Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.

A cluster randomised controlled trial of an early childhood parenting programme delivered through early childhood education centres in rural Zimbabwe.

BACKGROUND: Early childhood is a critical period for child development. Effective approaches to support families in low-resource settings in the use of responsive and stimulating parenting are needed. AIM: The aim of this study was to examine the effects of the Reach Up early childhood parenting programme on children's development, parenting attitudes and practices, when delivered through early childhood development (ECD) centres in Zimbabwe. METHODS: A cluster randomised controlled trial was conducted in Sanyati, a rural district in Zimbabwe. Twenty-four of 51 available centres were randomised to intervention (n = 12) or control (n = 12) groups. Sixteen mothers with a child aged 12-30 months were recruited from each centre's catchment area (n = 189 intervention; n = 193 control). The intervention comprised two home visits per month delivered by centre teaching assistants over a period of 27 months. Primary outcomes were child Developmental Quotient (DQ), Language, Eye and Hand coordination, Performance and Practical Reasoning subscale scores assessed at follow-up. Secondary outcomes were mothers' attitudes about child development, parenting practices and maternal depressive symptoms all measured at baseline and follow-up. Intention to treat analyses was conducted using mixed-effects regression models with the standard error adjusted for cluster and inverse proportionality weights to adjust for attrition. Significance was set at P < 0.05. RESULTS: A total of 285 (74.6%) of 382 children enrolled were tested, with 97 children lost to follow-up. The intervention improved the children's DQ by 3.55 points (95% CI 0.82 to 6.28), Eye and Hand by 3.58 (95% CI 0.59 to 6.56) and Practical Reasoning by 4.19 (95% CI 0.96 to 7.42). No significant improvements to Performance or Language scores, parenting attitudes, parenting practices and depressive symptoms were identified. CONCLUSIONS: A home visiting intervention delivered by ECD teaching assistants promoted children's development. This suggests that outreach from preschools may be an effective platform for delivery of parenting interventions.

Reduction in spontaneous and iatrogenic preterm births in twin pregnancies during COVID-19 lockdown in Melbourne, Australia: a multicenter cohort study.

BACKGROUND: Melbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes. METHODS: Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. Multivariable log-binomial regression models were used to compare perinatal outcomes between a pre-pandemic group to women in whom weeks 20+0 to 40+0 of gestation occurred entirely during one of two lockdown-exposure periods: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. RESULTS: Total preterm births < 37 weeks were significantly lower in exposure 1 compared with the pre-pandemic period (63.1% vs 68.3%; adjusted risk ratio 0.92 95% CI 0.87-0.98, p = 0.01). This was mainly driven by fewer spontaneous preterm births (18.9% vs 20.3%; adjusted risk ratio 0.95 95% CI 0.90-0.99, p = 0.04). There were also lower rates of preterm birth < 34 weeks (19.9% vs 23.0%, adjusted risk ratio 0.93 95% CI 0.89-0.98 p = 0.01) and total iatrogenic births for fetal compromise (13.4% vs 20.4%; adjusted risk ratio 0.94 95% CI 0.89-0.98, p = 0.01). There were fewer special care nursery admissions (38.5% vs 43.4%; adjusted risk ratio 0.91 95% CI 0.87-0.95, p < 0.001) but no significant changes in stillbirth (1.5% vs 1.6%; adjusted risk ratio 1.00 95% CI 0.99-1.01, p = 0.82). Compared with the pre-pandemic period, there were more preterm births < 28 weeks and neonatal intensive care unit admissions in exposure 2. CONCLUSIONS: Melbourne's first lockdown-exposure period was associated with lower preterm births in twins without significant differences in adverse newborn outcomes. Our findings provide insights into the influences on preterm birth and the optimal timing of delivery for twins.

Educational Outcomes for Children at 7 to 9 Years of Age After Birth at 39 vs 40 to 42 Weeks' Gestation.

Importance: Birth at 39 weeks' gestation is common and thought to be safe for mother and neonate. However, findings of long-term outcomes for children born at this gestational age have been conflicting. Objective: To evaluate the association of birth at 39 weeks' gestation with childhood numeracy and literacy scores at ages 7 to 9 years compared with birth at 40 to 42 weeks' gestation. Design, Setting, and Participants: In this Australian statewide, population-based cohort study using a causal inference framework based on target trial emulation, perinatal data on births between January 1, 2005, and December 31, 2011, were linked to educational outcomes at 7 to 9 years of age. Statistical analyses were performed from December 2022 to June 2023. Exposure: Birth at 39 weeks' gestation compared with birth at 40 to 42 weeks' gestation. Main Outcomes and Measures: Numeracy and literacy outcomes were assessed at 7 to 9 years of age using Australian National Assessment Program-Literacy and Numeracy data and defined by overall z score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Multiple imputation and doubly robust inverse probability weighted regression adjustment were used to estimate population average causal effects. Results: The study population included 155 575 children. Of these children, 49 456 (31.8%; 24 952 boys [50.5%]) were born at 39 weeks' gestation and were compared with 106 119 (68.2%; 52 083 boys [49.1%]) born at 40 to 42 weeks' gestation. Birth at 39 weeks' gestation was not associated with altered educational outcomes for children aged 7 to 9 years compared with their peers born at 40 to 42 weeks' gestation (mean [SE] z score, 0.0008 [0.0019] vs -0.0031 [0.0038]; adjusted risk difference, -0.004 [95% CI, -0.015 to 0.007]). Each educational domain was investigated, and no significant difference was found in grammar and punctuation (risk difference [RD], -0.006 [95% CI, -0.016 to 0.005]), numeracy (RD, -0.009 [95% CI, -0.020 to 0.001]), spelling (RD, 0.001 [95% CI, -0.011 to 0.0013]), reading (RD, -0.008 [95% CI, -0.019 to 0.003]), or writing (RD, 0.006 [95% CI, -0.005 to 0.016]) scores for children born at 39 weeks' gestation compared with those born at 40 to 42 weeks' gestation. Birth at 39 weeks' gestation also did not increase the risk of scoring below national minimum standards in any of the 5 tested domains. Conclusions and Relevance: Using data from a statewide linkage study to emulate the results of a target randomized clinical trial, this study suggests that there is no evidence of an association of birth at 39 weeks' gestation with numeracy and literacy outcomes for children aged 7 to 9 years.

Prevalence of Perinatal Anxiety and Related Disorders in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

Importance: Anxiety disorders are associated with poor maternal and neonatal outcomes. Women in low- and middle-income countries (LMICs) are thought to be disproportionally burdened by these disorders, yet their prevalence is unclear. Objective: To conduct a systematic review and meta-analysis to determine the prevalence of 6 anxiety and related disorders among perinatal women in LMICs. Data Sources: Embase, MEDLINE, PsycINFO, Cochrane Library, CINAHL, and Web of Science databases were searched from inception until September 7, 2023. Study Selection: Studies conducted in World Bank-defined LMICs and reporting prevalence of generalized anxiety disorder, obsessive-compulsive disorder, social anxiety disorder, posttraumatic stress disorder, panic disorder, or adjustment disorder during the perinatal period (conception to 12 months post partum) using a validated method were included. Data Extraction and Synthesis: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Study eligibility, extracted data, and risk of bias of included studies were assessed by 2 independent reviewers. Random-effects meta-analysis was used to estimate pooled point prevalence. Subgroup analyses were performed by specific anxiety disorder. Main Outcomes and Measures: Main outcomes were prevalence estimates of each anxiety disorder, measured as percentage point estimates and corresponding 95% CIs. Results: At total of 10 617 studies were identified, 203 of which met the inclusion criteria and reported the outcomes of 212 318 women from 33 LMICs. Generalized anxiety disorder was the most reported (184 studies [90.6%]) and most prevalent disorder at 22.2% (95% CI, 19.4%-25.0%; n = 173 553). Posttraumatic stress disorder was the second most prevalent (8.3%; 95% CI, 5.0%-12.2%; 33 studies; n = 22 452). Adjustment disorder was least prevalent (2.9%; 95% CI, 0.0%-14.1%; 2 studies; n = 475). The prevalence of generalized anxiety varied by country income status, with the highest prevalence among lower-middle-income countries (27.6%; 95% CI, 21.6%-33.9%; 59 studies; n = 25 109), followed by low-income (24.0%; 95% CI, 15.3%-33.8%; 11 studies; n = 4961) and upper-middle-income (19.1%; 95% CI, 16.0%-22.4%; 110 studies; n = 138 496) countries. Conclusions and Relevance: These findings suggest that 1 in 5 women living in LMICs experience anxiety disorders during pregnancy and post partum. Targeted action is needed to reduce this high burden.

The long-term risk of cardiovascular disease among women with a history of hypertensive disorders of pregnancy: a systematic review of clinical practice guidelines.

BACKGROUND: The lifelong risks of cardiovascular disease following preeclampsia and gestational hypertension are well-established. However, it is unclear whether this evidence has been translated into clinical practice guidelines. Thus, this review aimed to assess the quality and content of Australian clinical practice guidelines regarding the risk of cardiovascular disease following gestational hypertension and preeclampsia. METHODS: We conducted a systematic search of MEDLINE (Ovid), EMBASE (Ovid), and CINAHL databases, as well as hospital, obstetric society, and medical college websites. Publications were included if: they were a clinical practice guideline; were published in the previous ten years; and included recommendations for the management of future cardiovascular disease risk following hypertensive disorders of pregnancy. Quality assessment was performed using Appraisal of Guidelines for Research and Evaluation Instrument Version Two (AGREE-II) and AGREE Recommendations Excellence Instrument (AGREE-REX). RESULTS: Eighteen guidelines were identified, and of these, less than half (n = 8) included recommendations for managing future cardiovascular risk following hypertensive disorders of pregnancy. Across these eight, four main counselling recommendations were found regarding (1) risk of future cardiovascular disease; (2) risk factor screening; (3) lifestyle interventions; and (4) prenatal counselling for future pregnancies. The quality and content of these recommendations varied significantly, and the majority of guidelines (87.5%) were assessed as low to moderate quality. CONCLUSIONS: There are limited Australian clinical practice guidelines providing appropriate advice regarding future risk of cardiovascular disease following hypertensive disorders of pregnancy. The quality and content of these guidelines varied significantly. These findings highlight the need for improved translation from evidence-based research to enhance clinical care and guidance.

Developmental outcomes for survivors of placental laser photocoagulation for the management of twin-to-twin transfusion syndrome.

BACKGROUND: Fetoscopic laser coagulation of placental anastomoses reverses the pathological process in twin-to-twin transfusion syndrome, thereby increasing survival, but there are a paucity of studies addressing long-term neurodevelopmental outcome of survivors. This study aimed to ascertain the presence of neurodevelopmental disabilities in child survivors of monochorionic pregnancies managed by placental laser photocoagulation in the Australian state of Victoria. METHODS: All pregnancies undergoing placental laser photocoagulation with the Victorian Fetal Therapy Service between 2006-2017 were included. Information on each surviving child, including demographics, perinatal course, and developmental progress was collected from parents, and consent was sought to complete the Child Behaviour Checklist. Interviewers evaluated whether this information was consistent with a diagnosis of any of 14 neurodevelopmental conditions. A three-tiered outcome measure was allocated for each child: (1) unimpaired or developmentally normal, (2) mild or moderate neurological impairment, or (3) severe neurological impairment. Clinical predictors for adverse outcome were identified. RESULTS: Of 116 pregnancies (113 twin, 3 triplet), 96 (83%) resulted in 1 + surviving fetuses. 57/113 (50%) twin pregnancies resulted in 2 survivors, 36 (32%) in 1 survivor, and 20 (18%) in no survivors. Of the 235 fetuses, 154 (65.5%) survived to follow-up. Survival increased from 59% in 2006-2008 to 73% in 2015-2017. 90/154 (58%) survivors were followed up at a mean age of 7.5 [SD 3.0] years. Based on parental interview and Child Behaviour Checklist data, 28/90 (31%) participants were assessed as having neurodevelopmental impairment, 27 of mild-moderate severity and 1 severe. Speech/language disorders, attention deficit (hyperactivity) disorders, and fine motor impairment were most common. Neonatal length of stay conferred the highest risk of impairment. CONCLUSION: Substantial variation exists between fetal therapy services in the type and length of neonatal follow-up following fetoscopic laser coagulation, contributing to a lack of data on long-term outcomes. The findings from this study support increasingly urgent calls to undertake systematic and sustained follow-up of fetoscopic laser coagulation survivors until school age. Information from this study may assist parents in their decision-making when offered fetal surgery. Importantly, it highlights a group for targeted surveillance and early intervention.

Potential benefits of prenatal diagnosis of TGA in Australia may be outweighed by the adverse effects of earlier delivery: likely causation and potential solutions.

OBJECTIVE: Prenatal diagnosis of transposition of great arteries (TGA) is expected to improve postoperative outcomes after neonatal arterial switch operation (ASO); however, published reports give conflicting results. We aimed to determine the association between prenatal diagnosis and early postoperative outcomes after neonatal ASO. METHODS: Cohort study involving 243 newborns who underwent ASO (70% prenatally diagnosed) between 2010 and 2019. Multivariable regression was used to determine the association between prenatal diagnosis and (a) birth characteristics and (b) postoperative outcomes. RESULTS: Gestational age and birthweight centile were lower and small-for-gestational-age more common (11.8% vs 1.4%) in those diagnosed prenatally. Among births which followed labour induction or prelabour caesarean, prenatal diagnosis was associated with earlier gestation at birth (mean (SD), 38.5 (1.6) vs 39.2 (1.4), p=0.01). Among births which followed spontaneous labour, prenatal diagnosis was associated with earlier gestation at labour onset (38.2 (1.8) vs 39.2 (1.4), p=0.01). Prenatal diagnosis was associated with longer postoperative mechanical ventilation (incidence rate ratio 1.74, 95% CI 1.37 to 2.21), intensive care (1.70, 1.31 to 2.21) and hospital length of stay (1.37, 1.14 to 1.66) after ASO. Gestational age mediated up to 60% of the effect of prenatal diagnosis on postoperative outcomes. CONCLUSION: Among newborns undergoing ASO for TGA, prenatal diagnosis is associated with poorer early postoperative outcomes. In addition to minimising iatrogenic factors (such as planned births) resulting in earlier births, evaluation of other dynamics following a prenatal diagnosis which may result in poor fetal growth and earlier onset of spontaneous labour is important.

Early intervention to prevent adverse child emotional and behavioural development following maternal depression in pregnancy: study protocol for a randomised controlled trial.

BACKGROUND: Substantial evidence indicates that maternal depression during pregnancy (i.e., antenatal depression) is associated not only with maternal wellbeing but also with child emotional and behavioural development. Children of antenatally depressed women are at risk of emotional and behavioural problems, including internalising problems (e.g., anxiety and depression) and externalising problems (e.g., attention problems), that may last at least to adolescence. These enduring effects also constitute an enormous economic cost. Despite the seriousness of this problem, until recently there existed very few controlled studies evaluating whether active psychological treatment for antenatal depression can prevent adverse child outcomes. Our previous pilot randomised controlled trial (RCT) exploring the effect of cognitive behavioural therapy (CBT) for antenatal depression on child outcomes showed promising results. We aim to assess whether treating antenatal depression with an evidence-based 8-week structured CBT program can prevent or ameliorate adverse child developmental outcomes at 2 years of age. METHODS: Pregnant women ≤ 30 weeks gestation diagnosed with a depressive disorder are recruited and randomised to CBT or treatment as usual (TAU). The target sample size is 230 and the primary outcome measure is the infant Internalising scale of the Child Behaviour Checklist (CBCL) at 24 months of age. Secondary infant outcome measures at 24 months are the Externalising scale of the CBCL and the motor and cognitive development subscales of the Ages & Stages Questionnaire (ASQ-3). Additional secondary outcome measures are subscales of the Revised Infant Behaviour Questionnaire (IBQ-R), ASQ-3 and the ASQ-Socio-Emotional (ASQ-SE) at 3 and 12 months of age and the quality of mother-infant interaction at 3 and 24 months. Maternal measures, including demographic data, depression diagnosis, depressive and anxiety symptoms, perceived stress and parenting stress, are collected across all time points. DISCUSSION: The trial is ongoing and recruitment was slowed due to the COVID-19 pandemic. If results suggest a beneficial effect of antenatal depression treatment on infant outcomes, the project could have repercussions for standard antenatal care, for maternal and infant health services and for preventing the intergenerational transmission of mental health disorders. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register: ACTRN12618001925235 Date Registered: 27 November 2018.

Maternal feeding styles in infancy predict child body mass index z-scores at 72 months: findings from a cohort of Jamaican children.

Objective: To explore whether maternal feeding styles at 12 months predict child Body Mass Index (BMI) z-scores at 72 months and evaluate whether BMI z-scores at 18 months mediates the association. Methods: Data from 239 mother-child pairs participating in a parenting intervention were analyzed. Feeding information was ascertained at 12 months by questionnaire with feeding styles identified using factor analysis. Children's weight and length/height were measured at 18 and 72 months and BMI z-scores computed. Maternal sociodemographic data, depressive symptoms and language skills were obtained by questionnaire. Multilevel linear regression analysis was used to examine whether feeding styles predicted 72 month BMI z-scores. Complete case analysis was conducted and multiple imputation used to treat missing values of explanatory and outcome variables at 18 and 72 months. Mediational analysis was performed to assess the indirect effects of feeding styles on 72 month BMI z-scores via 18 month BMI z-scores. Results: Restrictive feeding at age 12 months predicted higher 72 month BMI z-scores in both complete case analysis [ß (95%CI): 0.19 (0.02, 0.37)] and multiple imputation [ß (95%CI): 0.20 (0.02, 0.39)]. Uninvolved, forceful, indulgent and responsive feeding styles were not significant predictors of 72 month BMI z-scores. A significant indirect effect was observed between restrictive feeding and child BMI z-scores at 72 months via 18 month BMI z-scores [ß (95% CI) 0.12 (0.03, 0.22)]. Conclusion: Restrictive feeding at 12 months was associated with higher BMI z-scores at 72 months and appeared to be mediated by BMI z-scores at 18 months.

Plasma lipids are dysregulated preceding diagnosis of preeclampsia or delivery of a growth restricted infant.

BACKGROUND: Lipids serve as multifunctional metabolites that have important implications for the pregnant mother and developing fetus. Abnormalities in lipids have emerged as potential risk factors for pregnancy diseases, such as preeclampsia and fetal growth restriction. The aim of this study was to assess the potential of lipid metabolites for detection of late-onset preeclampsia and fetal growth restriction. METHODS: We used a case-cohort of 144 maternal plasma samples at 36 weeks' gestation from patients before the diagnosis of late-onset preeclampsia (n = 22), delivery of a fetal growth restricted infant (n = 55, defined as <5th birthweight centile), gestation-matched controls (n = 72). We performed liquid chromatography-tandem mass spectrometry (LC-QQQ) -based targeted lipidomics to identify 421 lipids, and fitted logistic regression models for each lipid, correcting for maternal age, BMI, smoking, and gestational diabetes. FINDINGS: Phosphatidylinositol 32:1 (AUC = 0.81) and cholesterol ester 17:1 (AUC = 0.71) best predicted the risk of developing preeclampsia or delivering a fetal growth restricted infant, respectively. Five times repeated five-fold cross validation demonstrated the lipids alone did not out-perform existing protein biomarkers, soluble tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) for the prediction of preeclampsia or fetal growth restriction. However, lipids combined with sFlt-1 and PlGF measurements improved disease prediction. INTERPRETATION: This study successfully identified 421 lipids in maternal plasma collected at 36 weeks' gestation from participants who later developed preeclampsia or delivered a fetal growth restricted infant. Our results suggest the predictive capacity of lipid measurements for gestational disorders holds the potential to improve non-invasive assessment of maternal and fetal health. FUNDING: This study was funded by a grant from National Health and Medical Research Council.

A Remote Parenting Program and Parent and Staff Perspectives: A Randomized Trial.

OBJECTIVES: To assess impact and implementation of remote delivery of a parenting program following suspension of in-person visits during the coronavirus disease 2019 pandemic. METHODS: Impact of remote delivery of the Reach Up parenting program on parenting practices was evaluated by randomized trial in Jamaica. Mothers with children aged 5 to 24 months who met 1 of 7 at-risk criteria were enrolled at health centers. Participants were randomly assigned to intervention or control using random number tables generated by a statistician. Intervention comprised a manual for parents with illustrated play activities, phone calls, and short message service messages. The control group received usual care. Parent practices were measured using an adapted Family Care Indicators telephone-administered questionnaire by interviewers unaware of group assignment. Qualitative interviews were conducted with staff and parents in Jamaica and Brazil and staff in Ecuador to identify facilitators and barriers to remote delivery of Reach Up. RESULTS: Two hundred forty-seven participants were assessed at endline (control n = 130; intervention n = 117). Intervention increased parent activities that support child development, effect size 0.34 SD (95% confidence interval 0.03-0.53), and use of praise, odds 2 times higher with intervention. There were no benefits to interactive language or play materials. Qualitative results showed parents appreciated program continuation and felt motivated to help their child, and methods were acceptable to staff. Barriers included poor mobile phone access, difficulty contacting parents, and feedback limitations without in-person contact. CONCLUSIONS: Remote delivery methods have potential to contribute to scaling of parenting programs.

The Reach Up Parenting Program, Child Development, and Maternal Depression: A Meta-analysis.

BACKGROUND AND OBJECTIVES: Evidence is needed on effective approaches to build parents' ability to promote child development feasible in low- and middle-income countries. Our objective was to synthesize impact of the Reach Up early childhood parenting program in several low- and middle-income countries and examine moderation by family and implementation characteristics. METHODS: Systematic search using PubMed and Academic Search Elite/EBSCO Host. Randomized controlled trials of the Reach Up program from 1985 to February 2022 were selected. Data were extracted by 2 independent researchers. Primary outcomes were child cognitive, language, and motor development. Secondary outcomes were home stimulation and maternal depressive symptoms. We synthesized pooled effect sizes using random effect inverse-variance weighting and effect modification by testing pooled subgroup effect estimates using the χ2 test for heterogeneity. RESULTS: Average effect size across 18 studies ranged from 0.49 (95% confidence interval [CI] 0.32 to 0.66) for cognition, 0.38 (CI 0.24 to 0.51) for language, 0.27 (CI 0.13 to 0.40) for motor development, 0.37 (CI 0.21 to 0.54) for home stimulation, and -0.09 (CI -0.19 to 0.01) for maternal depressive symptoms. Impacts were larger in studies targeted to undernourished children, with mean enrollment older than age 12 months and intervention duration 6 to 12 months. Quality of evidence assessed with the Cochrane Assessment of Risk of Bias and GRADE system was moderate. Instruments used to assess child development varied. In moderator analyses, some subgroups included few studies. CONCLUSIONS: Reach Up benefits child development and home stimulation and is adaptable across cultures and delivery methods. Child and implementation characteristics modified the effects, with implications for scaling.

Comparison of Maternal Labor-Related Complications and Neonatal Outcomes Following Elective Induction of Labor at 39 Weeks of Gestation vs Expectant Management: A Systematic Review and Meta-analysis.

Importance: Elective induction of labor at 39 weeks of gestation is common. Thus, there is a need to assess maternal labor-related complications and neonatal outcomes associated with elective induction of labor. Objective: To examine maternal labor-related complications and neonatal outcomes following elective induction of labor at 39 weeks compared with expectant management. Data Sources: A systematic review of the literature was conducted using the MEDLINE (Ovid), Embase (Ovid), Cochrane Central Library, World Health Organization, and ClinicalTrials.gov databases and registries to search for articles published between database inception and December 8, 2022. Study Selection: This systematic review and meta-analysis included randomized clinical trials, cohort studies, and cross-sectional studies reporting perinatal outcomes following induction of labor at 39 weeks vs expectant management. Data Extraction and Synthesis: Two reviewers independently assessed study eligibility, extracted data, and assessed studies for bias. Pooled odds ratios (ORs) and 95% CIs were calculated using a random-effects model. This study is reported per the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 guideline, and the protocol was prospectively registered with PROSPERO. Main Outcomes and Measures: Maternal outcomes of interest included emergency cesarean section, perineal injury, postpartum hemorrhage, and operative vaginal birth. Neonatal outcomes of interest included admission to the neonatal intensive care unit, low 5-minute Apgar score (<7) after birth, macrosomia, and shoulder dystocia. Results: Of the 5827 records identified in the search, 14 studies were eligible for inclusion in this review. These studies reported outcomes for 1 625 899 women birthing a singleton pregnancy. Induction of labor at 39 weeks of gestation was associated with a 37% reduced likelihood of third- or fourth-degree perineal injury (OR, 0.63 [95% CI, 0.49-0.81]), in addition to reductions in operative vaginal birth (OR, 0.87 [95% CI, 0.79-0.97]), macrosomia (OR, 0.66 [95% CI, 0.48-0.91]), and low 5-minute Apgar score (OR, 0.62 [95% CI, 0.40-0.96]). Results were similar when confined to multiparous women only, with the addition of a substantial reduction in the likelihood of emergency cesarean section (OR, 0.61 [95% CI, 0.38-0.98]) and no difference in operative vaginal birth (OR, 1.01 [95% CI, 0.84-1.21]). However, among nulliparous women only, induction of labor was associated with an increased likelihood of shoulder dystocia (OR, 1.22 [95% CI, 1.02-1.46]) compared with expectant management. Conclusions and Relevance: In this study, induction of labor at 39 weeks was associated with improved maternal labor-related and neonatal outcomes. However, among nulliparous women, induction of labor was associated with shoulder dystocia. These results suggest that elective induction of labor at 39 weeks may be safe and beneficial for some women; however, potential risks should be discussed with nulliparous women.

Prevalence of Perinatal Depression in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

Importance: Women who experience depression during or within a year of pregnancy are at increased risk of morbidity and mortality. Although those living in low- and middle-income countries are thought to be at increased risk of perinatal depression, the true prevalence remains unclear. Objective: To determine the prevalence of depression among individuals living in low- and middle-income countries during pregnancy and up 1 year post partum. Data Sources: MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and the Cochrane Library were searched from database inception until April 15, 2021. Study Selection: Studies were included that reported the prevalence of depression using a validated method during pregnancy or up to 12 months post partum in countries defined by the World Bank as low, lower-middle, and upper-middle income. Data Extraction and Synthesis: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Two reviewers independently assessed study eligibility, extracted data, and assessed studies for bias. Prevalence estimates were calculated using a random-effects meta-analysis model. Subgroup analyses were performed among women who were considered at increased risk of developing perinatal depression. Main Outcomes and Measures: Point prevalence of perinatal depression was the main outcome measured as percentage point estimates with corresponding 95% CIs. Results: The search identified 8106 studies, of which data were extracted from 589 eligible studies reporting outcomes of 616 708 women from 51 countries. The pooled prevalence of perinatal depression across all studies was 24.7% (95% CI, 23.7%-25.6%). The prevalence of perinatal depression varied slightly by country income status. The highest prevalence was found in lower-middle-income countries, with a pooled prevalence of 25.5% (95% CI, 23.8%-27.1%; 197 studies from 23 countries including 212 103 individuals). In upper-middle-income countries, the pooled prevalence was 24.7% (95% CI, 23.6%-25.9%; 344 studies from 21 countries including 364 103 individuals) and in low-income countries, the pooled prevalence was 20.7% (95% CI, 18.4%-23.0%; 50 studies from 7 countries including 40 502 individuals). The East Asia and the Pacific region had the lowest prevalence of perinatal depression at 21.4% (95% CI, 19.8%-23.1%) and was significantly increased in the Middle East and North Africa at 31.5% (95% CI, 26.9%-36.2%; between-group comparison: P < .001). In subgroup analyses, the highest prevalence of perinatal depression was found among women who experienced intimate partner violence, at 38.9% (95% CI, 34.1%-43.6%). revalence of depression was also high among women with HIV (35.1% [95% CI, 29.6%-40.6%]) and those who had experienced a natural disaster (34.8% [95% CI, 29.4%-40.2%]). Conclusions and Relevance: This meta-analysis found that depression was common in low- and middle-income countries, affecting 1 in 4 perinatal women. Accurate estimates of the prevalence of perinatal depression in low- and middle-income countries are essential in informing policy, allocating scarce resources, and directing further research to improve outcomes for women, infants, and families.

Circulating Chemerin Is Elevated in Women With Preeclampsia.

BACKGROUND: Preeclampsia is a severe complication of pregnancy. Chemerin is an adipokine secreted from adipose tissue and highly expressed in placenta. This study evaluated the biomarker potential of circulating chemerin to predict preeclampsia. METHODS: Maternal plasma and placenta were collected from women with early-onset preeclampsia (<34 weeks), with preeclampsia and eclampsia, or before preeclampsia diagnosis (36 weeks). Human trophoblast stem cells were differentiated into syncytiotrophoblast or extravillous trophoblasts across 96 hours. Cells were cultured in 1% O2 (hypoxia) or 5% O2 (normoxia). Chemerin was measured by enzyme-linked immunosorbent assay (ELISA) and RARRES2 (gene coding chemerin) by reverse transcription-quantitative polymerase chain reaction. RESULTS: Circulating chemerin was increased in 46 women with early-onset preeclampsia (<34 weeks) compared to 17 controls (P < .0006). Chemerin was increased in placenta from 43 women with early-onset preeclampsia compared to 24 controls (P < .0001). RARRES2 was reduced in placenta from 43 women with early-onset preeclampsia vs 24 controls (P < .0001). Chemerin was increased in plasma from 26 women with established preeclampsia (P = .006), vs 15 controls. Circulating chemerin was increased in 23 women who later developed preeclampsia vs 182 who did not (P = 3.23 × 10-6). RARRES2 was reduced in syncytiotrophoblast (P = .005) or extravillous trophoblasts (P < .0001). Hypoxia increased RARRES2 expression in syncytiotrophoblast (P = .01) but not cytotrophoblast cells. CONCLUSIONS: Circulating chemerin was elevated in women with early-onset preeclampsia, established preeclampsia, and preceding preeclampsia diagnosis of preeclampsia. RARRES2 was dysregulated in placenta complicated by preeclampsia and may be regulated through hypoxia. Chemerin may have potential as a biomarker for preeclampsia but would need to be combined with other biomarkers.

School-age outcomes among IVF-conceived children: A population-wide cohort study.

BACKGROUND: In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. METHODS AND FINDINGS: Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. CONCLUSIONS: In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.