Chinese herbal medicine in treatment of polyhydramnios:a meta-analysis and systematic review.

OBJECTIVE: To compare the efficacy of Chinese herbal medicine (therapy A) or Chinese herbal medicine plus indomethacin (therapy B) with that of indomethacin alone (therapy C) in treating polyhydramnios. METHODS: Literatures published up to April 2012 were retrieved from PubMed, Embase and Cochrane library, Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific and Technological Periodical Database (VIP), Wangfang, and Traditional Chinese Medicine online. Two researchers collected data independently. The assessment of methodological quality was based on Cochrane handbook and the materials were analyzed with software RevMan 5.1.2. The outcome measure index was relative risk or difference of mean value (95% confidence interval). The following outcomes were evaluated (1) general clinical improvement rate; (2) maximum vertical pocket depth; (3) amniotic fluid index (AFI) value; (4) rate of fetal ductus arteriosus constriction; (5) incidence of adverse events. RESULTS: Based on the search strategy, 5 trails involving 1017 patients were finally included. Compared with therapy C, therapy A decreased the rate of fetal ductus arteriosus constriction (P<0.01). Therapy B was more effective than therapy C in general clinical improvement and decrease of AFI for polyhydramnios (P<0.01). No serious adverse events were reported in therapy A and therapy B. CONCLUSIONS: Compared with therapy C, therapy A and therapy B may appear to be more effective for polyhydramnios. However, the exact effect needs to be confirmed with well-designed large-scale clinical trials.

Indomethacin in pregnancy: applications and safety.

Preterm labor (PTL) is a major cause of neonatal morbidity and mortality worldwide. Among the available tocolytics, indomethacin, a prostaglandin synthetase inhibitor, has been in use since the 1970s. Recent studies have suggested that prostaglandin synthetase inhibitors are superior to other tocolytics in delaying delivery for 48 hours and 7 days. However, increased neonatal complications including oligohydramnios, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the patent ductus arteriosus have been reported with the use of indomethacin. Indomethacin has been also used in women with short cervices as well as in those with idiopathic polyhydramnios. This article describes the mechanism of action of indomethacin and its clinical applications as a tocolytic agent in women with PTL and cerclage and its use in the context of polyhydramnios. The fetal and neonatal side effects of this drug are also summarized and guidelines for its use are proposed.

Prenatal pharmacotherapy for fetal anomalies: a 2011 update.

Fetal therapy can be defined as any prenatal treatment administered to the mother with the primary indication to improve perinatal or long-term outcomes for the fetus or newborn. This review provides an update of the pharmacological therapies that are solely directed at the fetus with anomalies and outlines a future transcriptomic approach. Fetal anomalies targeted with prenatal pharmacotherapy are a heterogeneous group of structural, endocrine, and metabolic conditions, including congenital cystic adenomatoid malformation (CCAM), congenital adrenal hyperplasia, congenital heart block, fetal tachyarrhythmias, inborn errors of metabolism, fetal thyroid disorders, and polyhydramnios. To date, the majority of pharmacotherapies for fetal anomalies have been evaluated only in retrospective, uncontrolled studies. The way forward will be with an evidence-based approach to prenatal pharmacological interventions.

Neuroblastoma presented with polyhydramniosis.

Neuroblastoma is the most common extracranial solid tumor in pediatric age group. Clinical presentation of neuroblastoma is mostly related to origin of the tumor, extent of disease, and the presence of paraneoplastic syndromes. Here the authors report a neonate with neuroblastoma with an atypical presentation, diagnosed with postnatal abdominal ultrasonography performed due to polyhydramniosis in her mother during pregnancy.

Pregnancy in a patient with congenital analbuminaemia.

Congenital analbuminaemia is a rare autosomal recessive disorder that is characterised by a severe reduction or total absence of serum albumin. This condition has implications for therapeutics as a large proportion of commonly used drugs are plasma protein bound where albumin is the primary component of plasma protein. This is the first case report of pregnancy in a patient with congenital analbuminaemia in the medical literature. In the absence of drug dosage guidelines for patients with congenital analbuminaemia, a list of drugs which may be required for this patient during pregnancy, delivery and/or emergency situations were compiled by a multidisciplinary team. Our patient suffered from polyhydramnios during her pregnancy which was successfully managed with albumin transfusions and had a normal vaginal delivery with no complications in the intrapartum or postpartum period. The management and unique challenges of pregnancy in a patient with congenital analbuminaemia are discussed.

Renal dysgenesis in a monozygotic twin: association with in utero exposure to indomethacin.

We report oligohydramnios and renal dysgenesis in one of identical twins, which might have resulted from in utero exposure to early, prolonged high-dose indomethacin. The proposita was the second of twin girls born at 36 weeks of gestation. Pregnancy was complicated initially by polyhydramnios in both amniotic sacs and premature uterine contractions. After administration of indomethacin and terbutaline from 16 to 30 weeks' gestation, serial prenatal ultrasound examinations ultimately showed oligohydramnios in twin B and resolution of polyhydramnios in twin A. On day 5 twin B developed hematuria, hypertension, renal failure, hyponatremia, hyperkalemia, metabolic acidosis, sodium wasting and severe, transient inability to excrete potassium. Renal sonography showed enlarged, hyperechoic kidneys with almost no corticomedullary differentiation. Renal biopsy revealed immature glomeruli, dilated Bowman's spaces, dilated tubules, and interstitial fibrosis. The liver was histologically normal. Indomethacin may induce oligohydramnios and transient renal insufficiency in humans and renal dysgenesis in fetal monkeys; it might have induced the abnormalities in this patient.

TRAP sequence--successful outcome with indomethacin treatment.

A case of twin reversed arterial perfusion (TRAP) sequence (acardiac twin) complicated by hydramnios was managed by maternal administration of indomethacin. Successful outcome was achieved after 8.5 weeks of therapy with delivery of a normal live-born infant at 34 weeks.

Acute polyhydramnios recurrent in successive pregnancies. Management with multiple amniocenteses.

A patient with acute polyhydramnios in two successive pregnancies is described. In both this case and the only previously reported similar one, management by frequent transabdominal removal of relatively small amniotic fluid volumes was associated with prolongation of pregnancy and a living infant, suggesting that multiple amniocenteses can improve the otherwise hopeless prognosis associated with acute polyhydramnois.

Uterine blood flow velocity waveforms in pregnant women during indomethacin therapy.

Continuous-wave Doppler ultrasound was used to assess blood flow velocities and determine the pulsatility index of the uterine arteries in ten pregnant women at 23-33 weeks' gestation during indomethacin therapy for preterm labor or polyhydramnios. There was no statistically significant difference in the pulsatility index of the uterine arteries during maternal indomethacin treatment (mean +/- SD 0.85 +/- 0.29) compared with pre-treatment values (0.85 +/- 0.23). Although studies in animals have reported that indomethacin increases uterine impedance to flow, it appears that it does not affect the uterine impedance in humans.

Indomethacin therapy in the treatment of symptomatic polyhydramnios.

Eight gravidas with symptomatic polyhydramnios were managed with maternal indomethacin therapy. The mean gestational age at presentation was 28.6 +/- 3.5 weeks. Only patients requiring serial amniotic fluid decompressions for rapid amniotic fluid reaccumulation were enrolled in the study. An initial amniotic fluid decompression was performed and, when a second decompression was required, indomethacin was initiated. Amniotic fluid volume was measured with a para-amino hippuric acid dilution technique before and during indomethacin therapy. Fetal urine output, studied by serial bladder dimension ultrasonography, declined significantly during indomethacin therapy (P less than .05). Only one patient required further amniotic fluid decompression while on indomethacin. The mean (+/- SD) amniotic fluid volume was 1529 +/- 1070 mL after the initial amniocentesis, and was 2355 +/- 820 mL at the second amniocentesis just before indomethacin therapy. The mean amniotic fluid volume during indomethacin therapy was 1608 +/- 914 mL. We recommend initial amniotic fluid decompression followed by indomethacin therapy for the management of symptomatic polyhydramnios as an alternative to serial amniotic fluid decompressions.

Doppler assessment of the renal blood flow velocity waveform during indomethacin therapy for preterm labor and polyhydramnios.

To investigate the effects of indomethacin on the human fetal renal blood flow velocity waveform, 17 fetuses whose mothers were treated for preterm labor (N = 8) or polyhydramnios (N = 9) were studied. There were five growth-retarded fetuses (all in the group with polyhydramnios), 11 normal fetuses, and one fetus with red-cell alloimmunization. The indomethacin dose in all patients was 25 mg orally every 6 hours. The gestational age of the fetuses studied varied between 24-35 weeks (mean +/- SD 29.6 +/- 2.8). The fetal renal artery was studied at its origin from the aorta before and during the first 24 hours of indomethacin therapy. Seven fetuses manifested ductal constriction. Three fetuses also manifested tricuspid regurgitation. All ductal constrictions and the tricuspid regurgitations resolved in utero after discontinuation of indomethacin. There were no significant differences in the pulsatility index values of the renal artery before and during indomethacin therapy. These results suggest that there is no change in fetal renovascular parameters detectable with pulsatility index measurements during the first 24 hours of maternal indomethacin therapy.

The effects of indomethacin administration during pregnancy on women's and newborns' T-suppressor lymphocyte activity and on HLA class II expression by newborns' leukocytes.

It has been previously shown that T lymphocytes from human newborns and pregnant women exert a suppressive activity when assayed on the PWM-induced B cell maturation. The mechanisms of the suppression have remained entirely unknown. Prostaglandin E2, known to trigger T-cell mediated suppressive activity, may be involved. We took advantage of the treatment of pregnant women with indomethacin, because of premature labor or hydramnios, to investigate the role of prostaglandins in the activation of T suppressor (TS) activity. Administration of indomethacin (250 mg/day for 1-7 weeks, then 150 mg/day for 3-12 weeks) during the third trimester of pregnancy, abrogated the TS activity in the nine women and the three newborns tested. Abrogation of TS activity by indomethacin therapy led to normal PWM-induced B cell maturation in pregnant women but not in newborns. Moreover, the low expression of HLA class II antigens observed on normal newborn B lymphocytes and monocytes was corrected in newborns from indomethacin-treated mothers. Our results strongly suggest that prostaglandins may play a role in induction of TS activity observed in normal pregnant women and newborns and in the decreased expression of HLA class II antigens on newborns' leucocytes. Both phenomena could play a role in immunological interactions between mother and fetus.

Administration of prostaglandin inhibitors to the mother; the potential risk to the fetus and neonate with duct-dependent circulation.

Two infants were delivered by urgent Caesarean section at 34 weeks because of fetal distress. One rapidly developed severe cardiac failure and the other marked cyanosis. Their mothers had been prescribed indomethacin and mefenamic acid (Ponstan) to treat premature onset of labour and chronic polyhydramnios, respectively. Both infants had duct-dependent circulations, their cross-sectional echocardiography showing only a small (1-2 mm diameter) patent ductus arteriosus. The early onset and severity of their symptoms suggested that the maternal intake of prostaglandin inhibitors may have deleteriously led to early closure of their ducts, essential in duct-dependent circulations. Although such occurrences are rare, fetal cross-sectional echocardiography should be performed prior to administration of prostaglandin inhibitors during pregnancy.

Renal tubular dysgenesis-like lesions and hypocalvaria. Report of two cases involving indomethacin.

We describe a case of twins with twin-to-twin transfusion syndrome (TTS) who were found to have renal tubular dysgenesis (TRD)-like lesions and hypocalvaria attributed to indomethacin treatment of the mother for acute polyhydramnios. History of pregnancy, postnatal clinical course, pathological findings of the kidneys, and the skulls are presented and discussed. These findings include incompletely differentiated proximal tubules in the kidneys and hypoplastic calvaria in both twins. The renal tubular lesions were more marked in the donor than in the transfused twin, probably due to the greater degree of ischemia in that twin. This seems to be in favor of a vascular etiology of the renal defects. However, the fact that similar renal lesions and hypocalvaria were also present in the transfused twin seems to indicate that indomethacin played a role in their onset. This so-called kidney-skull connection has never been reported in conjunction with indomethacin therapy.

Treatment of polyhydramnios with indomethacin.

Polyhydramnios detected in a pregnancy should always be investigated thoroughly. We believe chromosomal abnormalities should be excluded, but that determination need not delay therapy. Indomethacin has been shown to reduce amniotic fluid volume in certain cases, but a strict monitoring schedule should be followed whenever it is administered. At our institution, we are investigating the effect on the fetus of newer, more selective prostaglandin synthetase inhibitors that should have beneficial effects similar to indomethacin, but be devoid of its unwanted side effects.

Efficacy and safety of indomethacin therapy for polyhydramnios.

The maternal and perinatal outcome of seven gravidas receiving 2.2-2.5 mg/kg per day of indomethacin for polyhydramnios are reported. Such therapy was started between 26 and 33 weeks of gestational age (mean, 30.4 weeks) and lasted for 20.1 days (range, 2-37 days). Median of amniotic fluid index ranged from 47 at the start of therapy (range, 32-53) to 15 (range, 2-50) when indomethacin was ended. Interval between the end of the therapy and the delivery ranged from 0 to 45 days (mean, 15 days). On average, pregnancies were prolonged by 5.1 weeks (range, 2-8 weeks). The newborn weight was 2678 g on average (range, 620-3700 g). Oligohydramnios was seen in two instances; one patient developed constriction of the fetal ductus arteriosus, which returned to normality after indomethacin suppression; one newborn in which other causes of neonatal bleeding could be excluded, developed a disseminated intravascular coagulation and died 15 h after birth. Finally, one mother presented an acute renal failure immediately after indomethacin administration; this patient completely recovered after indomethacin withdrawal. Thus, the benefit of pregnancy prolongation should be balanced against the increased risks for the newborn, mainly fetal ductus arteriosus constriction and possible bleeding disorders. A causal relationship of indomethacin administration to the latter complication warrants further investigation.

Treatment of symptomatic polyhydramnios with indomethacin.

Polyhydramnios carries a poor fetal prognosis with an expected neonatal death rate of nearly 30%. Approximately one-fourth of this perinatal mortality is a result of the effects of prematurity. The poor outcome with usual management of polyhydramnios led us to introduce the therapeutic use of prostaglandin synthetase inhibitors so as to decrease amniotic fluid volume and to prevent premature labor. Twenty-two women (20 singleton and two twin pregnancies) were included in a retrospective study from 1983 to 1992. Indomethacin was given at a dose of 3 mg/kg/day. Treatment was started at 28.2 +/- 3.8 weeks of amenorrhea and discontinued after 35 weeks. We observed a significant effect of indomethacin on amniotic fluid volume and avoided severe preterm delivery in all patients. Mean gestational age at birth was 37.5 +/- 1.6 weeks of amenorrhea (range 35.5-39 weeks). We did not observe any maternal or neonatal side effects of indomethacin therapy. However, we reported three neonatal deaths out of 24 infants: two related to undiagnosed fetal anomalies (one Nager syndrome and one cerebral malformation) and one related to umbilical cord entanglement in a monoamniotic twin pregnancy. Since our first report, several open studies supporting our data have been published. However, although indomethacin appears to be effective in the treatment of polyhydramnios, our goal is to analyze efficacy and side effects, so as to define conditions of clinical use.

Effect of indomethacin on the fetal ductus arteriosus during treatment of symptomatic polyhydramnios.

Ten pregnancies with 13 fetuses complicated by symptomatic polyhydramnios were treated with indomethacin. A baseline fetal echocardiogram was obtained before therapy, repeated 24 hours after the initiation of indomethacin and then performed weekly provided that the ductus arteriosus remained patent. The mean duration of indomethacin therapy was 28.3 +/- 18.9 days. The starting dose in all patients was 25 mg orally every six hours. The ductus arteriosus was noted to constrict in four patients, with the development of tricuspid regurgitation in one. One of the constrictions occurred after 23 days of therapy. In one patient with constriction a reduction of the indomethacin dosage was not associated with constriction, while in the other three, constriction was still evident at a reduced dosage. All constrictions and the tricuspid regurgitation resolved in utero within 24 hours after discontinuation of the indomethacin. We recommend careful monitoring of the fetal ductus arteriosus when treating symptomatic polyhydramnios with indomethacin.

Indomethacin therapy and chronic hemodialysis during pregnancy. A case report.

Numerous complications can prevent the successful outcome of a pregnancy conceived while a woman is undergoing chronic hemodialysis. Among the difficulties encountered, premature labor and polyhydramnios are common. In such a patient indomethacin was used to treat those problems, with the subsequent delivery of a healthy infant.

[Use of indomethacin in the therapy of poly-hydramnios. Description and comments on a case]. / Impiego dell'indometacina nella terapia del polidramnios. Descrizione e considerazioni su due casi clinici.

The Authors report their experience of two pregnancies complicated by polyhydramnios, treated with indomethacin (100 mg/day for 10 and 7 days respectively). The outcome of both pregnancies was foetal intrauterine death. The absence of foetal anomalies incompatible with life and the presence of tissue lesions by asphyxia led the Authors to think that indomethacin might have had a determinant role in the foetal death. This study suggests that the use of indomethacin in polyhydramnios is questionable.