Titrated low-dose vaginal and/or oral misoprostol to induce labour for prelabour membrane rupture: a randomised trial.

OBJECTIVE: To evaluate the clinical effectiveness and safety of titrated low-dose misoprostol for induction of labour (IOL) in the presence of prelabour rupture of membranes (PROM). DESIGN: Randomised controlled trial. SETTING: Maternity units in the UK (9) and Egypt (1). POPULATION: Women >34 weeks of gestation with PROM, singleton viable fetus and no previous caesarean section. METHODS: Subjects randomised to IOL with a titrated low-dose misoprostol regimen (oral except if unfavourable cervix, where initial dose vaginal) or a standard induction method, namely vaginal dinoprostone followed by intravenous oxytocin if the cervix was unfavourable or intravenous oxytocin alone if the cervix was favourable. MAIN OUTCOME MEASURES: Primary outcome measures were caesarean section and failure to achieve vaginal delivery within 24 hours. Analysis was by intention to treat. RESULTS: The trial did not achieve the planned sample size of 1890 due to failure in obtaining external funding. Seven hundred and fifty-eight women were randomised (375 misoprostol and 383 standard). There were less caesarean section (14 versus 18%, relative risk [RR] 0.79; 95% CI 0.57-1.09) and less women who failed to achieve vaginal delivery within 24 hours in the misoprostol group (24 versus 31%, RR 0.79; 95% CI 0.63-1.00), but the differences were not statistically significant. Subgroup analysis showed that with unfavourable cervix, misoprostol may be more effective than vaginal dinoprostone. There was no difference in hyperstimulation syndrome. There were more maternal adverse effects with misoprostol, but no significant differences in maternal and neonatal complications. CONCLUSIONS: Titrated low-dose misoprostol may be a reasonable alternative for IOL in the presence of PROM, particularly in women with an unfavourable cervix. Safety and rare serious adverse events could not be evaluated in a trial of this size.

A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles.

A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative vesicular trophoblast and no fetal development. Most CHM are sporadic and androgenetic, but recurrent HM have biparental inheritance (BiHM) with disrupted DNA methylation at differentially methylated regions (DMRs) of imprinted loci. Some women with recurrent BiHM have mutations in the NLRP7 gene on chromosome 19q13.42. Using bisulfite genomic sequencing at eight imprinted DMRs on DNA from two BiHMs, we found a pattern of failure to acquire or maintain DNA methylation at DMRs (PEG3, SNRPN, KCNQ1OT1, GNAS exon 1A) that normally acquire CpG methylation during oogenesis, but not at H19, which acquires CpG methylation during spermatogenesis. Secondary imprints at the GNAS locus showed variable abnormal patterns with both gain and loss of CpG methylation. We found novel missense and splice-site mutations in NLRP7 in women with non-familial recurrent BiHM. We identified and characterized a homozygous intragenic tandem duplication including exons 2 through 5 of NLRP7 that results in a predicted truncated protein in affected women of three unrelated Egyptian kindreds, suggesting a founder effect. Our findings firmly establish that NLRP7 mutations are a major cause of BiHM and confirm presence of a complex pattern of imprinting abnormalities in BiHM tissues.

Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring.

Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.

Recurrent pregnancy loss due to familial and non-familial habitual molar pregnancy.

OBJECTIVES: To present a series of women with recurrent molar pregnancies, including rare familial cases, and discuss etiology and treatment options. METHODS: We performed a detailed clinical evaluation and pedigree analysis of five Egyptian women with recurrent pregnancy loss due to molar pregnancy. RESULTS: The women had a history of four to nine consecutive hydatidiform moles but of no viable pregnancies. Two of the women had molar pregnancies with different husbands who themselves had viable offspring from previous wives; and three of them, who belonged to a family with extensive intermarriage, had a pedigree consistent with an autosomal recessive maternal-effect mutation. CONCLUSIONS: Recurrent pregnancy loss due to habitual molar pregnancy is uncommon and familial cases are extremely rare. The etiology of this disorder is not well understood but likely results from a maternal-effect mutation. Management options are limited, especially for couples who desire to have their own genetic offspring.

Second-trimester pregnancy termination: comparison of three different methods.

The object of this study was to compare intravaginal misoprostol and dinoprostone (prostaglandin E2) for second-trimester pregnancy termination, and to examine the role of the nitric oxide donor, glyceryl trinitrate, as a possible alternative to prostaglandins to induce cervical ripening in second-trimester pregnancy termination. This was a randomised clinical trial. The trial involved pregnant women between 13 and 28 weeks' gestation admitted with clear medical or obstetric indications for pregnancy termination, and was carried out in the department of obstetrics and gynecology, Assiut University Hospital, Egypt. Patients were classified into Group A, where pregnancy termination was induced by vaginal misoprostol 100 micrograms every 4 hours with a maximum dose of 500 micrograms; Group B, where induction was by vaginal dinoprostone 6 mg every 6 hours with a maximum dose of 24 mg; and Group C, where induction involved vaginal glyceryl trinitrate 500 micrograms every 6 hours with a maximum dose of 2.5 mg. Twenty-four hours after the start of induction, the rate of complete abortion in the three groups was 100%, 66.67% and 0%, respectively. The rate of complete abortion was 100% in the nitric oxide (glyceryl trinitrate)-induced group after introducing a complementary procedure. The induction-abortion interval was significantly shorter, the number of doses needed was less and the maximum Bishop score reached was greater with misoprostol than with dinoprostone. A higher rate of side effects occurred with the misoprostol-induced group (74%) compared with the other two groups (46.6% and 0%). Misoprostol is a cheap, effective drug for second-trimester pregnancy termination with short induction abortion intervals but a higher rate of side effects. Prostin E2 is also effective in termination of second-trimester pregnancy but is expensive and may require high doses to be administered. Glyceryl trinitrate is an effective drug for cervical ripening (softening) but it has no role in the stimulation of uterine contractions.

Uterine rupture in second trimester abortion in a grand multiparous woman. A complication of misoprostol and oxytocin.

Rupture of unscarred uterus during the second trimester is rare. There have been only 32 cases reported in the literature since 1968. A case of ruptured uterus in a grand multiparous woman is presented. To our knowledge, this might be the first reported case in the English literature of uterine rupture during second trimester termination of pregnancy using a prostaglandin E1 analogue (Misoprostol) and oxytocin.