Risk of spontaneous preterm birth elevated after first cesarean delivery at full dilatation: a retrospective cohort study of over 30,000 women.

BACKGROUND: Having a cesarean delivery at full dilatation has been associated with increased subsequent risk of spontaneous preterm birth. The Aberdeen Maternity and Neonatal Databank provides a rare opportunity to study subsequent pregnancy outcomes after a previous cesarean delivery at full dilatation over 40 years, with an ability to include a detailed evaluation of potential confounding factors. OBJECTIVE: This study aimed to investigate if having an initial cesarean delivery at full dilatation is associated with spontaneous preterm birth or other adverse pregnancy outcomes in the subsequent pregnancy. STUDY DESIGN: A retrospective cohort study was conducted including women with a first and second pregnancy recorded within the Aberdeen Maternity and Neonatal Databank between 1976 and 2017, where previous cesarean delivery at full dilatation at term in the first birth was the exposure. The primary outcome was spontaneous preterm birth (defined as spontaneous birth <37 weeks). Multivariate logistic regression was used to investigate any association between cesarean delivery at full dilatation and the odds of spontaneous preterm birth. Cesarean delivery at full dilatation in previous pregnancy was compared with: (1) any other mode of birth, and (2) individual modes of birth, including planned cesarean delivery, cesarean delivery in first stage of labor (<10-cm dilatation), and vaginal birth (including spontaneous vaginal birth, nonrotational forceps, Kielland forceps, vacuum-assisted birth, breech vaginal birth). Other outcomes such as antepartum hemorrhage and mode of second birth were also compared. RESULTS: Of the 30,253 women included, 900 had a previous cesarean delivery at full dilatation in the first pregnancy. Women with previous cesarean delivery at full dilatation had a 3-fold increased risk of spontaneous preterm birth in a second pregnancy (unadjusted odds ratio, 2.63; 95% confidence interval, 1.82-3.81; adjusted odds ratio, 3.31; 95% confidence interval, 2.17-5.05) compared with those with all other modes of first birth, adjusted for maternal age, diabetes mellitus, body mass index, smoking, preeclampsia, antepartum hemorrhage, socioeconomic deprivation (Scottish Index of Multiple Deprivation 2016), year of birth, and interpregnancy interval (in second pregnancy). When compared with women with vaginal births only, women with cesarean delivery at full dilatation had 5-fold increased odds of spontaneous preterm birth (adjusted odds ratio, 5.37; 95% confidence interval, 3.40-8.48). Compared with first spontaneous vaginal birth, first instrumental births (nonrotational forceps, Kielland forceps, and vacuum births) were not associated with increased risk of spontaneous preterm birth in the second birth. After an initial cesarean delivery at full dilatation, 3.7% of women had a repeated cesarean delivery at full dilatation and 48% had a planned cesarean delivery in the second birth. CONCLUSION: This study is a substantial addition to the body of evidence on the risk of subsequent spontaneous preterm birth after cesarean delivery at full dilatation, and demonstrates a strong association between cesarean delivery at full dilatation in the first birth and spontaneous preterm birth in subsequent pregnancy, although the absolute risk remains small. This is a large retrospective cohort and includes a comprehensive assessment of potential confounding factors, including preeclampsia, antepartum hemorrhage, and lengths of first and second stage of labor. Future research should focus on understanding possible causality and developing primary and secondary preventative measures.

Have we overlooked the role of mifepristone for the medical management of tubal ectopic pregnancy?

Ectopic pregnancy is a risk of both spontaneous and assisted reproduction pregnancies. The majority of ectopic pregnancies abnormally implant within a fallopian tube (extrauterine pregnancies). In haemodynamically stable women, medical or expectant treatment can be offered. Currently accepted medical treatment is using a drug called methotrexate. However, methotrexate has potential adverse effects, and a significant proportion of women will still require emergency surgery (up to 30%) to remove the ectopic pregnancy. Mifepristone (RU-486) has anti-progesterone effects and has a role in managing intrauterine pregnancy loss and termination of pregnancy. On reviewing the literature and given progesterone's pivotal role in sustaining pregnancy, we propose that we may have overlooked the role of mifepristone in the medical management of tubal ectopic pregnancy in haemodynamically stable women.

Inherited susceptibility to miscarriage: a nested case-control study of 31,565 women from an intergenerational cohort.

BACKGROUND: Miscarriage can be a devastating outcome for couples, and most miscarriages are unexplained. Many adverse obstetric outcomes (such as preeclampsia, preterm birth, and growth restriction) are thought to be inherited. It is possible that these conditions could share similar pathophysiologic mechanisms (such as endothelial dysfunction) with miscarriage. Therefore, it was hypothesized that there could be a susceptibility to miscarriage transmitted from mother to daughter. OBJECTIVE: This study aimed to investigate the association between a maternal history of miscarriage and the risk of miscarriage in daughters. STUDY DESIGN: A case-control study nested within an intergenerational cohort was conducted. Mother-daughter pairs were identified from the intergenerational cohort within the Aberdeen Maternity and Neonatal Databank, United Kingdom. A mother's history of miscarriage was the exposure. The primary outcome was miscarriage in daughters. There were 31,565 mother-daughter pairs who were eligible for inclusion. A population average model that used generalized estimating equations with robust standard errors was used to estimate the odds of a mother's history of miscarriage in daughters with a miscarriage compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multiadjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Daughters who miscarried had 11% greater odds of being born to mothers with a history of miscarriage (adjusted odds ratio, 1.11; 95% confidence interval, 1.01-1.22). Daughters with recurrent miscarriage (≥2) were also more likely to be born to a mother with a history of miscarriage (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49). CONCLUSION: There may be an inherited predisposition to miscarriage transmitted from mother to daughter. Future research should investigate genetic or familial environmental factors that may predispose women to miscarriage.

Family history and risk of miscarriage: A systematic review and meta-analysis of observational studies.

INTRODUCTION: Miscarriage, a spontaneous pregnancy loss at <24 weeks' gestation, is a common complication of pregnancy but the etiologies of miscarriage and recurrent miscarriage are not fully understood. Other obstetric conditions such as preeclampsia and preterm birth, which may share similar pathophysiology to miscarriage, exhibit familial patterns, suggesting inherited predisposition to these conditions. Parental genetic polymorphisms have been associated with unexplained miscarriage, suggesting there could be a genetically inherited predisposition to miscarriage. This systematic review and meta-analysis of observational studies aimed to assess the association between family history of miscarriage and the risk of miscarriage in women. MATERIAL AND METHODS: A systematic review and meta-analysis of observational studies was carried out in accordance with Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Electronic searches using databases (MEDLINE, EMBASE and CINAHL) were carried out to identify eligible studies from 1946 until 2019. Observational studies (cohort or case-control) were included. Human studies only were included. Participants were women of reproductive age. Exposure was a family history of one or more miscarriage(s). The primary outcome was miscarriage in women. Abstracts were screened and data were extracted by two independent reviewers. Study quality was assessed using Critical Appraisal Skills Program (CASP) tools. Data were pooled from individual studies using the Mantel-Haenszel method to produce pooled odds ratios (ORs) with 95% confidence intervals (95% CI). Systematic review registration number (PROSPERO): CRD42019127950. RESULTS: Thirteen studies were identified in the systematic review; 10 were eligible for inclusion in the meta-analysis. Twelve studies reported an association between family history of miscarriage and miscarriage in women. In all, 41 287 women were included in the meta-analysis. Women who miscarried were more likely to report a family history of miscarriage (pooled unadjusted OR 1.90, 95% CI 1.37-2.63). Overall study quality and size varied, with few adjusting for confounding factors. Results should be interpreted with caution as the associations presented are based on unadjusted analyses only. CONCLUSIONS: Women who miscarry may be more likely to have a family history of miscarriage. Further research is required to confirm or refute the findings.

Inherited predisposition to stillbirth: an intergenerational analysis of 26,788 mother-daughter pairs.

BACKGROUND: Previous evidence suggests that placental dysfunction, which includes preeclampsia, is inherited from mother to daughter, but heritability of stillbirth has never been investigated. OBJECTIVE: The purpose of this study was to investigate whether there is an inherited predisposition to stillbirth that is transmitted from mother to daughter. STUDY DESIGN: We carried out a nested case-control study within the intergenerational cohort held in the Aberdeen Maternity and Neonatal Databank. All mothers who had at least 1 daughter in Aberdeen, United Kingdom, between 1949 and 2000 were included. Mother-daughter pairs were linked with the use of the Scottish Community Health Index number. The main exposure was the mother's history of stillbirth. The primary outcome was stillbirth in any of the daughter's pregnancies. A population average model that used generalized estimating equations with robust standard errors was used to estimate odds of a mother's history of stillbirth in daughters with a stillbirth compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multi-adjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Among the daughters, 384 had a history of ≥1 stillbirths (cases); 26,404 only ever had livebirths (control subjects). We found no statistically significant association between mothers' history of stillbirth (adjusted odds ratio, 0.63; 95% confidence interval, 0.24-1.63) or miscarriage (adjusted odds ratio, 1.01; 95% confidence interval, 0.71-1.42) and stillbirth in daughters. CONCLUSION: This is the first study to investigate an inherited predisposition to stillbirth. There was no evidence of an inherited predisposition to stillbirth transmitted from mother to daughter.

Maternal Serum Melatonin Increases During Pregnancy and Falls Immediately After Delivery Implicating the Placenta as a Major Source of Melatonin.

Melatonin is a neuroendocrine hormone which regulates circadian rhythm and is also an antioxidant. The role of melatonin in pregnancy is emerging. The enzymes needed for endogenous synthesis of melatonin have been identified in the placenta, although the contribution to circulating maternal melatonin in normal pregnancy is unclear. This work aimed to determine serum levels of melatonin and its major metabolite 6-hydroxymelatonin sulfate (6-OHMS) in normal pregnant women during each trimester of pregnancy, and immediately after delivery. Blood samples were obtained from a cohort of healthy pregnant women during each trimester of pregnancy (n = 26), from women scheduled for elective Cesarean section (CS) before and after delivery (n = 15), along with placental samples, and from healthy non-pregnant women as controls (n = 30). Melatonin and its major metabolite, 6-OHMS, were measured using enzyme immunoassay. Levels of serum melatonin were significantly higher during pregnancy than in non-pregnant women (P = 0.025) and increased throughout pregnancy (P < 0.0001). In women undergoing CS, serum melatonin decreased markedly 24 h after delivery (P = 0.0013). Similar results were seen for serum levels of 6-OHMS, and placental tissue 6-OHMS levels correlated with week of gestation at delivery (p = 0.018). In summary, maternal melatonin production is higher in pregnant than in non-pregnant women, increases significantly during pregnancy with highest levels in the third trimester, and decreases abruptly after delivery. These results suggest that the placenta is a major source of melatonin and supports a physiological role for melatonin in pregnancy.

Obesity and stillbirth.

Recent years have witnessed a rise in maternal obesity, which is independently associated with an increased risk of stillbirth. The pathophysiology is unclear, but it is likely related to abnormal placental function, and inflammatory, metabolic and hormonal imbalances in the mother. Obesity is associated with conditions such as diabetes, which can also cause stillbirth. In order to reduce the risk of obesity-associated stillbirth, women of reproductive age should be actively encouraged to optimise their pre-pregnancy weight as the safety of weight loss interventions during pregnancy is unproven. Obese and extremely obese women should be treated as high-risk obstetric patients, with increased antenatal surveillance and specialist input. The postnatal period may be a useful time to provide weight management advice to women to prevent interpregnancy weight gain and reduce the risk of stillbirth in subsequent pregnancies.