Middle East Fertility Society Journal 23 (2018) 310–314

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Middle East Fertility Society Journal

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Original Article

Nitric oxide donors for treatment of isolated oligohydramnios:

A randomized controlled trial
Ahmed Walid Anwar Morad ⇑, Ayman Ahmed Abdelhamid
Department of Obstetrics and Gynecology, Faculty of Medicine; Banha University; Egypt1

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To evaluate the effect of vaginal isosorbide mononitrate (IMN) plus oral hydration compared
Received 7 February 2018 with oral hydration alone in improving the amniotic fluid index (AFI) and obstetric and perinatal out-
Revised 13 March 2018 comes in pregnancies complicated by isolated oligohydramnios (IO).
Accepted 3 April 2018
Design: A randomized controlled trial.
Available online 12 April 2018
Setting: Obstetrics and Gynecology Department, Benha University Hospital.
Materials and methods: The study included 210 singleton pregnancies (>28 gestational weeks) compli-
Keywords:
cated by IO. Participants were scheduled into two equal groups. The study group received vaginal isosor-
Nitric oxide donors
Isolated oligohydramnios
bide mononitrate plus oral hydration and the control group received oral hydration plusplacebo vaginal
Amniotic fluid index tablet. The amniotic fluid index was assessed at randomization, 24 h after treatment then weekly till
Oral hydration delivery.
Results: One-hundred participants completed the study in each group. A significant increase of AFI was
detected 24 h after treatment in both groups. This effect did not continue for more than one week unless
IMN was added. The mean AFI was significantly higher in IMN group at the final assessment. The IMN
group had significantly higher gestational age on the time of delivery, prolonged randomization delivery
interval, a lower cesarean delivery rate, and their neonates were less likely to have low birth weight, low
Apgar score, and admission to the neonatal intensive care unit. Neonatal deaths were reported in one case
of the study group and 5 in the control group, and the difference was not significant.
Conclusion: Nitric oxide donors may offer a promising choice in improving amniotic fluid volume and
pregnancy outcomes in cases of isolated oligohydramnios.
Ó 2018 Middle East Fertility Society. Production and hosting by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction The pathophysiological explanation of IO is not clearly under-

Oligohydramnios refers to an amniotic fluid index (AFI) less
than the fifth percentile expected for the gestational age, and AFI
5 cm is used as a cutoff for diagnosis [1]. It complicates 3–5% of
pregnancies, and in less than 50% of the cases, the diagnosis is con-
firmed without fetal-maternal etiologic risk factors and is so-called
‘‘isolated oligohydramnios” (IO) [2].
Promising evidence proposes that IO at a term is a weak marker
of perinatal outcome. In term pregnancies induction of labor would
be reasonable [3], however; conservative management with strict
follow-up should be a gold standard in a preterm IO [4].
Peer review under responsibility of Middle East Fertility Society.
⇑ Corresponding author at: Benha Faculty of Medicine, Al-Sadat Street, Benha,
Alkalubia, Egypt.
E-mail addresses: awalid217@fmed.bu.edu.eg (A.W. Anwar Morad), ayman.
shedid@fmed.bu.edu.eg (A.A. Abdelhamid).
1
http://fmed.bu.edu.eg/.
stood, however; it has been deemed a sign that reflects chronic
or late-onset impairment of placental function [5].
Several medical modalities have been attempted to treat oligo-
hydramnios. Although short-term improvement in AFI is satisfac-
tory, the long-term effect is questionable.
Isosorbide mononitrate (IMN) is an in vivo NO donor and is used
in several obstetric indications. Endothelial nitric oxide (eNO) syn-
thesized by nitric oxide synthases (NOS) from the precursor, L-
arginine, is the chief regulator of fetal- placental perfusion. Nitric
oxide induces vasodilatation and inhibits platelet aggregation.
These mechanisms improve uteroplacental perfusion as; they aug-
ment the volume and reduce the viscosity of blood in the fetoma-
ternal circulation [6,7].
The purpose of this work was to compare Isosorbide mononi-
trate (IMN) plus oral hydration therapy with oral hydration alone
in increasing the AFI in pregnancies complicated by isolated oligo-
hydramnios and to assess related pregnancy outcomes.

https://doi.org/10.1016/j.mefs.2018.04.002
1110-5690/Ó 2018 Middle East Fertility Society. Production and hosting by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A.W. Anwar Morad, A.A. Abdelhamid / Middle East Fertility Society Journal 23 (2018) 310–314
2. Materials and methods
This randomized controlled trial was approved by the Local
Ethics Committee of Obstetrics and Gynecology Department,
Benha University Hospital, and registered at Clinical Trials.gov:
NCT02712125. Participants were recruited among those attending
the antenatal care clinic of Benha University Hospital, from August
2013 to April 2017. Participants had a singleton pregnancy, at 28–
36 weeks gestation, with unexplained oligohydramnios (AFI < 5
cm). Pregnant women with oligohydramnios associated with
intrauterine growth restriction, fetal congenital anomalies, nonre-
assuring Non Stress Test (NST) or abnormal fetal Doppler indices,
rupture of membranes, active labor, preexisting chronic medical
problems (e.g., hypertension, severe hypotension, pregestational
diabetes, lung, heart, kidney disease, or closed angle glaucoma),
pregnant treated with vasodilator or antiprostaglandins, sensitive
or had contraindications to NO donors were all the exclusion crite-
ria. All participants gave written informed consent and had the
right to be withdrawn from the study at any time.
Participants were randomly allocated to one of two equal
groups by a computer-generated random number table. The study
group received oral hydration pulse 20 mg isosorbide mononitrate
(IMN) (Effox, Mina Pharma Co, Egypt; under license of Schwartz
Pharma, Germany) vaginally once daily and the control group
received oral hydration plus placebo vaginal tablet once daily.
Group allocation was concealed for both participant and doctor
by using numbered opaque sealed envelopes, opened in sequence
by a third person (study nurse). Participants were ordered to drink
2 L of water or fruit juice within two hours plus the daily water
requirement. Patients were advised to rest in the left lateral posi-
tion after oral hydration. Drug treatment continued until the AFI
Fig. 1. CONSORT flowchart of participants in the trial.
311
reached the normal value or until delivery. Hospital admission
was considered for at least 24 h, and participants were followed
for any maternal or fetal adverse outcomes. All participants had
ultrasonographic examination 24 h after receiving treatment to
reassess AFI. Women with at least 20% increase in AFI were dis-
charged. The amniotic fluid index was estimated using the stan-
dard technique described by Phelan et al. [8] using an abdominal
convex probe of 3.5 MHz (Voluson, 730 Pro V, GE Medical System),
by a single Ultrasonographer to avoid interobserver variability. The
mean of two AFI measures was recorded.
Participants continued antenatal vitamins. A single course of
intramuscular Dexamethasone in a total dose of 24 mg
(6 mg/12 h) was given to any pregnant less than 34 completed
weeks of gestation to promote fetal lung maturity.
Patient’s follow-up included, AFI, biophysical profile, and fetal
Doppler once weekly and NST twice weekly till delivery. Partici-
pants were readmitted to hospital with any maternal or fetal
adverse events. The primary outcome measure was the change in
AFI. Secondary outcomes were treatment onset to delivery interval,
gestational age at birth, indications, and mode of delivery and
neonatal outcome regards birth weight, stillbirth or neonatal
death, 5-min Apgar score and the need for neonatal admission
and the side-effects of isosorbide mononitrate if any.
2.1. Sample size calculation
A previous randomized study [9] showed a 32.3% increase in the
mean AFI following maternal oral hydration in cases of oligohy-
dramnios. We presumed a 20% increase in the AFI in combined
IMN and hydration group would be of clinical significance. Conse-
quently; each group required 95 participants to give the study, 80%
312 A.W. Anwar Morad, A.A. Abdelhamid / Middle East Fertility Society Journal 23 (2018) 310–314

Table 1 of AFI in both groups detected from 24 h up to one week after treat-
Basic characteristics of the participants in both groups. ment. The amniotic fluid volume (AFV) was higher in the IMN group
Variables IMN–Hydration Hydration-Only p at the final estimation (10.659 ± 0.61 compared with 5.333 ± 1.434
Group (n = 100) Group (n = 100) cm, P < 0.001). The incidence of participants continued undelivered
Maternal age (y) 24.18 ± 1.153 23.86 ± 0.975 0.67 was significantly higher for those assigned to IMN/Hydration from
Parity {n (%)} the 3rd week following treatment onward (P = 0.0015). Table 3
Primigravida 47 (47%) 51 (51%) 0.67 shows significantly better maternal, fetal and neonatal outcomes
Multigravida 53 (53%) 49 (49%)
BMI (kg/m2) 22.69 ± 0.563 23.11 ± 0.584 0.31
in the IMN–hydration group compared to hydration only group.
Gestational age at 31.92 ± 0.323 32.062 ± 0.285 0.51 Neonatal deaths were reported in one case of the study group and
randomization (week) 32 (28.1–35.8) 32 (28.5–35.6) 5 in the control group, and the difference was not significant. A
AFI at randomization 3.715 ± 0.109 3.626 ± 0.101 0.24 headache, palpitations, and hypotension, the commonest side
(Cm)
effects in the study, were significantly higher in IMN–hydration
BMI, body mass index; AFI, amniotic fluid index; kg/m2, kilogram per squared group compared to the hydration-only group. These were mild, tol-
meter; IMN, isosorbide mononitrate; n (%)}, number (percent). Data presented as, erable, and did not require a stoppage of therapy.
number (percent), median (minimum-maximum) or mean ± standard deviation.

power at a confidence interval of 95% using a two-tailed chi-square
test with a 0.05 significance level (type a error). The sample size
was increased to 105 participants in each group after assuming a
dropout incidence of 10%.
2.2. Statistical analysis
The collected data were statistically analyzed using SPSS ver-
sion 15.0. Qualitative data were expressed as numbers and per-
centages and the differences were tested using Fisher exact test
or the Chi-square test as appropriate. Quantitative data were
expressed as mean ± SD, and/or median (minimum-maximum).
Means were compared using the unpaired or paired Student’s t-
test as appropriate. Odds ratio with 95% confidence interval (CI)
were calculated for Qualitative data when possible. The statistical
significance was considered at a p-value level <0.05.
3. Results
Fig. 1 shows the flow of participants during the study. Table 1
shows no significant differences between the basic characteristics
of the study and control groups. Table 2 shows a significant increase
4. Discussion
The current study shows a significant increase of AFI following
maternal oral hydration in pregnancies complicated by IO. These
findings agree with, Gizzo et al. [4] in their systematic review
and meta-analysis, reporting the simplicity and effectiveness of
maternal oral hydration compared to intravenous hydration for
increasing amniotic fluid volume (AFV) in cases of IO, and superi-
ority of hypotonic solutions to isotonic solutions. Unfortunately;
these effects are short-lived, reported being less than 24 h [10]
up to one-week [11]. In the current study, the improvement of
AFI was not continued after the 1st week of hydration unless
IMN was added that was not fully understood. We suggest that this
time-limited effect of hydration only regimen was attributed to
increasing intramembranous absorption and fetal swallowing that
act as countercurrent mechanisms of increased amniotic fluid, start
to function shortly after improvement of AFI [12].
The favorable effect of IMN in AFI was suspected to be through
the increase in the fetal urine output, the main source of amniotic
fluid in the second half of pregnancy. Isosorbide mononitrate
induces vascular relaxation, improves microcirculation via inhibi-
tion of platelet aggregation. Consequently, it increases uteropla-
cental perfusion, fetal renal blood flow with subsequent increase
in fetal urine production. The reported improvement in the AFI

Table 2
The changes in the amniotic fluid index in both groups throughout the study.

AFI (Cm) IMN–Hydration Group p1 Hydration-Only Group p2 p3

At randomization No. continued (%) 100 (100%) 100 (100%) – –
AFI (Cm) 3.715 ± 0.109 3.626 ± 0.101 0.24
After 24 h No. continued (%) 100 (100%) 100 (100%) – –
AFI (Cm) 6.37 ± 0.152 < 0.001 6.22 ± 0.148 < 0.001 0.15
After 1 wk No. continued (%) 100 (100%) 100 (100%) – –
AFI(Cm) 7.39 ± 0.118 < 0.001 6.34 ± 0.097 0.17 <0.001
After 2 wk No. continued (%) 100 (100%) 98 (98%) 0.498
AFI (Cm) 8.105 ± 0.168 5.412 ± 0.164 <0.001
After 3 wk No. continued (%) 97 (97%) 83 (83%) 0.0015
AFI(Cm) 9.392 ± 0.341 4.755 ± 0.263 <0.001
After 4 wk No. continued (%) 90 (90%) 35 (35%) 0.0001
AFI (Cm) 9.684 ± 0.47 4.843 ± 0.37 <0.001
After 5 wk No. continued (%) 75 (75%) 9 (9%) 0.0001
AFI (Cm) 10.179 ± 0.485 4.444 ± 0.558 <0.001
After 6 wk No. continued (%) 41 (41%) 3 (3%) <0.0001
AFI (Cm) 10.659 ± 0.61 5.333 ± 1.434 <0.001
After 7 wk No. continued (%) 23 (23%) 0 –
AFI(Cm) 10.217 ± 0.824 0 –
After 8 wk No. continued (%) 0 0 –
AFI (Cm) 0 0 –

AFI: amniotic fluid index.

Data presented as number (%) or mean ± standard deviation.
p1 within IMN–hydration group.
p2 within hydration-only group.
p3 between both groups.
 A.W. Anwar Morad, A.A. Abdelhamid / Middle East Fertility Society Journal 23 (2018) 310–314 313

Table 3
Maternal, fetal, and neonatal outcomes of participants in both groups.

Variables IMN-Hydration Group (n = 100) Hydration-Only Group (n = 100) p OR (95% CI)

Maternal outcomes
Gestational age at delivery (wk) 36.76 ± 0.33 35.08 ± 0.33 <0.001
37 (34–40) 35 (31–38.5)
Randomization delivery interval (days) 39.99 ± 1.74 29.26 ± 1.28 <0.001
40 (17–54) 28 (11–42)
Meconium stained liquor 11 (11%) 39 (39%) 0.0001 0.2 (0.1–0.5)
Type of delivery
- Spontaneous 80 (80%) 47 (47%) 0.0001
- Indicated 20 (20%) 53 (53%)
Mode of delivery
- Normal vaginal delivery 60 (60%) 30 (30%) <0.001
- Instrumental 3 (3%) 3 (2%)
- Cesarean 37 (37%) 67 (67%)
Indications of cesarean delivery
- Repeated cesarean 25 (67.6%) 15 (22.4%) 0.00002
- Dysfunctional labor 2 (5.4%) 3 (4.5%)
- Abnormal CTG 4 (10.8%) 40 (59.7%)
- Abnormal fetal Doppler 2 (5.4%) 5 (7.5%)
- Others 4 (10.8%) 4 (5.9%)
Complication of therapy 60 (60%) 15 (15%) <0.0001 8.5 (4.3 to 16.7)
Perinatal outcomes
Birth weight (g) 2739.3 ± 70.52 2569.7 ± 87.61 0.003
5-min Apgar score < 7 11 (11%) 32 (32%) 0.0005 0.3 (0.1–0.6)
Admission to NICU 13 (13%) 36 (36%) 0.0003 0.3 (0.1–0.5)
Perinatal deaths
- IUFD 0 0 0.13 –
- Neonatal 1 (1%) 5 (5%) 0.19 (0.02–1.7)

CTG, cardiotocography; NICU, neonatal intensive care unit; IUFD, intrauterine fetal death; OR, odds ratio; CI, confidence interval. Data presented as number (%), median
(minimum-maximum) or mean ± standard deviation.

with IMN was in line with other studies evaluating other NO
agents; NO precursors (L-arginine) and NO mediator (Sildenafil
citrate) in the treatment of idiopathic oligohydramnios and
preeclampsia or intrauterine growth restriction associated oligo-
hydramnios [13,14].
The results of the current trial show better pregnancy outcomes
in cases treated with IMN plus hydration compared to hydration
alone. Antepartum variable deceleration was the commonest
abnormality in the hydration only group due to cord compression,
was the main indication of cesarean deliveries. However; vaginal
birth was significantly higher in IMN-hydration group that may
be attributed to successful induction of labor due to the cervical
ripening effect of IMN. The current study shows statistically signif-
icant low Apgar score, birth weight and statistically significant
higher admission to neonatal intensive care units (NICU) with
increase period of NICU stay in hydration only group compared
to IMN- hydration group. These findings may be attributed to a
higher rate of preterm deliveries in the hydration only group sec-
ondary to the waning of the transient improvement of AFI. These
findings agree with Sherm et al. [15] found that the rates of labor
induction, cesarean deliveries, and short-term neonatal morbidity
are significantly higher in term pregnancies complicated by IO.
Rossi and Prefumo, [3] reported a higher risk of obstetric interven-
tion in term and post-term pregnancies complicated by IO, how-
ever; perinatal outcomes are comparable to those of pregnancies
with normal AFV. The promising effect of IMN- oral hydration on
maternal and perinatal outcomes agrees with Maher et al. [14]
reported promising results when comparing Sildenafil - hydration
therapy with hydration alone in the third trimester IO. The discrep-
ancy between our results and what was reported by other authors
may be attributed to; (1) heterogeneity in patient characteristics,
diagnostic criteria, hydration strategies, and outcome measures,
(2) our patients included a group of pregnancies remote from the
term, and (3) oligohydramnios in such low-risk pregnancies was
presumed to be a marker of delayed onset suboptimal placental
perfusion, therefore; perinatal outcomes improved markedly by
adding IMN.
Isosorbide Mononitrate is classified as FDA pregnancy risk cat-
egory B as no fetal toxic effects have been reported in experimental
animal studies, however; human studies are inadequate. Therefore,
its use during a pregnancy should be limited to proper indications
[16]. Headache, palpitations, and hypotension are the commonest
side effects reported with the IMN use in the current study. These
side effects are mild and did not need a stoppage of treatment.
Bullarbo et al. [17] agree, however; Hatanaka et al. [18] disagree
with these findings regarding their studies evaluating IMN use
for cervical ripening at the term. The mild severity of IMN side-
effects in the current study may be attributed to the vaginal route
of administration whereby; the drug is a subject to the first uterine
pass effect, the uterine concentration of the drug is high, however;
the serum level is low with delay reaching to the peak concentra-
tion [19]. The effect of the drug is related to the local uterine con-
centration, however; the side effects are related to serum level.
The strengths of the current study include; (1) randomized, (2)
double-blinded, (3) placebo was used in the control group, (4) the
first study to use NO donors vaginally as a conservative therapy for
IO, (5) maternal rest in the left lateral position was standardized
during hydration, therefore; the improving effect of this factor in
AFV was equalized in all patients, and (6) a wide range of gesta-
tional ages (more than 28 weeks) were studied with long-term fol-
low-up and assessment of AFI improvement and pregnancy
outcome. The limitations of the current study include; (1) response
to therapy was evaluated by a subjective method (AFI) rather than
the estimation of definite AFV, (2) treatment compliance was not
evaluated, and (3) no postnatal assessment of the newborn for
anomalies as oligohydramnios may seem to be unexplained at
diagnosis, however; it may be a warning of an anomaly not
revealed until delivery.
314 A.W. Anwar Morad, A.A. Abdelhamid / Middle East Fertility Society Journal 23 (2018) 310–314
5. Conclusion
Isosorbide Mononitrate may offer a promising choice in improv-
ing amniotic fluid volume and pregnancy outcomes in pregnancies
complicated by isolated oligohydramnios.
Conflict of interest
The authors declare that they have no conflict of interest.
Author contributions
Ahmed Walid Anwar Morad; Contributed to conception and
design of the study, ultrasound examination, data collection and
statistical analysis, interpretation of data, and manuscript drafting
and revision. Ayman Ahmed Abdelhamid Shedid; contributed to
the clinical work and was responsible for overall supervision. All
authors read and approved the final manuscript.
Acknowledgment
The authors thank all pregnant women who agreed to join in
this study, the medical staff at the Obstetrics and Gynecology
Department, Benha University, Egypt Hospital for their help in
managing the cases throughout the hospital treatment till their
discharge. The authors also, thank Dr. Sherief Altaher (Community
and Public-Health Department, Benha Faculty of Medicine) for per-
forming the statistics of this study.
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