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.

Cesarean section at full dilatation in the first birth is not associated with an increased risk of subsequent miscarriage: A historical cohort study.

INTRODUCTION: Cesarean section at full dilatation has been associated with an increased risk of subsequent preterm birth. We hypothesized that there may be an increased risk of miscarriage in pregnancies that follow cesarean section at full dilatation. This study aimed to determine if a first-term (≥37 weeks) cesarean section at full dilatation is associated with an increased risk of miscarriage in the next pregnancy. MATERIAL AND METHODS: A historical cohort study was conducted using routinely collected hospital data within the Aberdeen Maternity and Neonatal Databank (AMND). The population included were women who had a first-term birth and who had a second birth recorded within the AMND. Logistic and multinomial regression was used to determine any association with miscarriage at any gestation and for early (<13 weeks gestation) and late (13-23 + 6 weeks gestation) miscarriage, with cesarean section at full dilatation defined as the exposure. Miscarriage in the second pregnancy (spontaneous loss of intrauterine pregnancy prior to 24 weeks gestation) was the primary outcome. RESULTS: In total, 33 452 women were included. Women who had a first cesarean section at full dilatation were no more likely to have a miscarriage at any gestation than women with all other modes of first birth (including all vaginal births, planned CS, and the first stage of labor (<10 cm dilated CS)) [adjusted OR 0.84 (0.66-1.08); p = 0.18]. There was no association with early or late miscarriage after a CSfd, though the sample size for late miscarriage was small. CONCLUSIONS: This is the first observational study to investigate the risk of miscarriage following first-term CSfd. We found no association between miscarriage at any gestation following a first-term CSfd compared to all other modes of first birth.

Subsequent pregnancy outcomes after second trimester miscarriage or termination for medical/fetal reason: A systematic review and meta-analysis of observational studies.

INTRODUCTION: Women with a prior stillbirth or a history of recurrent first trimester miscarriages are at increased risk of adverse pregnancy outcomes. However, little is known about the impact of a second trimester pregnancy loss on subsequent pregnancy outcome. This review investigated if second trimester miscarriage or termination for medical reason or fetal anomaly (TFMR/TOPFA) is associated with future adverse pregnancy outcomes. MATERIAL AND METHODS: A systematic review of observational studies was conducted. Eligible studies included women with a history of a second trimester miscarriage or termination for medical reasons and their pregnancy outcomes in the subsequent pregnancy. Where comparative studies were identified, studies which compared subsequent pregnancy outcomes for women with and without a history of second trimester loss or TFMR/TOPFA were included. The primary outcome was livebirth, and secondary outcomes included: miscarriage (first and second trimester), termination of pregnancy, fetal growth restriction, cesarean section, preterm birth, pre-eclampsia, antepartum hemorrhage, stillbirth and neonatal death. Studies were excluded if exposure was nonmedical termination or if related to twins or higher multiple pregnancies. Electronic searches were conducted using the online databases (MEDLINE, Embase, PubMed and The Cochrane Library) and searches were last updated on June 16, 2023. Risk of bias was assessed using the Newcastle-Ottawa scale. Where possible, meta-analysis was undertaken. PROSPERO registration: CRD42023375033. RESULTS: Ten studies were included, reporting on 12 004 subsequent pregnancies after a second trimester pregnancy miscarriage. No studies were found on outcomes after second trimester TFMR/TOPFA. Overall, available data were of "very low quality" using GRADE assessment. Meta-analysis of cohort studies generated estimated outcome frequencies for women with a previous second trimester loss as follows: live birth 81% (95% CI: 64-94), miscarriage 15% (95% CI: 4-30, preterm birth 13% [95% CI: 6-23]).The pooled odds ratio for preterm birth in subsequent pregnancy after second trimester loss in case-control studies was OR 4.52 (95% CI: 3.03-6.74). CONCLUSIONS: Very low certainty evidence suggests there may be an increased risk of preterm birth in a subsequent pregnancy after a late miscarriage. However, evidence is limited. Larger, higher quality cohort studies are needed to investigate this potential association.

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.

Maternal and perinatal outcomes of prolonged second stage of labour: a historical cohort study of over 51,000 women.

BACKGROUND: Prolonged second stage of labour has been associated with adverse maternal and perinatal outcomes. The maximum length of the second stage from full dilatation to birth of the baby remains controversial. Our aim was to determine whether extending second stage of labour was associated with adverse maternal and perinatal outcomes. METHODS: A retrospective cohort study was conducted using routinely collected hospital data from 51592 births in Aberdeen Maternity Hospital between 2000 and 2016. The hospital followed the local guidance of allowing second stage of labour to extend by an hour compared to national guidelines since 2008 (nulliparous and parous). The increasing duration of second stage of labour was the exposure. Baseline characteristics, maternal and perinatal outcomes were compared between women who had a second stage labour of (a) ≤ 3 h and (b) > 3 h duration for nulliparous women; and (a) ≤ 2 h or (b) > 2 h for parous women. An additional model was run that treated the duration of second stage of labour as a continuous variable (measured in hours). All the adjusted models accounted for: age, BMI, smoking status, deprivation category, induced birth, epidural, oxytocin, gestational age, baby birthweight, mode of birth and parity (only for the final model). RESULTS: Each hourly increase in the second stage of labour was associated with an increased risk of obstetric anal sphincter injury (aOR 1.21 95% CI 1.16,1.25), having an episiotomy (aOR 1.48 95% CI 1.45, 1.52) and postpartum haemorrhage (aOR 1.27 95% CI 1.25, 1.30). The rates of caesarean and forceps delivery also increased when second stage duration increased (aOR 2.60 95% CI 2.50, 2.70, and aOR 2.44 95% CI 2.38, 2.51, respectively.) Overall adverse perinatal outcomes were not found to change significantly with duration of second stage on multivariate analysis. CONCLUSIONS: As the duration of second stage of labour increased each hour, the risk of obstetric anal sphincter injuries, episiotomies and PPH increases significantly. Women were over 2 times more likely to have a forceps or caesarean birth. The association between adverse perinatal outcomes and the duration of second stage of labour was less convincing in this study.

Incidence and management of premature rupture of membranes in Victoria, Australia: A retrospective cohort study of 636 590 births between 2009 and 2017.

BACKGROUND: Premature rupture of membranes (PROM) is a complication affecting 7-12% of pregnancies in which fetal chorioamniotic membranes rupture before labour begins. Preterm PROM (PPROM) (ie <37 weeks gestation) precedes one-third of preterm births, exposing the fetus to increased morbidity from placental abruption, respiratory distress syndrome and sepsis. AIM: To analyse trends in the incidence and mode of birth in preterm and term PROM in Victoria, Australia between 2009 and 2017. MATERIALS AND METHODS: This retrospective population-based cohort study included all singleton pregnancies from 2009 to 2017. We examined women with PROM (both <37 weeks (PPROM) and at term). Management was assessed in three categories: (a) expectant management; (b) induction of labour (IOL); and (c) elective caesarean section (elCS). A multinomial logistic regression model was used to adjust for confounders influencing the choice of management. RESULTS: Of 636 590 singleton pregnancies, 52 669 (8.3%) births with PROM at term (42 439; 6.7%) or PPROM (10 230; 1.6%) were identified. Of these, the majority were managed expectantly (n = 22 726; 43.1%), or with IOL (25 931; 49.2%). While elCS represented only 7.6% of these cases (n = 4012), its use rose consistently from 2009 to 2017 for PROM at term and PPROM alike. For women with PPROM at 34-36 weeks the odds of elCS increased by 5% annually (adjusted odds ratio (aOR) 1.05; 95% CI 1.02-1.08) and 2% for IOL (aOR 1.02; 95% CI 1.00-1.05) vs expectant management. CONCLUSIONS: The use of elCS and IOL in PPROM is rising in Victoria, particularly between 34 and 36 completed weeks of pregnancy. Research is needed to determine the drivers for this increase.

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

BACKGROUND: Monitoring of in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) is necessary to detect as well as reduce the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the optimal ovarian response needed for assisted reproduction treatment. Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation IVF and ICSI treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered.  OBJECTIVES: To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. SEARCH METHODS: In this update conducted in March 2020, two review authors searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, the National Research Register, and web-based trial registers. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS: Two review authors (IK, AW) independently selected the studies, extracted data and assessed risk of bias. We resolved disagreements by discussion. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. MAIN RESULTS: We did not identify any new eligible studies in this update in 2020. The evidence based on the six trials identified in 2014 remained unchanged. They included 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment. None of the six studies reported our primary outcome of live birth rate. Two studies presented pregnancy rate per initiated cycle and per embryo transfer, respectively. Four studies reported pregnancy rate per woman with pooled data; we are uncertain of the effect of monitoring with TVUS only versus combined monitoring on clinical pregnancy rate per woman (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests in women with a 36% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate using TVUS only would be between 31% and 46%. We are uncertain of any effect in the mean number of oocytes retrieved per woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).  We are uncertain whether monitoring with TVUS only versus combined monitoring affected the incidence of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that in women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate monitored by TVUS only would be between 2% and 8%. The cycle cancellation rate was similar in both arms of two studies (0/34 versus 1/31, 1/25 versus 1/25; OR 0.57; 95% CI 0.07 to 4.39; N = 115; I² = 0%; low quality evidence).  The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. AUTHORS' CONCLUSIONS: This review update found no new randomised trials. Evidence from the six studies previously identified did not suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. The choice of one or the other method may depend upon the convenience of its use, and the associated costs. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.

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.

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

BACKGROUND: Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels to ensure safe practice by reducing the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the good ovarian response needed for assisted reproduction treatment. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered. OBJECTIVES: To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, the National Research Register, and web-based trial registers such as Current Controlled Trials. The last search was conducted in May 2014. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. SELECTION CRITERIA: Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. DATA COLLECTION AND ANALYSIS: Three review authors independently selected the studies, extracted data and assessed risk of bias. They resolved disagreements by discussion with the rest of the authors. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. MAIN RESULTS: With this update, four new studies were identified resulting in a total of six trials including 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment.None of the six studies reported our primary outcome of live birth rate. Pooled data showed no evidence of a difference in clinical pregnancy rate per woman between monitoring with TVUS only and combined monitoring (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests that compared with women with a 34% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate in women using TVUS only was between 29% and 44%.There was no evidence of a difference between the groups in the reported cases of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that compared with women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate in women monitored by TVUSS only was between 2% and 8%.There was no evidence of a difference between the groups in the mean number of oocytes retrieved pre woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. AUTHORS' CONCLUSIONS: This review update found no evidence from randomised trials to suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. A combined monitoring protocol including both TVUS and serum estradiol may need to be retained as precautionary good clinical practice and as a confirmatory test in a subset of women to identify those at high risk of OHSS. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.

Introduction of the Mediterranean diet in pregnancy and the incidence of gestational diabetes mellitus: A systematic review of randomised controlled trials and meta-analysis.

OBJECTIVES: To determine if introducing the Mediterranean diet in pregnancy reduces the incidence of gestational diabetes. STUDY DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). A literature search was conducted using the following databases: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and CINAHL with no language or date restrictions. Studies were deemed eligible if the population was pregnant women, the intervention was the Mediterranean diet, and the outcome was gestational diabetes. Quality assessment was carried out using the Cochrane risk of bias tool. A random effects model using Revman software was used to pool results, generating a summary risk ratio with 95 % confidence intervals (95 %CI). RESULTS AND CONCLUSIONS: The search identified three eligible studies. Across the trials, 2348 women were included. Two of the three trials defined the intervention as the Mediterranean diet supplemented with extra virgin olive oil (EVOO) and pistachios, with the control group being Mediterranean diet alone. Meta-analysis of these trials found a significant reduction in the incidence of gestational diabetes in the intervention group compared to the control group (risk ratio=0.71, 95% confidence interval=(0.57, 0.88)). In addition, this was consistent with the results of the remaining eligible trial which defined the intervention as Mediterranean diet and the control as a standard UK diet (risk ratio = 0.71, 95% confidence interval = (0.55, 0.90)). At present evidence is scarce regarding whether adopting a Mediterranean diet reduces the risk of gestational diabetes. A large multi-centre randomised controlled trial is needed to definitively determine the impact of the Mediterranean diet in pregnancy on the incidence of gestational diabetes.

Intergenerational trends in reproduction: Infertility and pregnancy loss.

This review article summarises the evidence for intergenerational trends observed to date within infertility and pregnancy loss. There appears to be evidence of intergenerational trends between mothers and daughters for the age at menopause, endometriosis, polycystic ovarian syndrome (PCOS), male factor infertility and miscarriage. At present, there is no evidence for a predisposition to stillbirth between mothers and daughters. One study found an association with familial predisposition for ectopic pregnancy. Very few studies have considered the potential for paternal transmission of risk of infertility or pregnancy loss. The majority of studies to date have significant limitations because of their observational design, risk of recall bias and risk of confounding. Therefore, high-quality well-designed research, with multi-centre collaboration and utilisation of registry-based data sources and individual patient data, is needed to understand whether infertility and pregnancy loss may have heritable factors. Epidemiological findings need to be followed up and investigated with translational research to determine the possible causalities as well as any implications for clinical practice.

Isolated choroid plexus cysts and health and developmental outcomes in childhood and adolescence - A systematic review.

OBJECTIVES: Choroid plexus cysts (CPCs) are incidental findings on ultrasound examination of the fetal brain. It is not known if isolated CPCs are associated with any adverse health or neurodevelopmental outcomes during the life course. This systematic review aimed to collate and synthesize the evidence on whether or not isolated choroid plexus cysts are associated with an increased risk of adverse health or developmental outcomes during childhood and adolescence. METHODS: A search strategy was developed specifically for this study and applied to four electronic databases Medline (Ovid), Embase (Ovid), Web of Science, and Google Scholar. Studies were assessed and selected for inclusion if there was a measurement of CPC (including single or multiple; unilateral or bilateral; isolated or presenting alongside other markers) during the antenatal or early neonatal period (<7 days) with follow-up of children and adolescents for health and developmental outcomes measured at any time from age 1 month onwards. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Due to heterogeneity in the types of outcome measures included and the timing of measurement of outcomes across the studies, it was not possible to pool data across studies and a narrative description of findings was presented. RESULTS: Eight studies (three cohorts and five case series) met the inclusion criteria. Different methods were used for outcome assessment, such as in-person assessment, parent questionnaires, medical records, and telephone interviews with parents. Six studies measured outcomes only once during the specified duration of follow-up; two studies carried out paediatric reviews of the children several times during follow-up. There were no differences in developmental outcomes or physical health between babies with CPCs reported in the three cohort studies, and no abnormalities were detected in the children that were followed up in four of the five case series studies. Most of the included studies were graded as low quality due to the small sample size, high risk of selection bias, unclear definitions of CPC or lack of a comparison group. CONCLUSIONS: The studies conducted to date do not provide evidence of adverse physical health outcomes or neurodevelopmental delays in babies with CPCs. However, most of these studies were small and included a narrow range of outcomes. Further research is needed to explore the relative incidence of outcomes such as ASD, ADHD, epilepsy and educational attainment in children with CPCs.

Evaluation of infection control advice for patients at risk of chemotherapy-induced neutropenia in 2 pediatric oncology centers: Cape Town, South Africa, and Newcastle-Upon-Tyne, UK.

Childhood cancers are treated with myelotoxic chemotherapy. Resultant neutropenia can lead to life-threatening infections. There is no consistent guidance on infection control precautions for neutropenic patients who are not yet febrile or infected. Although it is not possible to eradicate infection risk, it is conceivable that the risk could be reduced by effective infection prevention. This study compared infection control measures advised to pediatric and adolescent oncology patients receiving chemotherapy in 2 centers (Cape Town, South Africa, and Newcastle, UK). Prospective, observational, cross-sectional surveys of staff and patients/parents were undertaken using standardized, study-specific questionnaires. Seventy-eight staff and 56 patients/parents participated. Precautions advised in Newcastle were significantly different to Cape Town (all P < .05), except both agreed inpatient isolation was unnecessary. Over 40% of patients/parents felt isolation was important (P < .01). In Cape Town, staff and patients had similar views. In Newcastle, patients/parents had stricter opinions on particular precautions than staff, for example, attending school, playing outside and avoiding busy places (P < .01). Patient/parent responses were similar between centers. Over 90% of staff felt advising patients/parents about hand washing was important. Currently infection prevention advice is inconsistent. Further research is needed to elucidate effective guidance for infection prevention in pediatric neutropenic patients.

The impact of mitigation measures on perinatal outcomes during the first nine months of the COVID-19 pandemic: A systematic review with meta-analysis.

Worldwide reports have produced conflicting data on perinatal outcomes during the COVID-19 pandemic. This systematic review and meta-analysis addressed the effect of mitigation measures against COVID-19 on preterm birth, stillbirth, low birth weight, and NICU admission during the first nine months of the pandemic. A search was performed using MEDLINE, Embase and SCOPUS for manuscripts published up until 24th May 2021. Studies that reported perinatal outcomes (preterm birth, stillbirth, low birth weight, NICU admission) during the COVID-19 pandemic with a pre-pandemic control period were included. Risk of bias assessment was performed using ROBINS-I tool. RevMan5 was used to perform meta-analysis with random-effects models. A score of the stringency of mitigation measures was calculated from the Oxford COVID-19 Government Response Tracker. Thirty-eight studies of moderate to serious risk of bias were included, with varied methodology, analysis and regional mitigation measures, using stringency index scores. There was no overall effect on preterm birth at less than 37 weeks (OR 0.96, 95% CI 0.92-1.00). However, there was a reduction in preterm birth at less than 37 weeks (OR 0.89, 95% CI 0.81-0.98) and 34 weeks (OR 0.56, 95% CI 0.37-0.83) for iatrogenic births and in singleton pregnancies. There was also a significant reduction in preterm births at less than 34 weeks in studies with above median stringency index scores (OR 0.71, 95% CI 0.58-0.88). There was no effect on risk of stillbirth (OR 1.04, 95% CI 0.90-1.19) or birth weight. NICU admission rates were significantly reduced in studies with above median stringency index scores (OR 0.87, 95% CI 0.78-0.97). The reduction in preterm births in regions with high mitigation measures against SARS-CoV-2 infection is likely driven by a reduction in iatrogenic births. Variability in study design and cohort characteristics need to be considered for future studies to allow further investigation of population level health measures of perinatal outcomes.

Has the human papillomavirus (HPV) immunization programme improved obstetric outcomes in spontaneous delivery? An ecological study.

OBJECTIVE: To measure the rates of adverse obstetric outcomes in spontaneous delivery in a population of young women with high uptake of the bivalent human papillomavirus (HPV) vaccine. STUDY DESIGN: This was a population-based ecological study with data from the Aberdeen Maternity and Neonatal Databank, UK. All women born between 1986-1996 with spontaneous singleton live birth at age 20-30 years were included for analysis. Exposure was defined according to maternal year of birth and HPV immunisation eligibility: pre-immunisation cohort (1986-1990), catch-up immunisation cohort (1991-1994) and routine immunisation cohort (1995-1996). Outcomes were defined as spontaneous preterm birth (PTB), low birth weight (LBW) and pre-labour preterm rupture of membranes (pPROM). Generalized estimating equation models were applied, adjusted for deprivation, smoking status, marital status, body mass index, parity, maternal age and year of infant delivery. RESULTS: A total of 6515 spontaneous singleton live births were included in final analysis, with 5134 births included in the pre-immunisation cohort, 1250 in the catch-up immunisation cohort and 131 in the routine immunisation cohort. Compared with the pre-immunisation cohort, no statistically significant reduction on PTB, LBW or pPROM were observed in either immunised cohorts. The adjusted odds ratio (aOR) on PTB was 0.64 (95 % confidence interval, 0.40-1.03) in the catch-up cohort and 0.71 (0.28-1.77) in the routine cohort. The corresponding aOR were 0.88 (0.54-1.45) and 0.51 (0.16-1.62) for LBW and 1.62 (0.58-4.54) and 1.51 (0.21-11.01) for pPROM. CONCLUSIONS: We did not observe a significant reduction on PTB, LBW or pPROM among spontaneous singleton live birth in either HPV immunised cohorts, although the additional benefit in improving obstetric outcomes cannot be excluded because of the limits of the sample size and the study design. Further demonstration is warranted when more women in the fully HPV immunised cohorts embark on pregnancy.

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.

The impact of third- or fourth-degree perineal tears on the second pregnancy: A cohort study of 182,445 Scottish women.

This study aimed to investigate the reproductive impact of a third- or fourth-degree tear in primigravid women. A retrospective population-based cohort study was conducted using data from Scottish Morbidity Records (SMR02). Primigravid women with a vaginal birth in Scotland from 1997 until 2010 were included. Exposure was third- or fourth-degree tear in the first pregnancy. The second pregnancy rate, interpregnancy interval and third- or fourth-degree tear in a second pregnancy were the primary outcomes. A nested case-control study was used to determine factors associated with repeat third- or fourth-degree tears in a second vaginal birth. Cox regression analysis and logistic regression were used to look for associations. Initial third- or fourth-degree tear occurred in 2.8% women (5174/182445). The percentage of third- or fourth-degree tears in first vaginal births increased from 1% in 1997 to 4.9% in 2010. There was no difference in having a second pregnancy (adjusted Odds Ratio (aOR) 0.98 (99%CI 0.89-1.09)) or the median interpregnancy interval to second pregnancy (adjusted Hazard Ratio (aHR) 1.01 (99%CI 0.95-1.08)) after an initial third- or fourth-degree tear. Women were over four times more likely to have a repeat injury in a subsequent vaginal birth (n = 149/333, aOR 4.68 (99% 3.52-6.23)) and were significantly more likely to have an elective caesarean section in their second pregnancy (n = 887/3333, 26.6%; 12.75 (11.29-14.40)). Increased maternal age and birthweight ≥4500g were risk factors for repeat injury. Third- and fourth-degree tears are increasing in Scotland. Women do not delay or avoid childbirth after initial third- or fourth-degree tear. However, women are more likely to have a repeat third- or fourth-degree tear or an elective caesarean section in the second pregnancy. Strategies to prevent third- or fourth-degree tears are needed.