Background: Maternal effect mutations in the components of the subcortical maternal complex (SCMC) of the human oocyte can cause early embryonic failure, gestational abnormalities and recurrent pregnancy loss. Enigmatically, they are also associated with DNA methylation abnormalities at imprinted genes in conceptuses: in the devastating gestational abnormality biparental complete hydatidiform mole (BiCHM) or in multi-locus imprinting disease (MLID). However, the developmental timing, genomic extent and mechanistic basis of these imprinting defects are unknown. The rarity of these disorders and the possibility that methylation defects originate in oocytes have made these questions very challenging to address. Methods: Single-cell bisulphite sequencing (scBS-seq) was used to assess methylation in oocytes from a patient with BiCHM identified to be homozygous for an inactivating mutation in the human SCMC component KHDC3L. Genome-wide methylation analysis of a preimplantation embryo and molar tissue from the same patient was also performed. Results: High-coverage scBS-seq libraries were obtained from five KHDC3L^c.1A>G oocytes, which revealed a genome-wide deficit of DNA methylation compared with normal human oocytes. Importantly, germline differentially methylated regions (gDMRs) of imprinted genes were affected similarly to other sequence features that normally become methylated in oocytes, indicating no selectivity towards imprinted genes. A range of methylation losses was observed across genomic features, including gDMRs, indicating variable sensitivity to defects in the SCMC. Genome-wide analysis of a pre-implantation embryo and molar tissue from the same patient showed that following fertilisation methylation defects at imprinted genes persist, while most non-imprinted regions of the genome recover near-normal methylation post-implantation. Conclusions: We show for the first time that the integrity of the SCMC is essential for de novo methylation in the female germline. These findings have important implications for understanding the role of the SCMC in DNA methylation and for the origin of imprinting defects, for counselling affected families, and will help inform future therapeutic approaches.

This case-control study was performed to compare the pregnancy outcomes of women aged 40 years and older with those of 20- to 30-year-old women. Among 28,507 women who delivered in the Zeinabieh and Hafez hospitals affiliated to Shiraz University of Medical Sciences between September 2001 and October 2004, 574 women (2.01%) were 40 years old or older at the time of delivery. Eight cases were excluded because of multifetal pregnancies. From the 566 remaining cases, 200 women (case group) were selected by simple random sampling and their hospital admission charts were retrospectively reviewed. They were compared with 200 20- to 30-year-old mothers (control group). The mean age for the case group was 41.56 +/- 2.06 years and that for the control group was 24.63 +/- 2.89 years. The mean birth weight was 2,869 +/- 848 g for the case group and 2,895 +/- 834 g for the control group (p = 0.75). The incidences of preeclampsia, gestational hypertension, cesarean delivery, abruptio placenta, preterm delivery, and 5-minute Apgar scores < 7 were significantly higher in the older group (p < 0.05). Some complications such as diabetes, chronic hypertension and perinatal mortality were more common in the older mothers, but the differences were not statistically significant. A comparison of complications with respect to parity showed that preterm birth (p = 0.002) and low birth weight (p = 0.04) occurred more frequently in primiparous older women. However, preeclampsia (p = 0.002) and abruptio placenta (p = 0.012) were more common in multiparous older women. Maternal and neonatal complications increased in women aged 40 years and above, but neonatal outcomes were similar to those in the younger age group.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of ovulation induction that usually occurs after gonadotropin stimulation, followed by human chorionic gonadotropin administration, for infertility treatment. The existing knowledge about the pathophysiology, risk factors, and primary and secondary methods for the prevention of OHSS is reviewed in this manuscript. The clinical manifestations and characteristics of mild, moderate, severe, and critical forms of the syndrome are defined. The methods of handling affected cases as outpatient or in-hospital management methods as well as indications for hospitalization are summarized in this review. The clinical and biochemical routes of assessing and monitoring hospitalized patients with OHSS, various drugs and medical treatment strategies including indications for aspiration of the ascitic fluid and pleural effusion, and also rare indications for surgery are briefly explained in this article. Severe OHSS, which two decades ago was considered an iatrogenic life-threatening condition, can now be effectively prevented or managed during the early stages. An OHSS-free clinic can be established nowadays by carefully considering the endocrinology of ovulation and using appropriate and dose-adjusted pharmaceutical agents, which are summarized and discussed in this review.