographic data showing a
small mass which was well-delineated, localized and
not extensive. Part of the overlying myometrium was
likewise excised with the mass to ensure that the mass
was fully dissected.
Aside from surgical removal of uterine AVM,
other conservative management reported less
frequently include the coagulation of uterine AVM
under hysteroscopic guidance, laparoscopic bipolar
coagulation of uterine vessels and unilateral ligation
of the uterine artery and ovarian ligament.8
Bilateral hypogastric artery ligation was done in
Case 1 in anticipation of intraoperative hemorrhage
during the excision of the uterine mass. Bilateral
hypogastric artery ligation is indicated in cases where
prophylactic reduction of blood flow is needed. And
as expected, we hardly experienced any bleeding
during the dissection of the uterine wall and
subsequent excision of the uterine AVM. Uterine
artery embolization was not done in Case 1 as this
emergency procedure was not available in our
institution in 2006.
Uterine artery embolization (UAE) has become
the treatment of choice, as more centers have the
facilities and training to perform this interventional
techniques.13 Angiographic arterial embolization has
recently become the preferred management protocol
because it involves a minimally invasive procedure.
Transcatheter embolization of the right uterine
artery was done in Case 2 using pledgets of absorbable
gelatine sponge (Gelfoam). The choice of embolic
agent varies with operator experience and preference.
Various embolization materials have been used
including gelatine sponge, coils, isobutyl-2cyanoacrylate, detachable balloons, thrombin, and
polyvinyl alcohol.
Various studies have shown that UAE is
successful in 95% of cases even though complications
have been reported in approximately 10% of the cases.
The side effects of the procedure, such as low-grade
temperature, pain, or infection have been
documented. Of these, pelvic pain was the main side
effect, even requiring opiate and non-steroidal
analgesia. In addition, the procedure has the expected
disadvantage of insufficient embolization,
demanding a repeat procedure.8
The advantages of transcatheter arterial
embolization include avoidance of surgical risks;
outstanding success rates, low complication rates, and
preservation of fertility.13 Moreover, successful cases
of post-embolization pregnancy have been reported.
Eling and co-workers did a retrospective audit
of cases of uterine arteriovenous malformations at
The Canberra Hospital and reviewed the literature
reporting on pregnancies occurring after the
diagnosis of uterine AVM. A total of 63 pregnancies
occurred post treatment, seven (13.9%) ending in
miscarriage. Average time to conceive post diagnosis
was 19 months ± 16.3 (range 2-72). A total of 54
healthy infants were born to mothers post AVM
diagnosis. The authors concluded that successful
uncomplicated pregnancy is achievable for women
after the diagnosis and treatment of uterine AVM.
CONCLUSION
Two cases of AVM were presented. Together
with the 2 cases published in the local literature
(Appendix A), a diagnostic and treatment flow chart
was created (Appendix B)
1.
In patients with vaginal bleeding and history of
uterine trauma, Gray scale ultrasound with color
Doppler can reliably aid in the evaluation of a
suspected AVM; but the features of AVM may
be similar to other pelvic structures or
pathologies. Angiography remains the gold
standard in the diagnosis.
2. The determination of β-hCG may be used in
differentiating other pelvic pathologies. Uterine
AVM is characterized by a negative β-hCG which
is usually weakly elevated in retained products
of conception and grossly elevated with
gestational trophoblastic diseases.
3. Medical management may be used but is limited
to hemodynamically stable patients with close
clinical follow up.
4. Hysterectomy is the treatment of choice for a
symptomatic AVM if the patient no longer desires
fertility.
5. In resource-poor countries, where there is limited
access to medical facilities, bilateral hypogastric
artery ligation followed by excision of the mass
may be done.
6. In centers with the facilities and training to
perform interventional techniques, transcatheter
embolization of the uterine arteries may be
employed. Angiographic arterial embolization
has recently become the preferred management
protocol because it involves a minimally invasive
procedure.
With the awareness of the existence of this disease
and its variable clinical presentations and correlating
them with diagnostic modalities, treatment can be
optimized for each individual patient.
Appendix A. Clinical summary of the four cases of AVM.
Appendix B. Diagnostic and treatment flowchart.
8.
9.
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Renu A, Batra A, Saxena P, Gupta P, Minoch B. Arteriovenous
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Sy JE. Arteriovenous malformation of the uterus. Phil J Obstet Gynecol
2003; 70-5.
Cacha HC, Moran JB. The role of embolization in the management of
postpartum hemorrhage and uterine vascular malformations. Phil J
Obstet Gynecol 2012; 36 (4): 189-96.
Levis J, Gus Gl. Uterine arteriovenous malformations. In Clinical
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Syla BH, Fetiu SS, Tafarshiku SS. Transabdominal two- and threedimensional color Doppler imaging of a uterine arteriovenous
malformation. Ultrasound Obstet Gynecol 2011; 37: 376-8.
Charge S, Williams J, Whitridge J. William's Gynecology, 2nd ed.
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a review of current literature. J Clinical Ultrasound 1979; 7: 383-5.
Ginsberg NA, Hammer R, Parihk S, Tamura R, Sabbagha RE,
Arteriovenous malformation of the uterus associated with a missed
abortion. Ultrasound Obstet Gynecol 1998; 206: 115-23.
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arteriovenous malformations: gray-scale and Doppler US features
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W.B. Saunders. 2008.
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Milingos, D, Doumplis D, Sieunarine K, Savage P, Lawson PD, Smith
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Cancer 2007; 735-7.
A Positive Life - Preventing Maternal to Child HIV
Transmission
MAUREEN G. LARANANG, MD
AND
MARIA LORENA L. SANTOS, MD, FPOGS
Department of Obstetrics and Gynecology, Cardinal Santos Medical Center
A positive life and future free from human
immunodeficiency virus (HIV) infection is attainable. This
poses a challenge to an obstetrician in preventing maternal
to child transmission because every child deserves the right
to be born free from HIV.
The transmission of HIV from an HIV-positive mother to
her child during pregnancy, labor, delivery or breastfeeding
is called mother-to-child transmission. In the absence of
any interventions transmission, rates range from 15-45%.
This rate can be reduced to levels below 5% with effective
interventions. Hence, early identification and treatment of
all pregnant women infected with HIV is the best way to
prevent neonatal disease and improve women's health.
We report a case of a 26-year-old G3P1 (1010), Pregnancy
uterine, 37 weeks age of gestation by last menstrual period,
diagnosed with Acquired Immunodeficiency Syndrome
(AIDS), WHO Stage II-III with recurrent respiratory tract
infection, unexplained severe weight loss >10% since April
1, 2011 and had been on highly active antiretroviral
therapy (HAART) since then. Patient delivered to a live,
term, female, 38-39 weeks by pediatric aging, via emergency
low segment cesarean section with bilateral tubal ligation.
Infant antiretroviral prophylaxis was given for 6 weeks,
and breastfeeding was discouraged. Polymerase Chain
Reaction (HIV RNA detection) testing was done on the
infant after 8 weeks of life with negative results. Infant
remains well and uninfected with HIV 6 months postnatal.
Key words: mother-to-child transmission (PMTCT), antiretroviral prophylaxis, treatment
A
n estimated 330 000 children were newly infected
with HIV in 2011, over 90% of them through
mother-to-child transmission (MTCT). Without
treatment, about half of these infected children will
die before their second bir thday. Without
intervention, the risk of MTCT ranges from 20% to
45%. With specific interventions in non-breastfeeding
populations, the risk of MTCT can be reduced to
less than 2%, and to 5% or less in breastfeeding
populations.1
In high-income countries the number of new
HIV infections among children and maternal and
child deaths due to HIV was virtually zero. At the
other end of the equation, in low- and middleincome countries, too few women are receiving HIV
prevention and treatment services to protect
themselves or their children. This inequity must
change. The life of a child and a mother has the
same value, irrespective of where she or he is born
and lives.
More dreadful even is the less favora ble
epidemiological trend in the Philippines (Figure 1) 1
from 2001 to 2011, where the number of people
newly infected in 2011 was at least 25% higher than
in 2001.
In May 2013, there were 415 new HIV antibody
sero-positive individuals confirmed by the STD/
AIDS Cooperative Central Laboratory (SACCL)
and reported to the HIV and AIDS Registry of the
Department of Health. 2 This was 65% higher
compared to the same period last year (Figure 2).
Despite the foregoing, the world has an
unprecedented opportunity to make new HIV
infections among children history. It is possible to
stop new HIV infections among children and keep
their mothers alive if pregnant women living with
HIV and their children have timely access to quality
life-saving antiretroviral drugs-for their own health,
as indicated, or as a prophylaxis to stop HIV
transmission during pregnancy, deliver y and
breastfeeding. When antiretroviral drugs are available
as prophylaxis, HIV transmission can be reduced to
less than 5%.3
Preventing Maternal to Child HIV Transmission / Laranang and Santos
To prevent the transmission of HIV from mother
to baby, the World Health Organization (WHO)
promotes a comprehensive approach, which includes
the following four components:4
1. Primary prevention of HIV infection among
women of childbearing age.
2. Preventing unintended pregnancies among
women living with HIV.
3. Preventing HIV transmission from a woman
living with HIV to her infant.
4. Providing appropriate treatment, care and
support to mothers living with HIV and their
children and families.
Acquired Immunodeficiency Syndrome (AIDS)
is an inevitable HIV- related condition, a "point
Figure 1. Changes in the incidence rate of HIV infection among adults 15-49 years old, 2001-2011,
selected countries (Source: UNAIDS Global Report 2012).
Figure 2. (Source: HIV and AIDS Registry, National Epidemiology Center, DOH Global).
of no return" for those not on ART. However,
its course can be delayed due to availability and
widespread universal access to combination
antiretroviral therapy (ART). Women should not
be an exception to these: Treatment should be
universal for HIV positive women for PMTCT
(Prevention of Maternal to Child Transmission).
However, successful PMTCT is relatively uncommon
in the Philippines primarily due to the unreliable
funding for such care and treatment. As this
makes up only 1.6% of the Philippines HIV/
AIDS budget. Despite this, the Philippine National
AIDS Council’s 4th AIDS medium term plan and
its country report for the period January 2006 to
December 2007 to the United Nations General
Assembly Special Sessions (UNGASS) states that it
will endeavour to improve access to treatment, care
and support to HIV infected persons.5
It is emphasized here that maternal to child
transmission is a common route for transmission of
HIV among children and mortality among these
children is high. Thus, prevention of transmission
should be every obstetrician's goal. Correlating with
my case report, maternal to child transmission was
prevented by compliance to antiretroviral therapy,
avoidance of breastfeeding and proper timing and
manner of delivery which are all evidence based
inter ventions. Through these, we were able to
eliminate the chance of maternal to child
transmission of HIV.
Objectives
This report aimed to present a case of an HIVinfected pregnant woman where mother-to-child
transmission of HIV was prevented using the current
DOH guidelines on PMTCT.6
Specifically, this report aimed to:
1. Give an overview of the mechanism of Mother
to Child Transmission (MTCT) of HIV.
2. Discuss the current screening procedures and
protocols of HIV infected mothers based on
the Prevention of Mother to Child Transmission
(PMTCT) guidelines set forth by DOH.
3. Discuss the key points of PMTCT Antiretroviral
Therapy (ART) and infant management.
4. Discuss the position of POGS regarding
breastfeeding in the context of HIV.
5. Discuss labor and delivery practices in the
PMTCT.
THE CASE
This is the case of H4-11-RLV-006, a 26 year old
female, G3P1 (1-0-1-0), married, Filipino, Roman
Catholic, housewife, born on October 14, 1986 in
Benguet, currently residing in Camp 6, Kennon
Road, Tuba, Benguet, who was admitted in our
institution on November 15, 2012 due to labor pains.
Patient is cognizant of pregnancy at 6-7 weeks
age of gestation. She had her regular prenatal checkup which started at 8 weeks age of gestation to an
obstetrician-gynecologist/infectious disease specialist
at a tertiary medical center. Patient was already a
diagnosed case of HIV infection when she first
consulted.
Routine prenatal work-ups were done which
included the following: complete blood count (CBC)
and urinalysis. Both of which showed results within
normal limits. Baseline fetal biometry was likewise
done which revealed a single, live, intrauterine
pregnancy; crown-rump length compatible with 8
weeks and 5 days age of gestation with good cardiac
and somatic activity. Prenatal supplements were
started and regular follow-up scheduled.
At 19 weeks age of gestation, patient had on
and off cough, accompanied by low-grade fever
and dyspnea.
Consult was made where an
impression Community-Acquired Pneumonia
(CAP), low risk was given, which was later
confirmed by a chest x-ray. She was then started
on the following: Cefixime 200 mg/tab 1 tablet
twice a day for 10 days, Azithromycin 500 mg/
tab 1 tab OD for 5 days and Salbutamol +
Guaifenesin 1 capsule twice a day for 3-5 days.
Prenatal supplements were continued. Patient was
compliant with her medications, affording relief
and improvement of symptoms.
The rest of her pregnancy remained uneventful.
She continued to receive routine prenatal care at
the specialty clinic of the tertiary medical center and
fetal well-being studies were done accordingly. She
was scheduled for elective (repeat) low segment
cesarean section at 38 weeks age of gestation.
However, patient developed hypogastric pains 8 days
prior to scheduled elective delivery. The said labor
pains were described to be persistent, mild to
moderate in severity, radiating to the lumbosacral
area, occurring every 30-45 minutes, lasting for
20-30 seconds. There were no associated vaginal
bleeding nor watery vaginal discharge. The above
symptoms prompted consult and subsequent
admission.
Ob-Gyne History
The patient is a Gravida 3 Para 1 (1-0-1-0). Last
menstrual period was on March 1, 2012, giving her
an AOG of 37 weeks upon admission.
Her first pregnancy was last April 2010 and was
carried to term via emergency low segment cesarean
section for a non-reassuring fetal status,
oligohydramnios, gestational hypertension. Her
second pregnancy was last November 2011 with an
abortive outcome, non-septic and non-induced,
where she underwent dilatation and curettage.
The patient had her menarche at 13 years old,
subsequent menses occurred at regular monthly
intervals, with duration of 4-5 days, consuming 3-4
moderately soaked pads per day. No associated
dysmenorrhea. She only had 1 sexual partner. She
denies any history of gynecologic illness in the past.
No family planning method was used.
Past Medical History
No known history of hypertension, diabetes
mellitus, heart disease, asthma nor allergies.
She was diagnosed to have an HIV infection last
April 1, 2011 at a tertiary medical center, one year
after having given birth to her first child. She never
had a history of blood transfusion in the past and
denied injecting drug use, hence leaving heterosexual
intercourse with her husband as the only risk factor
for the acquisition of the HIV infection. The
husband later disclosed that he had an extramarital
unprotected sexual intercourse.
When their first
child reached 11 months, they noticed he started
having oral sores and recurrent respiratory tract
infection, and was not as active and playful as before.
Their child was admitted repeatedly at the Pediatrics
Department of a tertiary medical center for various
conditions like bacterial, viral and fungal infections
specifically pneumonia, pulmonary tuberculosis, oral
candidiasis, and perianal abscess. In the infant's
most recent admission last March 25, 2011,
physicians were suspicious regarding a possible
immunocompromised status, hence HIV was
entertained.
The parents were referred to the HIV/AIDS Core
Team (HACT) of the institution for HIV counseling
and testing (HCT). Both parents were willing to be
counselled. After having given consent for the testing,
screening was done, which revealed "reactive" results
for both, i.e., HIV antibody was present. As per
protocol,7 they were submitted to a national reference
laborator y, STD AIDS Cooperative Central
Laboratory (SACCL), in San Lazaro Hospital
for confirmatory testing. Western Blot confirmatory
testing showed "positive" results. Maternal to child
transmission, infant prophylaxis and compliance to
antiretroviral therapy were emphasized. The patient
was also given options on the manner of delivery.
Both options vaginal and cesarean section delivery
were offered and its benefits and risks were
thoroughly discussed.
The child, who at the time was 11 months old,
underwent Polymerase Chain Reaction (PCR) testing
Unfortunately, the child
again, as per protocol.7
expired last April 1, 2011 due to multi-organ failure
of multiple opportunustic infections on top of an
immunocompromised condition.
The husband and wife underwent baseline
CD4 count/immunophenotyping determination, a
test necessary for staging of the disease and
determination of eligibility for antiretroviral therapy
(ART), the cut- off value being <350 cells/μ l. Both
of them were eligible for initiation of ART, hence,
was started on Lamivudine (3TC) + Zidovudine
(AZT/ZDV) 1 tab BID and Nevirapine 200mg per
tab BID on May 6, 2011. CD4 cell counts were
continuously monitored. (Appendix B)
On admission, patient was conscious, coherent,
ambulatory, not in cardiorespiratory distress with
vital signs BP: 130/80, PR: 80 RR: 20 Temp. 36.6ºC.
Pertinent physical examination revealed pink
palpebral conjunctivae, anicteric sclerae, no oral
sores, no palpable cervical lymphadenopathies.
Abdomen was globular, with a fundic height of
30cm, FHT 145bpm located over the left lower
quadrant, normoactive bowel sounds. Diagnostic
examinations include complete blood counting
with blood typing, AST, ALT, BUN, creatinine
which revealed normal results.
The patient was scheduled for cesarean section
the day after she was admitted because we prepared
the whole OR team for the operation. Universal
precautions were strictly followed.
Patient then underwent emergency repeat Low
Segment Cesarean Section (LSCS), and delivered
to a live, term, female, 38-39 weeks by pediatric aging,
with a birthweight of 2.7 kg, Apgar score of 8/9.
After routine newborn procedures (cord clamping,
Crede's prophylaxis, vitamin K administration,
anthropometric measurements), infant was
immediately started on antiretroviral prophylaxis
with Nevirapine 50mg/5ml for 6 weeks.
Breastfeeding was discouraged. Plasma samples were
submitted for PCR at 8 weeks old, results of which
were "negative". HIV infection among infants less
than 18 months old is confirmed after 2 positive
results by PCR.
Currently, the baby is doing well. She had her
regular subsequent check-ups at the Pediatrics
department in our institution. She had her repeat
PCR done at 6 months of age and we are still waiting
for the result.
Annex IV-B. Current HIV diagnostic testing algorithm for infant
<18months old*.
*HIV infection among infants ≥ 18 months old is confirmed after 2
positive results by PCR.
DISCUSSION
Mother-to-child transmission is only one of the
routes by which HIV may be transmitted:
unprotected sexual intercourse, injecting drug use
and blood transfusion.
A positive life and future free from HIV is
attainable. This poses a challenge to an obstetrician
in preventing maternal to child transmission because
every child deserves the right to be born free from
HIV.
Significant progress is being made in the global
scale-up of prevention of mother-to-child
transmission of HIV (PMTCT), including in high
burden and resource-limited settings like the
Philippines. For the first time, the elimination of
mother-to-child transmission of HIV (MTCT) is now
considered a realistic public health goal and an
important part of the campaign to achieve the
millennium development goals. In the light of the
global effort, it is critically important to provide the
best evidence-based interventions to reduce the risk
of transmission from an HIV-infected mother to her
newborn child, while at the same time promoting
the health of both the mother and the child.
We report the case of a heterosexual mother
(person) living with human immunodeficiency virus/
acquired immunodeficiency syndrome (PLWHA)
who got pregnant, with which we were able to
prevent mother-to-child transmission of HIV by
adopting the prescribed evidence-based interventions,
policies and guidelines from the Department of
Health (DOH) Administrative Order No. 2009-0016
Policies and Guidelines on the Prevention of Mother
to Child Transmission of HIV and DOH Department
Memorandum 2010-0028 Policies and Guidelines on
HIV Counseling and Tesing in Community and
Health Facility Settings),World Health Organization
(WHO) PMTCT antiretroviral (ARV) guidelines on
treating pregnant women and preventing infection
in infants April 2012. This is the first case reported
in our institution. We confirmed this through PCR
at 2 months old.
HIV-1 RNA was not detected. HIV infection
among infants less than 18 months is confirmed after
2 positive results by PCR.
The mechanisms of HIV transmission is through
blood transfusion, sexual contact, mother to child
transmission and injecting drug use.
The first descriptions of AIDS in children and
of possible transmission from mother-to-child were
published in the early 1980s.8,9 Remarkable progress
has been made in the years since then in the
prevention of mother-to-child transmission
(PMTCT), leading to extremely low rates of infection
in well- resourced countries - one of the major
advances in HIV prevention.
The introduction of the first antiretroviral drug,
Zidovudine (AZT, ZDV), and the subsequent use of
this in pregnant women led to the landmark Pediatric
AIDS Clinical Trial Group Protocol 076
(PACTG076) Study, published in 1994. In this
double-blind, randomized, placebo-controlled trial,
a r egimen of oral Zidovudine (ZDV) given
prenatally, intrapartum and postpartum reduced
transmission from mother to child by 67.5%, from
22.6% in the placebo group to 7.6% in the ZDV
group.10 In the years that followed, trials of shortercourse treatments in low-resource settings, with
zidovudine alone11,12 or zidovudine and lamivudine13,
demonstrated that these regimens were effective in
reducing transmission to around 10-15%.14 In 1999,
the HIVNET 012 trial,15 using a very simple regimen
of a single dose of Nevirapine for mothers at the
onset of labor and a single dose to the infant within
72 hours of birth, demonstrated a reduction of 42
percent compared to a week- long course of
zidovudine stated in labor.15 This simple and
inexpensive regimen was soon recommended
by the international agencies, and it has enabled
the expansion of PMTCT services in low-resourced
settings, reaching several million mothers and infants
by 2007.16
The main idea is to provide recommendations
to healthcare workers dealing with HIV + women
who are planning or who are actually already
pregnant regarding the PMTCT of HIV infection.
Simply put, our job is to identify the woman who is
infected with HIV, and implement measures known
to minimize the chance of transmission to the baby.
Transmission of HIV from mother to child can occur
ante par tum, during labor and deliver y, or
postpartum through breastmilk transmission. In
the absence of treatment or prophylaxis, most
transmission is thought to occur during the
intrapartum period17 (Figure 3).
Figure 3. Interventions to prevent mother-infant HIV transmission,
by timing (Source: Emerging evidence on prevention of motherto-child transmission of HIV. Dr Ying-Ru Lo, Coordinator
Prevention in the Health Sector HIV Department, World Health
Organization, Geneva. Satellite symposium Scaling up
comprehensive prevention of mother-to-child transmission
programmes International AIDS Conference Mexico D.F., 3 August
2008.
The proportions of transmission at different stages
are changed by the use of prophylactic interventions,
with combination antiretroviral therapy almost
eliminating antepartum and intrapartum
transmission, and short-course antiretrovirals having
less effect on antepartum transmission, although
achieving a major reduction in intrapartum
transmission.18,19,20
HIV Screening Among Mothers
The use of antiretroviral strategies in
pregnancy and modifications of infant feeding to
reduce the risk of transmission rely on the
identification of HIV-positive women. Obviously, the
necessary initial step is screening for HIV. Due to the
very nature of HIV infection, counseling is a crucial
component of testing.
Antenatal care services must be available and
accessible at an early stage of pregnancy to identify
HIV-positive mothers and to provide antiretroviral
regimens. These services need to provide HIV testing
and counseling, which must be acceptable to pregnant
women to ensure uptake.
The low uptake of testing is one of the major
reasons for the failure of PMTCT programs, as HIV
testing is the entry point to care.21,22,23 The reasons
for this are multifactorial, including fear and
stigmatization, lack of service infrastructure, staff
attitudes and stigma, service delivery failures, staff
attitudes and cost. This low uptake resulted in
recommendations for routine testing in pregnancy,
or an "opt-out" universal approach where all
pregnant women are informed that HIV testing will
be performed in the routine prenatal tests unless the
mother declines this testing.24
The routine offer of HIV testing in pregnancy
could make a significant difference to the success of
PMTCT programs, although there may be other
remaining challenges in these programs, including
difficulties in delivering results, and the fear of
recognition by hospital staff from the community.25,26
With improved access to HIV testing, many more
women will enter pregnancy aware of their HIV
infection.
HIV Counseling and Tesing (HCT) in the
Philippines27 whether client- initiated or providerinitiated, is still on a voluntary basis, i.e., even
after a thorough and comprehensive counseling
carried out by the trained healthcare provider, the
final decision whether to undergo testing still rests
on the client or patient.
The Department of Health has sixteen (16) accredited
treatment hubs in the Philippines which provide
treatment, care, and support to people living with
HIV/AIDS (PLWHA) and provides counseling
and testing to those client voluntarily seeking
counseling and testing; and, to expand the availability
and access of antiretrovirals (ARVs) in strategic
locations in the country.28 After the initial screening
tests, confirmatory testing (figure 4) are carried out
in either San Lazaro Cooperarive Central
Laboratory (SACCL) or Research Institute of
Tropical Medicine (RITM).27
Figure 5. WHO Clinical Staging of HIV/AIDS for adults and
adolescents with confirmed HIV infection (Source: DOH
Administrative Order No. 2009-0006 (Subject: Guidelines on
Antiretroviral Therapy (ART) Among Adults and Adolescents with
HIV Infection).
Mother to Child Transmission
Figure 4. Current HIV diagnostic testing algorithm for adults and
infants ≥ 18months old (Source: DOH Administrative Order No.
2010-0028 (Subject: Policies and guidelines in the Conduct of
HIV Counseling and Testing in Community and Health Facility
Settings).
Thereafter, staging of HIV/AIDS is done either
through clinical staging using the WHO staging
guidelines (Figure 4) or, when available, using
Immunophenotyping or CD4 count determination
for decisions regarding ART initiation. (Figure 5).
CD4 T cell count or CD4 count otherwise known
as cell differentiated count. Normal value ranges
from 800-1000 cc. CD4 +T cell is a marker of the
strength of a person's immune system. As HIV
destroys CD4 cells, the infected person's immune
system is weakened. The importance of this test is
that we will be able to determine the stage of the
disease and to predict risk of complication. The
lower the CD4 count, the more severe the HIV
infection is, the higher the CD4 count, the better the
health status is.39
Once the HIV-positive woman is identified, the
next concern of the health care provider is provision
of anti-retroviral therapy (ART), which is known to
significantly reduce MTCT. Whether this is
undertaken by the woman's obstetric care provider,
or referred to a specialist is a matter of professional
choice. However, it is important that the principles
of ART and the pharmacology of the drugs used
should be known to the health care provider.
PMTCT ART Guidelines: DOH and WHO
Prevention of mother-to-child transmission
(PMTCT) of HIV is a dynamic and rapidly changing
field. Current WHO PMTCT antiretroviral (ARV)
guidelines 3 on treating pregnant women and
preventing infection in infants were a major step
towards more efficacious regimens.
To maximize prevention of HIV transmission
and maternal and infant survival, it is critical that
care of both the mother and the infant is optimized.
A key issue in deciding what ARV regimen to choose
for an HIV-infected pregnant woman is whether the
ARVs are being provided for treatment of the
woman's HIV disease or solely for prophylaxis of
MTCT. In the former case, treatment means that
ARVs are started during (or even before) pregnancy
and continued throughout life, whereas ARVs given
solely for prophylaxis are stopped when the risk of
MTCT is no longer present. In both cases, effective
linkages between PMTCT services and HIV care and
treatment programmes are needed.
Since the majority of HIV-infected pregnant
women are asymptomatic or have only mild
symptoms, it is critical that services provide access to
CD4 counts to determine which women should
initiate lifelong ART. In the Philippines, only Baguio
General Hospital and Medical Center provides CD4
count services in Northern Luzon. Prophylaxis
interventions, which are provided solely to prevent
transmission and stopped after transmission risk has
ceased (e.g. on complete cessation of breastfeeding
or after delivery if replacement feeding is used),
would therefore be restricted to women who are not
eligible for treatment according to current
recommendations.
For HIV-infected pregnant women, the
initiation of ART for their own health is
recommended for all women who have CD4
cell counts of ≤350 cells/mm3, irrespective of WHO
clinical staging, and for all women in WHO clinical
stage 3 or 4, irrespective of the CD4 cell count (figure
6). These criteria for initiating ART for pregnant
women are the same as for non-pregnant
women.29
irrespective of gestational age and should continue
with it throughout pregnancy, delivery, during
breastfeeding (if breastfeeding) and thereafter. The
timing of ART initiation for HIV-infected pregnant
women is the same as for non- pregnant women, i.e.
as soon as the eligibility criteria are met.
The preferred first-line ART regimen in pregnancy
comprises of an AZT + 3TC backbone combined
with a non-nucleoside reverse transcriptase inhibitor
(NNRTI): AZT + 3TC + NVP or AZT + 3TC + EFV
(figure 7). Alternative recommended regimens are
TDF + 3TC (or FTC) + NVP and TDF + 3TC (or
FTC) + EFV. The preferred first-line ART regimens
recommended for HIV-infected pregnant women are
the same as for non- pregnant women, and for adults
in general. However, EFV should not be started in
the first trimester, and NVP should be used instead.
EFV may be used in the second and third trimesters.
EFV (Efavirenz) should not be used for the first
trimester because of its teratogenic effects. Limited
data from animal studies have shown that
anencephaly, microphthalmia and cleft palate were
seen in 3 (20%) of 15 monkeys exposed to efavirenz
in the first trimester. One case of meningomyelocele
has been reported in the literature after first
trimester efavirenz exposure.40
The decision should be guided by the capacity
and experience of maternal, newborn, child health
and HIV/AIDS programmes, the readiness of
PMTCT services, cost and operational feasibility.
Maternal ART should be coupled with the daily
administration of NVP or twice-daily AZT to infants
from birth or as soon as feasible thereafter until 4 to
6 weeks of age, irrespective of the mode of infant
feeding. ART has been reported to be safe for use
during pregnancy, hence the decision should be to
continue taking them.
Figure 6. Eligibility criteria for initiating antiretroviral treatment
or prophylaxis in HIV-infected pregnant women based on CD4
cell count and WHO clinical stage (Source: WHO Antiretroviral
Drugs for Treating Pregnant Women and Preventing HIV Infection
in Infants, 2010 version).
The available data show that maternal ART
during pregnancy and continued during
breastfeeding is the most effective intervention for
maternal health and is also efficacious in reducing
the risk of HIV transmission and infant death in this
group of women with the highest risk of MTCT.
Therefore, HIV- infected pregnant women in need
of treatment for their own health should start ART
Figure 7. Antiretroviral treatment options recommended for HIVinfected pregnant women who are eligible for treatment (Source:
WHO Antiretroviral Drugs for Treating Pregnant Women and
Preventing HIV Infection in Infants, 2010 version).
All HIV-infected pregnant women who do not
need ART for their own health require an effective
ARV prophylaxis to prevent HIV transmission during
pregnancy, labor and delivery, postpartum and
during the breastfeeding period. ARV prophylaxis
should be started from as early as 14 weeks of
gestation (second trimester) or as soon as possible
thereafter if women present later in pregnancy, in
labor or at delivery.
For all HIV-infected pregnant women who are
not in need of ART for their own health, a choice
of one of two equally efficacious ARV prophylaxis
options is recommended (Figure 8). There is a strong
benefit in providing effective and sustained ARV
prophylaxis to women not eligible for ART during
Figure 8. ARV-prophylaxis options recommended for HIV-infected
pregnant women who do not need treatment for their own health
(Source: WHO Antiretroviral Drugs for Treating Pregnant Women
and Preventing HIV Infection in Infants, 2010 version).
pregnancy, labor and delivery, and to either the
women or their infants throughout breastfeeding.
Both recommended options provide a significant
reduction in the risk of MTCT. Both options have
advantages and disadvantages in terms of feasibility,
acceptability and safety for mothers and infants, as
well as cost.
The WHO guidelines emphasize the importance
of providing lifelong antiretroviral therapy (ART)
to all HIV-infected pregnant women eligible for such
treatment and recommend two short-term
antiretroviral prophylaxis options (Option A and
Option B), for women not eligible under current
criteria, as determined by CD4 count, for treatment
for their own health.
Recently, a third option, to provide lifelong
ART to all HIV-infected pregnant women,
regardless of CD4 cell count, has emerged (Option
B+), and a number of countries are already adopting
or considering this approach (Figure 8).
The new option (Option B+) proposes further
evolution-not only providing The same triple ARV
drugs to all HIV-infected pregnant women beginning
in the antenatal clinic setting but also continuing
this therapy for all of these women for life. Important
advantages of Option B+ include: further
simplification of regimen and service delivery and
harmonization with ART programmes, protection
against mother-to-child transmission in future
pregnancies, a continuing prevention benefit against
sexual transmission to serodiscordant partners, and
avoiding stopping and starting of ARV drugs.
Labor and Delivery
The next important concerns in connection with
prevention of MTCT of HIV are labor and delivery.
Generally, abdominal delivery by elective cesarean
section is recommended. However, there are
conditions when vaginal delivery may be an option.
Continuing research into vertical transmission
of HIV suggests that a substantial number of cases
occur as the result of fetal exposure to the virus
during labor and delivery; the precise mechanisms
are not known. Transmission could occur by
transplacental maternal-fetal microtransfusion of
blood contaminated with the virus during uterine
contractions or by exposure to the virus in maternal
cervicovaginal secretions and blood at delivery.30
In theory, the risk of vertical transmission in
mothers with high viral loads could be reduced by
performing cesarean delivery before the onset of labor
and before rupture of membranes. Data from two
prospecticve cohort studies, 31,32 an international
randomized trial, 33 and a meta-analysis 34 indicate
that there is significant relationship between the mode
of delivery and vertical transmission of HIV, i.e.,
delivery by elective cesarean section is efficacious in
reducing mother- to-child transmission of HIV.
However, incidence rates of postpartum morbidity
after cesarean section delivery are higher than with
vaginal delivery. Pregnant women infected with
HIV should be informed about the risks and
potential benefits of delivery by cesarean section.
Cesarean delivery should be scheduled at
completed 38 weeks age of gestation (as opposed to
the 39 weeks recommended for persons not infected
with HIV, because of the substantially higher risk of
entering labor or rupturing membranes after 38
weeks of completed gestation. On the other
hand, performing a cesarean delivery at 38 versus 39
completed weeks of gestation confers a small
increased risk of infant respiratory distress possibly
requiring mechanical ventilation), especially for
women who: 1. have no prenatal consults; 2. have
not received anti-HIV medications during pregnancy;
3. have a viral load greater than 1,000 copies/mL at
36 weeks AOG; 4. have unknown viral load near
the time of delivery.
Method of delivery is much more complicated
when the woman spontaneously begins labor or her
membranes rupture. Longer duration of ruptured
membranes may be associated with a higher rate of
mother-to-child transmission. The International
Perinatal HIV group meta-analysis34 found that the
risk of vertical transmission increased by 2% for every
increase of 1 hour in the duration of ruptured
membranes. When membranes are ruptured longer
than 4 hours prior to delivery, the rate of HIV
transmission to the infant increases.
The role of vaginal delivery should be discussed
with the patient. Vaginal delivery may be performed
when the risk of mother-to-child transmission of HIV
is low, and these are for HIV positive women who:
1. take anti-HIV medications during pregnancy; and,
2. have a viral load less than 1,000 copies/mL near
the time of delivery and if ever membranes rupture,
the time elapsed should not be more than 4 hours to
delivery.
The following precautions should be observed
during labor to lessen the risk of MTCT: 1. fetal scalp
electrodes and scalp blood sampling for fetal pH
should be avoided because lacerations to fetal skin
can increase the risk of HIV transmission; 2. forceps
and vacuum extraction should also be avoided;
3. delaying amniotomy can reduce the risk of
transmission by about 50% if the woman gives birth
within four hours; 4. episiotomy should be reserved
for obstetric indications, like if delivery is significantly
delayed by an intact perineum (and is thereby
increasing fetal exposure to maternal fluids), to
prevent the risk of infection to the mother or
additional bleeding that could theoretically result in
an increased risk of maternal-to-child transmission.
Women who present to the labor-and-delivery
room in labor or with ruptured membranes can be
given oxytocin to augment labor when progress is
slow. Partographs, which record the progress of
labor and monitoring maternal and fetal status
during labor, should be routinely done, and referrals
should be made on the basis of this monitoring to
prevent prolonged labor. Family support should be
encouraged during labor, both for its psychosocial
benefits and because this support may reduce the need
for invasive procedures such as artificial rupture of
membranes and use of instruments during delivery.
Provide immediate postpartum care following
recommendations of Essential Newborn Care (ENC)
practices, with some modifications: 1. avoid vigorous
suctioning of the infant's mouth and pharynx right
after delivery as this may create trauma to the
mucus membranes, unless absolutely necessary;
2. delayed clamping of the umbilical cord IS NOT
recommended. (umbilical cord cutting and care
should be handled in a way that minimizes the
infant's and the health provider's exposure to
blood); 3. immediately bathe and thoroughly dry
the newborn infant in the first hours after delivery
to remove maternal blood and body fluids, and
to minimize heat loss; 4. skin-to-skin bonding
should be encouraged regardless of whether a
mother has chosen to breastfeed; 5. latchingon is done only if breastfeeding has been chosen;
6. advise the patient on breast care if she is not
breastfeeding.
According to the ACOG Committee Opinion
No. 234 (May 2000), patients should be counselled
that in the absence of antiretroviral therapy, the risk
of vertical transmission is approximately 25%. With
ZDV therapy, the risk is reduced to 5-8%. When care
includes both ZDV therapy and scheduled cesarean
delivery, the risk is approximately 2%. It is important
to discuss the option of scheduled cesarean delivery
as early as possible in every pregnant woman with
HIV infection. The risks which are greater for the
mother must be balanced with the benefits expected
for the neonate. Patient's autonomy should always
be respected in making decisions to perform a
cesarean delivery because the potential for maternal
morbidity is significant.
Breastfeeding
Where antepartum and intrapartum
transmission have been reduced by antiretroviral
prophylaxis, breastfeeding becomes the major source
of transmission in low-resource settings.35 Breastmilk transmission is an important cause of HIV
infection in children, accounting for up to half of
the global infections, 36 or more than 200,000
infections in children annually. Reductions in the
risk of MTCT which can be achieved by
antiretroviral strategies may be completely negated
by the effect of breastfeeding, but this risk needs to
be balanced against the risk of morbidity and
mortality caused by replacement feeding in lowresource settings. The safe prevention of
transmission through breastfeeding and the
improvement of HIV-free sur vival in exposed
children remains one of the most difficult issues in
PMTCT. Breastfeeding by an infected mother adds
an additional 5-20% risk for an overall transmission
rate of 20 - 45%.
The Philippine Obstetrical and Gynecological
Society (POGS) Task Force on HIV 201237 has the
following position statement regarding infant
feeding in the context of HIV: "HIV infection is listed
as one of the medical conditions where replacement
feeding may be permanently justified but recent
evidence has been surfacing that the risks of HIV
MTCT associated with breastfeeding may be
significantly reduced when antivirals are instituted.
Previous recommendations from 2006 expected
health workers to individually counsel all HIVinfected mothers about the various infant feeding
options, and it was then for the mothers to decide
between them.
To d ay, n a t i o n a l o r s u b n a t i o n a l h e a l t h
authorities must decide which option will be
recommended for their country - either Option
A: Where ARVs are available, mothers known to
be HIV-infected are recommended to breastfeed
until 12 months of age; or Option B: Total
avoidance of all breastfeeding.
In the Philippines, where breastfeeding is
staunchly supported and practiced in many
localities, and where formula feeding is similarly
widely acce pted, available and practiced in
situations where breastfeeding cannot be sustained,
and where health services for common infant
conditions related to diarrhea and other infections
are in place, but where HIV-AIDS related services
still need to be planned and consistently
implemented, and ARVs are still not widely
availab le, affordable, accessible, feasible or
sustained, then as of this time, Option B (avoidance
of breastfeeding), as is practiced in many of
our neighboring countries, is the strategy that may
give Filipino infants of HIV (+) mothers the greatest
chance of HIV-free survival.
ARV inter ventions to prevent postnatal
transmission of HIV make breastfeeding even more
advantageous for child development and survival.
Howeve r, the absence of ARVs should not
necessarily be a contraindication for HIV-infected
mothers to breastfeed where environmental and
social circumstances are not safe or supportive of
replacement feeding. It is important to prevent the
misconception that HIV-infected mothers should
only breastfeed if they or their infants are taking
ARVs.
It is expected that the principles and
recommendations and programmatic experiences
related to their implementation will be
reviewed again by international health authorities
in 2012 or 2013. The position of the Task Force
and review of forthcoming research and evidence,
as well as a review of available HIV-AIDS related
services in the Philippines, shall be revisited in
2015."
Positive Life: Our Success Story
Ours is not a perfect, happily, ever-after kind of
story. We had to learn from a terrible mistake from
the past that led to the success story we live to tell.
The husband and wife were oblivious to the fact
that they were infected with HIV, being asymptomatic
and all, hence no consultations. They carried their
first child to term, delivered via emergency low
segment cesarean section for prelabour rupture of
membranes for more than 24 hours. Post-operative
course of the mother and early postnatal life of the
exclusively breastfed infant was unremarkable. Until
the latter had repeated bouts of infections, to which
the child succumbed. The child's illness and death
paved the way for the parents' being diagnosed and
later receiving treatment, care and support for their
HIV infection. The couple were extensively and
comprehensively counseled regarding contraception,
and should it fail and pregnancy occurs, the chances
of the HIV infection being transmitted to the
newborn, just like what happened to their first child.
But the couple were determined on having a normal
and complete family despite the circumstances they
were in, hence, the present pregnancy.
There is no room for judgment in this situation:
an HIV+ woman desirous of pregnancy, and was
indeed determined to be so. This poses a challenge
to an obstetrician in preventing maternal to child
transmission because every child deserves the right
to be born free from HIV. The next logical step:
implement measures and evidence-based
interventions known to minimize, if not eliminate,
the chance of mother-to-child transmission of HIV.
PMTCT is only possible if the mother's status
is known. Hence, consenting to an HIV testing is
an important entry point of care. The mother, not
having a clue nor suspicion that she may be infected
with HIV, did not volunteer to have herself counseled
then tested, i.e., client-initiated counseling and testing.
The healthcare provider, on the hand, not being able
to elicit any risk factors (multiple sex partners, people
who inject drugs, history of sexually transmitted
infection including syphilis, husband or partner has
multiple sex partners/has history of sexually
transmitted infection/known to inject drugs) for
possibly acquiring HIV infection, or any other
sexually transmitted infections for that matter, did
not offer HIV counseling and testing, i.e., providerinitiated counseling and testing. Initial, yet crucial,
step was missed, hence MTCT was not prevented in
the first pregnancy. The routine offer of HIV testing
in pregnancy could make a significant difference to
the success of PMTCT programs, although there may
be other remaining challenges in these programs,
including difficulties in delivering results, and the
fear of recognition by hospital staff from the
community. With improved access to HIV testing,
many more women will enter pregnancy aware of
their HIV infection. The tertiary institution in which
the patient is accessing prenatal services happens to
be one of the DOH-accredited HIV treatment hubs,
hence equipped with the antiretroviral medicines,
CD4 machine, and facilities needed by the expectant
mother.
Now that we have an HIV+ pregnant woman in
our clinic, what do we do next? Whether this is
undertaken by the woman's obstetric care provider
or referred to a specalist is a matter of professional
choice. Do we start her on antiretrovirals? Since
our case is already on antiretrovirals, the next logical
question is: is it safe for her to continue taking
them throughout pregnancy? Our patient is on the
following regimen since May 2011: Lamivudine
(3TC) + Zidovudine (AZT/ZDV) and Nevirapine
(NVP). They have been reported to be safe for use
during pregnancy, hence the decision should be to
continue taking them, along with prenatal
supplements. One can see that nothing out of the
extra-ordinary is warranted in providing care for an
HIV+ pregnant woman: scheduled monthly prenatal
visits, fetal well-being surveillance, supplements and
most importanly, continue taking the antiretrovirals.
The decision on the route of delivery for our
case was a little difficult to reach, because she had a
previous cesarean section in her first pregnancy in
2009. Do we allow vaginal delivery after cesarean
section (VDACS) or do we do an elective scheduled
cesarean section? As we are utilizing evidence-based
interventions, such were applied in the decisionmaking. According to an ACOG Committee
Opinion 38 (Number 234, May 2000), "…Women
infected with HIV, whose viral loads are greater
than 1,000 copies per milliliter, should be
counseled regarding the potential benefit of scheduled
cesarean delivery to further reduce the risk of vertical
transmission of HIV beyond that achievable with
antiretroviral therapy alone." The POGS Taskforce
on HIV 37 agrees with this, further stating that:
"Cesarean delivery should be scheduled at completed
38 weeks age of gestation (as opposed to the 39 weeks
recommended for persons not infected with HIV,
because of the substantially higher risk of entering
labor or rupturing membranes after 38 weeks of
completed gestation." If our case was a primi,
discussion of the option of scheduled cesarean
delivery should begin as early as possible in
pregnancy with every pregnant woman with HIV
infection to give her an adequate opportunity to
consider the choice and plan for the procedure. The
risks, which are greater for the mother, must be
balanced with the benefits expected for the neonate.
Ultimately, the patient's autonomy must be
respected when making decision to perform a
cesarean delivery, because the potential for maternal
morbidity is significant.
Reductions in the risk of MTCT which can be
achieved by antiretroviral therapies may be
completely negated by the effect of breastfeeding, but
this risk needs to be balanced against the risk of
morbidity and mortality caused by replacement
feeding in low-resource settings like ours in the
Philippines. POGS took this into consideration,
hence their postion in recommending "total
avoidance of breastfeeding" in HIV+ women who
just gave birth, as was followed in this case.
Provision of infant prophylaxis with Nevirapine
for 6 weeks postnatal was the final intervention to
be done in this case. The infant received
antiretroviral prophylaxis within 6-12 hours of birth,
then extended until 6 weeks postnatal. On the 8th
week of life, we submitted specimen for PCR, and
the results were Negative.
The ingredients of a successful PMTCT are
simple and straightforward. Do your homework:
read updated guidelines on the issue at hand and
follow them; and, refer to institutions that have the
capability and facilities in attending and managing
such cases.
As the AIDS pandemic has evolved in complex
ways over the past three decades, so has the field of
HIV prevention. PMTCT reflects that evolution, and
reveal both the many accomplishments we have made
and the persistent challenges that confront us in
attempting to reduce or eliminate HIV transmission.
DISCUSSION
Elimination of vertically acquired HIV
infection should be every obstetrician's primary
goal. However, reported barriers to this goal remain,
including inadequate or late access to antenatal care,
late or non-identification of HIV infection in
pregnant women, sub-optimal application of
PMTCT interventions and poor uptake of and/or
adherence to PMTCT interventions. Although
innovations in rapid HIV testing and post-exposure
prophylaxis may prevent some transmissions in
women with no or limited antenatal care, this should
not be seen as an alternative to improving antenatal
care for women at risk of HIV infection, including
screening.
Early identification and treatment of all pregnant
women with HIV is the best way to prevent neonatal
disease and also may improve women's health. It is
important that early screening and treatment should
be implemented for every HIV pregnant positive
woman.
In the absence of any intervention a substantial
proportion of children born to women living with
HIV acquire the virus from their mothers during
pregnancy, labour, deliver y and breastfeeding.
Without intervention, the risk of transmission is
15%-30% in non-breastfeeding populations.
Breastfeeding by an infected mother
adds an
additional 5%-20% risk for an overall transmission
rate of 20%-45%.15 A combination of interventions
(including combination antiretroviral therapy,
cesarean section and avoidance of breastfeeding) is
associated with a vertical transmission rate of less
than 1%-2%.16
It is recommended to develop appropriate
strategies for perinatal and subsequent ART for use
in the developing world, particularly considering the
impact of perinatal ART for PMTCT on the
effectiveness of postnatal ART regimens.
The ingredients to a successful PMTCT: A
competent obstetrician, updated guidelines on
evidence based interventions, proper referral to
institutions, willingness of the mother to be screened
and treated and compliance to ART. It is a shared
effort between health care workers and HIV+
pregnant women and this is not simply achieved
overnight. A timely, consistent and holistic approach
is needed to integrate PMTCT services in the care
for HIV pregnant patients to strengthen maternal,
newborn and child health programmes. Through
these, we can achieve our goals in the prevention
of mother to child transmission.
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Anti-NMDAR Encephalitis in a Young Woman with an
Ovarian Teratoma
ANGELICA STEPHANIE K. M UNOZ, MD; M ARIA REGINA P. MANAHAN, MD, FPOGS
AND
MAE C. SYKI-YOUNG, MD, FPOGS
Department of Obstetrics and Gynecology, Makati Medical Center
A 32-year-old nulligravid being treated for urinary tract
infection presented with disorientation and difficulty in
sleeping. She had a normal initial physical examination
and her vital signs were stable. Neurologic examination
showed subtle signs of impairment in mental state. The
patient was admitted at a tertiary medical institution with
an impression of acute confusional state, transient global
amnesia and urinary tract infection. Twenty-four hours after
admission, the patient became restless and disoriented and
had delusions and hallucinations. Computer Tomography
(CT) scan and transrectal ultrasound showed a left ovarian
newgrowth, probably a dermoid cyst. With the
neuropsychiatric manifestations, ovarian teratoma and the
patient's disease presentation, anti-N-methyl-D-aspartate
receptor (Anti-NMDAR) encephalitis was highly suspected.
The patient's serum and cerebrospinal fluid sent for
immunomodulatory testing were positive for anti-NMDAR
antibodies, confirming the diagnosis. To the best of our
knowledge, this is the only recorded case of anti-NMDAR
encephalitis with ovarian teratoma in the Philippines. The
importance of the case lies in the timely diagnosis and the
classical manifestation of the disease that was seen during
the patient's stay at the hospital.
Key words: encephalitis, ovarian teratoma
A
nti-N-methyl-D-aspartate receptor (NMDAR)
encephalitis is an under-diagnosed, underrecognized syndrome. This is due to lack of specific
laboratory tests, radiologic findings and awareness
among practitioners.
The classic pr esentation of anti-NMDAR
encephalitis involves a confluence of psychiatric,
neurologic and autonomic symptoms, often with a
viral prodrome, and it is found to be associated with
teratomas. Psychosis, hallucinations, memory loss
and personality changes are the earliest symptoms;
for this reason psychiatry is often consulted.
Dyskinesias (especially orofacial), ataxia, seizures
and decreased level of consciousness may follow,
prompting referral to a neurologist. Days to weeks
later, autonomic instability may occur, manifesting
as cardiac arrhythmia, hypotension and
hypoventilation, requiring supportive care in the
intensive care unit (ICU).
This condition is potentially treatable once
diagnosis is made. First line management includes
immunotherapy, steroids and surgical removal of the
teratoma. Patients who had early tumor removal
showed better outcome with fewer neurologic
relapses.1,2
There has been an increase in the number of
reported cases of anti-NMDAR encephalitis, with
over 600 cases worldwide and many case series in
the neuroscience literature.1,3-5 However, there is a
lack of awareness of this condition among
obstetrician-gynecologists. Though the disease is
mainly neurologic, the role of the gynecologist in
the treatment cannot be discounted.
In the Philippines, the incidence of anti-NMDAR
encephalitis is unknown. There have been three cases
reported with the disease presenting as a neurologic
disorder without associated teratomas.6 This case is
one of the first fully documented cases of a classic
presentation of anti-NMDAR encephalitis in the
Philippines.
THE CASE
A previously healthy 32-year old female,
nulligravid was admitted at a tertiary medical center
Anti-NMDAR Encephalitis in a Young Woman with an Ovarian Teratoma / Munoz, et al.
in January 2013 due to behavioral changes. She had
a 6-day history of dysuria, vomiting, loss of appetite
and generalized body weakness, and was treated for
urinary tract infection on an outpatient basis.
On the day prior to admission, the patient was
withdrawn, disoriented and had difficulty sleeping,
prompting admission.
On assessment, the patient was fully conscious
with normal vital signs and physical examination.
Neurologic examination showed subtle signs of mild
cognitive impairment, seen when she was asked to
draw a clock, wherein some numbers were drawn
outside the circle, but still in chronological order
from 1 to 12. The rest of the neurologic examination
was normal. The patient was admitted with an
impression of acute confusional state, transient global
amnesia and urinary tract infection. A complete
blood count, blood culture and electroencephalogram (EEG) done were all normal. There
was pyuria (WBC 10/hpf) and bacteriuria (54/hpf)
on urinalysis. Treatment with oral Ciprofloxacin
500mg twice a day was initiated.
Twenty-four hours after admission, the patient
developed restlessness and psychotic manifestations
such as shouting spells, hallucinations and delusions.
At this time, further work-up was done. KUB
ultrasound showed urinary retention. Thyroid
ultrasound showed multi-nodular goiter, for which
the patient was referred to the Endocrinology service
and was started on levothyroxine. Urine drug testing
done
was
negative
for
phencyclidine,
tetrahydrocannabinol and amphetamine. Magnetic
Resonance Imaging (MRI/MRA) of the brain with
gadolinium contrast was unremarkable. The patient
was referred to the Nephrology and Psychiatry
services for co-management.
Over the next few days, the behavioral changes
persisted, consisting of inappropriate remarks,
hyperactivity and shouting spells. The patient had
poor sleep, with fair appetite and had frequent
episodes of agitation. Vital signs remained normal.
At this time, viral encephalitis was considered.
However, the cerebrospinal fluid (CSF) examination
was normal. Other microbiologic studies were also
unremarkable.
On the 5th hospital day, repeat EEG was done
with findings of excess theta-delta slowing seen
bilaterally, with rare epileptiform discharges on both
frontal areas. The patient was started on
Levetiracetam intravenously. Urine culture came out
on the 6th day, with growth of Extended Spectrum
Beta Lactamase-producing (ESBL) E. coli. The
patient was placed on contact precaution, and was
started on Ertapenem, which was eventually shifted
to Meropenem. She developed ileus with noted
increase in abdominal girth. Whole abdominal
ultrasound showed a suspicious left ovarian cyst that
was probably physiologic. Due to persistent anorexia,
a nasogastric tube (NGT) was inserted and osterized
feeding was started.
The patient gradually became catatonic with rigid
posturing of the upper extremities. She did not
respond when questioned or resist eye opening upon
ocular examination. She did not have spontaneous
eye opening. At this time, she had episodes of sinus
tachycardia (up to 120bpm). There also was persistent
abdominal distention despite the NGT. CT scan of
the whole abdomen done showed minimal ascites,
ileus, minimal bilateral pleural effusion and a 3.4cm
x 3.3cm left adnexal cyst with fat-stranding suggestive
of a teratoma. The patient was referred to a
gynecologist for further assessment of the left adnexal
cyst. Transrectal ultrasound done on day 5 of the
menstrual cycle showed the left ovary to be converted
to a unilocular cyst filled with anechoic fluid and
irregular dense echoes, measuring 5.46cm x 3.18cm
x 3.74cm, suggestive of a mature teratoma.
With the neuropsychiatric manifestations, the
presence of an ovarian teratoma and the patient's
disease presentation, Anti-NMDAR encephalitis was
highly suspected. Samples of CSF and serum were
sent to Spain for immunomodulatory testing on the
13th day of admission. Meanwhile, the patient was
started on intravenous Immunoglobulin at 400 mg/
kg/day and Methylprednisolone 1 gram IV infusion
every 12 hours, both given for 5 days. The patient
was scheduled for laparoscopic oophorectomy on the
14th hospital day, however, she had dysautonomia
with fever, desaturation to as low as 77% - 84% and
tachycardia of 120s bpm. The patient remained in a
catatonic state, and had no withdrawal to pain. She
was admitted to the Medical Intensive Care Unit due
to deterioration in cardio-respiratory status and the
need for assisted ventilation.
Subsequently, the patient was noted to have
orofacial dyskinesias and involuntary movements of
the hands and feet. Video EEG showed diffuse theta
- delta slowing, with three involuntary movements.
The patient remained hyperpyretic and tachycardic
with episodes of hypoventilation, necessitating
intubation.
Considering the nature of the disease,
oophorectomy was warranted and the patient
underwent laparoscopic left oophorectomy on the
16th hospital day (Figure 1). Histopathology
confirmed a mature teratoma with tissue representing
all three germ layers such as skin, sebaceous glands,
cartilage, glandular epithelium and immature
neuroepithelial elements (Figures 2 & 4). The reports
of the samples of serum and CSF sent for
immunomodulatory testing were available on the
18th day of admission and were positive for antiNMDAR antibodies.
Over the next days, the patient was still observed
to have dysautonomia and was started on triple
pressors with Dopamine, Dobutamine and
Nore pine phrine. Orofacial dyskinesias and
involuntary movements persisted. Repeat urine
culture was done, now with growth of Candida.
Fluconazole 400mg IV was started. The patient
developed pancytopenia probably secondary to an
infectious process, requiring multiple blood
transfusions. A tracheostomy tube was eventually
inserted due to prolonged mechanical ventilation.
On the 51st hospital day (35th post-operative
day), there was a decrease in the involuntar y
movements, and orofacial dyskinesias were no longer
noted. The patient was transferred to a regular
hospital room. Vital signs were now stable, and the
patient was weaned from assisted ventilation. On
Figure 1. Left ovarian teratoma.
Figure 3. Section from the ovarian teratoma showing keratinized
stratified squamous epithelium, sebaceous glands and adipocytes.
Figure 2. Section from ovarian teratoma showing immature
neuroepithelial elements.
Figure 4. Section from the ovarian teratoma showing chondrocytes,
gastric glands and adipocytes.
the 55th hospital day (39th post-operative day), she
was noted to have semi-purposeful movements, with
grimace and brisk withdrawal of all extremities on
pain stimulation.
There was continued improvement in the
neurologic status of the patient. Her eyes remained
closed, but she would now grimace on name-calling,
and was able to follow simple commands like raising
her arms, waving goodbye and counting from 1 to
10 by fingers. The patient was able to communicate
by giving a thumbs-up or thumbs-down sign when
asked. She was also now able to nod or shake her
head, and give her correct age and birthday through
hand gestures.
The patient opened her eyes on the 64th hospital
day (48th postoperative day). Physical and
occupational therapy was continued. The
tracheostomy tube was removed on the 73rd hospital
day. The patient was able to say her name and simple
words. She continued to improve with stable vital
signs and full wakefulness. She was able to follow
commands and had symmetric, spontaneous and
purposeful movement of all extremities, with mild
weakness. The rest of the hospital stay was focused
on therapy sessions. Neuropsychological testing was
done. This did not reveal impairment in orientation,
working memory, language and attention, but
showed mild impairment in motor and executive
functions. The patient was discharged stable on the
100th hospital day (84th post-operative day), able to
walk with the aid of a quadricane. She is able to do
basic activities of daily living such as feeding herself
and brushing her teeth.
DISCUSSION
This case highlights several important discussion
points. Perhaps the most important is that antiNMDAR ence phalitis is an under-recognized
syndrome.
Vitaliani, et al. in 2005 first reported the
association of paraneoplastic encephalitis, psychiatric
symptoms and hypoventilation in women found to
have ovarian teratomas.7 It was in 2007 when the
group of Dalmau, et al. discovered that this
paraneoplastic encephalitis was associated with
antibodies to the N-methyl-D-aspartate receptor.
Their study reported 12 women positive for NR1/
NR2 subunit heterodimers of the N-methyl-Daspartate receptor.8 Up to 59% of patients have been
found to have teratomas, most commonly an ovarian
teratoma.7,8
More recently, Dalmau, et al. described a case
series of this new category of autoimmune
encephalitis associated with antibodies to the
N-methyl-D-aspartate receptor. 1,8,9 This receptor,
predominantly expressed in the hippocampus and
forebrain, is also expressed by the nervous tissue
contained in teratomas. Anti-NMDAR encephalitis
has also been documented in patients with testicular
teratoma10 and small cell lung cancer.11
Anti-NMDAR encephalitic patients appear to
develop a somewhat predictable course of illness,
during which a number of symptoms are frequently
observed. Psychiatric symptoms manifest early in
the course of illness, and patients are likely to display
schizophrenia-like behaviors, such as psychosis and
hallucinations. This is consistent with the
observation that NMDAR antagonists can cause
healthy individuals to develop schizophrenia-like
symptoms. 12-14 Other neurologic symptoms also
develop in nearly every patient, including dystonias,
orofacial movements, particularly oral dyskinesias,
and choreoathetosis; none of these have epileptic
origins. However, seizures themselves, often of a
tonic-clonic nature, are common, with no correlative
epileptiform discharges that permitted localization
on EEG.1,5,15-20 Mental status changes, though seen
in some patients at presentation, consistently
developed later in the course of illness, with many
patients becoming non-responsive and non-verbal.
Autonomic instability is almost always observed.
Anti-NMDAR encephalitis most commonly
affects women (80%) with a median age of 23 years.1
However, cases have been reported in children and
adolescents, the youngest patient being 2 years old.21
It is also found that it is more likely to be found in
people of Asian or Pacific Islander descent.5 This is
surprising, given that teratomas, which are the most
common tumors associated with anti-NMDAR
encephalitis, demonstrate no racial bias, though
malignant ones are more common among Asians.15
However, the diagnosis ought to be considered in
the differential diagnoses of all patients presenting
with findings of "viral encephalitis"-regardless of age
or sex.
The case presented follows the classic multiple
stage clinical presentation of anti-NMDAR
encephalitis in literature. The patient is a 32 year
old female, of Chinese - Filipino descent. She had a
prodromal 6-day history of a flu-like illness. She
later developed psychiatric manifestations such as
insomnia, delusions and hallucinations. In most
reported cases, the patients were initially thought to
have a psychiatric disorder or a viral encephalitis.
Such was the concern in this patient. She was
initially started on antipsychotic and empiric antiviral
medications. However, microbiologic work-up came
back negative. The patient developed orofacial
dyskinesias, and eventually required mechanical
ventilation due to hypoventilation and
dysautonomia. It was only due to the finding of an
adnexal mass on whole abdominal CT scan that antiNMDAR encephalitis was highly suspected. Because
of this, samples of her serum and cerebrospinal fluid
were sent to Dr. Dalmau's laboratory in Spain for
anti-NMDAR immunomodulatory testing.
The diagnosis of anti-NMDAR encephalitis is
established by detection of NMDA r eceptor
antibodies in the CSF and sometimes in the serum.
To date, there have been no reported false positives
to the test. The antibodies are IgG antibodies21 and
the major antigens are the NR1/NR2B heteromers
of the NMDA receptor, though reactivity with other
NR1/NR2 heteromers is also seen. It is possible that
inhibition of NMDA receptors by the antibodies
causes a reduction in gamma-aminobutyric acid
release in presynaptic neurons, which leads to
disinhibition of postsynaptic glutamate release in the
prefrontal or subcortical structures, contributing to
the development of psychosis and dyskinesias.5
Results of conventional investigations including
examination of cerebrospinal fluid (CSF), brain
imaging and electroencephalogram (EEG) are nonspecific. However, lymphocytic pleocytosis,
oligoclonal banding, increased CSF protein,
hyperintensity on T2 magnetic resonance imaging
(MRI), decreased uptake in hippocampal structures
on functional MRI and epileptiform activity on EEG
have been described.1,22,23
In a case series of 100 patients, 25 had severe
neurological deficits or died. 1 The estimated
mortality is 4%.20 Treatment of anti-NMDA receptor
encephalitis is best achieved by combined tumor
removal and immunotherapy. This combination may
speed recovery and reduce the incidence of relapse.
Immunomodulator y agents including steroids,
intravenous immunoglobulin and plasma exchange
are the first line of therapy. Second line agents used
are cyclophosphamide, azathioprine and rituximab.
While waiting for confirmatory testing of the
serum and CSF, the patient was started on antiNMDAR-directed treatment. She was given
intravenous immunoglobulin and corticosteroids.
In patients with anti-NMDAR encephalitis and
an ovarian teratoma, surgical resection of the tumor
and subsequent immunotherapy are the treatment
modalities with the most significant effect on
outcome. 9 Previous studies showed that these
ovarian teratomas contain neural tissue which
express the NR1 and NR2 subunits.16 Indeed in the
present case, the ovarian teratoma had neural
elements. In Dalmau's case series, patients whose
tumor was identified and resected within four months
of the onset of symptoms had fewer severe deficits at
the conclusion of follow up than the rest of the
patients. Therefore, it would seem that early surgery
in these patients would be of utmost importance in
preventing worsening of neurologic status. In patients
with anti-NMDAR encephalitis, the presence of a
tumor (usually ovarian teratoma) is dependent on
age, sex and ethnicity, being more frequent above 18
years of age.20 The frequency of ovarian teratomas
was 56% in women more than 18 years old, but only
31% in women less than 18 years old.21 It remains a
subject of debate whether empiric salpingooophorectomy should be performed in patients
without clinical evidence of a tumor. Patients with
a tumor that may be surgically removed respond
faster and better than those without tumor. Overall,
75%-80% of patients, with or without tumor, have
substantial clinical recovery.20 In the case presented,
the patient underwent laparoscopic oophorectomy
for removal of the teratoma. The decision to perform
oophorectomy rather than cystectomy was based on
previous reported cases, as to ensure the complete
removal of the tumor.
Tachycardia observed in the patient may be
explained by sinus node dysfunction. Other cardiac
manifestations linked to anti-NMDAR encephalitis
are bradycardia and cardiac pauses.20
Gynecologists need to be aware of this condition
and our important contribution towards patient
recover y. Clinicians should be aware of this
distinctive presentation of encephalitis and severe
movement disorder, particularly in young women
with an "incidental" ovarian tumor, because timely
treatment can reduce long-term disability and
improve survival.
CONCLUSION
We have re ported a case of anti-NMDAR
encephalitis with an ovarian teratoma. To our
knowledge, this is the first diagnosed and the only
recorded case in the Philippines. Anti-NMDAR
encephalitis is a complex syndrome with
characteristic symptomatology. It is a recognizable,
diagnosable and treatable illness. Patients, in general,
will have good outcomes, particularly with aggressive
and prompt therapy.
Diagnosis and management necessitates
awareness and communication among various
medical professionals including inter nists,
neurologists, psychiatrists, intensivists, cardiologists,
infectious disease specialists, radiologists,
gynecologists and pathologists. Our observation
stresses the importance of a high index of suspicion
with prompt diagnosis and treatment, and emphasis
on supportive care.
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