Long-term Health Of Offspring Research Articles

Baseline characteristics of the participants of China National Birth Cohort

Objective: To explore the effects of environmental, genetic factors as well as the interactions in early life on the short-term and long-term health of offspring and to systematically evaluate the pregnancy outcomes and health of offspring after birth between families with assisted reproductive technology (ART) conception and families with spontaneous conception. Methods: The China National Birth Cohort (CNBC), a multicenter prospective birth cohort study, includes both families with ART conception and families with spontaneous conception. Since 2016, CNBC has recruited families from 24 hospitals located in 12 provinces, municipalities and autonomous regions throughout China. Information and biospecimens were collected before ART treatment, embryo transfer, at early, second, third trimester and delivery, and at 42 days, 6, 12 and 36 months after birth. Results: By June 2020, CNBC had included 27 044 families with ART conception and 29 589 families with spontaneous conception. The majority of the participants are urban residents. Among the families with ART conception, 65.5% of the men and 63.7% of the women had college degrees or higher. The mean age distribution of men and women was (33.83±5.52) and (32.38±4.67) years. 83.2% of women were primiparas, and the prevalence rates of current regular smokers and current alcohol drinkers were 0.8% and 2.1% in women. Among the families with spontaneous conception, 81.5% of the men and 86.5% of the women had college degrees or higher. The mean age distribution of men and women was (32.06±5.09) and (30.40±4.27) years. 67.2% of women were primiparas, and the prevalence rates of current regular smokers and current alcohol drinkers were 0.1% and 2.2% in women. The baseline characteristics were different between the families with ART conception and spontaneous conception in different regions. Conclusion: CNBC provides a powerful and rich resource in studying the impact of genetic, environmental factors and interactions in early life and ART treatment on the health of offspring after birth.

Relevance of dietary glycemic index, glycemic load and fiber intake before and during pregnancy for the risk of gestational diabetes mellitus and maternal glucose homeostasis

To date, the prevalence of Gestational diabetes mellitus (GDM) in China was 17.5%. Given the substantial relevance of GDM for medium- and long-term health of both mother and offspring and the paucity of existing data on the link between maternal diet and glucose homeostasis during pregnancy in Asian population, additional studies are needed. To examine the relevance of dietary glycemic index (GI), glycemic load (GL) and fiber intake before and during pregnancy for the development of GDM and glucose homeostasis over the course of pregnancy. Cox proportional hazards analysis and linear mixed effects regressions were performed on data from 9317 women for whom three food frequency questionnaires (pre-pregnancy, 1st and 2nd trimesters) and biochemical measures during pregnancy were available. Investigated outcome variables included GDM risk, fasting plasma glucose (FPG), glycated hemoglobin (HbA1C), and homeostasis model assessment insulin resistance (HOMA-IR) in the 1st, 2nd and 3rd trimesters. Women in the highest tertile of dietary GI (or GL) before pregnancy, in the 1st, or the 2nd trimester respectively had a 12% (15%), 25% (23%) or 29% (25%) higher risk of developing GDM than those in the lowest tertile (all p for trend≤0.02). Women with the highest dietary fiber intake before pregnancy, in the 1st or 2nd trimester had a 11%, 17% or 18% lower GDM risk (all p for trend≤0.03). Moreover, increases in GI or GL and decreases in fiber intake over the course of pregnancy (1st to 3rd trimesters) were independently associated with adverse concurrent developments in FPG, HbA1C and HOMA-IR (p≤0.03). Our study indicates that dietary GI, GL and fiber intake before and during pregnancy affects glucose homeostasis of pregnant Chinese women.

Revisiting preeclampsia: a metabolic disorder of the placenta.

Preeclampsia (PE) is a leading cause of maternal and neonatal mortality and morbidity worldwide, impacting the long-term health of both mother and offspring. PE has long been characterized by deficient trophoblast invasion into the uterus and consequent placental hypoperfusion, yet the upstream causative factors and effective interventional targets for PE remain unknown. Alterations in the metabolism of preeclamptic placentas are thought to result from placental ischemia, while disturbances of the metabolism and of metabolites in PE pathogenesis are largely ignored. In fact, as one of the largest fetal organs at birth, the placenta consumes a considerable amount of glucose and fatty acid. Increasing evidence suggests glucose and fatty acid exist as energy substrates and regulate placental development through bioactive derivates. Moreover, recent findings have revealed that the placental metabolism adapts readily to environmental changes, altering its response to nutrients and endocrine signals; this adaptability optimizes pregnancy outcomes by diversifying available carbon sources for energy production, hormone synthesis, angiogenesis, immune activation, and tolerance, and fetoplacental growth. These observations raise the possibility that carbohydrate and lipid metabolism abnormalities play a role in both the etiology and clinical progression of PE, sparking a renewed interest in the interrelationship between PE and metabolic dysregulation. This review will focus on key metabolic substrates and regulatory molecules in the placenta and aim to provide novel insights with respect to the metabolism's role in modulating placental development and functions. Further investigations from this perspective are poised to decipher the etiology of PE and suggest potential therapies.

Long-term Health of Offspring of Women With Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) presents as a constellation of clinical manifestations that can be varied among patients; however, the hormonal derangement associated with PCOS is uniformly characterized by excess androgens and abnormal insulin activity. The alteration in the normal hormonal milieu in these patients and subsequently during their pregnancies is theorized to alter the normal development of the fetus. This in utero exposure and its relationship with behavioral development, metabolic disease, and reproductive outcomes in male and female offspring of mothers with PCOS are under investigation and remains controversial.

Maternal Malnutrition Affects Hepatic Metabolism through Decreased Hepatic Taurine Levels and Changes in HNF4A Methylation.

Fetal programming implies that the maternal diet during pregnancy affects the long-term health of offspring. Although maternal diet influences metabolic disorders and non-alcoholic fatty liver disease in offspring, the hepatic mechanisms related to metabolites are still unknown. Here, we investigated the maternal diet-related alterations in metabolites and the biological pathway in male offspring at three months of age. Pregnant rats were exposed to 50% food restriction during the prenatal period or a 45% high-fat diet during the prenatal and postnatal periods. The male offspring exposed to food restriction and high-fat diets had lower birth weights than controls, but had a catch-up growth spurt at three months of age. Hepatic taurine levels decreased in both groups compared to controls. The decreased hepatic taurine levels in offspring affected excessive lipid accumulation through changes in hepatocyte nuclear factor 4 A methylation. Moreover, the alteration of gluconeogenesis in offspring exposed to food restriction was observed to a similar extent as that of offspring exposed to a high fat diet. These results indicate that maternal diet affects the dysregulation in hepatic metabolism through changes in taurine levels and HNF4A methylation, and predisposes the offspring to Type 2 diabetes and non-alcoholic fatty liver disease in later life.

Associations between gestational diabetes mellitus and the neurodevelopment of offspring from 1 month to 72 months: study protocol for a cohort study

IntroductionGestational diabetes mellitus (GDM) is a common gestational disease and an important global public health problem. GDM may affect the short-term and long-term health of offspring, but the associations between...

Sedentary behaviour and physical activity across pregnancy and birth outcomes.

Shorter gestation or smaller birth size are indicators of a suboptimal fetal environment and negatively impact short- and long-term offspring health. Understanding how modifiable maternal behaviours, such as moderate-to-vigorous intensity physical activity (MVPA) or sedentary behaviour (SED), improve fetal outcomes could inform strategies to improve health across the lifespan. The objective of this study was to examine the association of MVPA and SED across pregnancy trimesters on gestational age at delivery and newborn anthropometrics. The MoM Health Study measured SED (thigh-mounted activPAL3 micro) and MVPA (waist-worn Actigraph GTX3) in each trimester of pregnancy. Birth outcomes (gestational age at delivery, birthweight, birth length, and head circumference) were abstracted from medical records and used to calculate ponderal index (grams*100/cm3 ) and size-for-gestational age percentiles. Associations of group-based trajectories and trimester-specific SED and MVPA with birth outcomes were analysed using regression models. Low, medium, and high trajectory groups were generated SED and MVPA in 103 and 99 pregnant women, respectively. High vs low SED trajectory was associated with earlier gestational age at delivery (β -1.03weeks, 95% CI -2.01, -0.06), larger head circumference (β 0.83cm, 95% CI 0.24, 1.63), longer birth length (β 1.37cm, 95% CI 0.09, 2.64), and lower ponderal index (β -0.24g*100/cm3 , 95% CI -0.42, -0.06), after adjustment for demographics, pre-pregnancy BMI, and (for newborn anthropometric outcomes) gestational age. The association of high SED with lower ponderal index was the most robust across progressively adjusted models (β -0.25g*100/cm3 , 95% CI -0.44, -0.07). SED trajectory was not associated with birthweight or size-for-gestational age. High vs low MVPA trajectory was only associated with smaller head circumference (β -0.86cm, 95% CI -1.70, -0.02). Higher SED during pregnancy may result in shorter gestation and inhibited fetal growth. Further research evaluating the effect of reducing SED during pregnancy on birth outcomes is warranted.

Periconceptional ethanol exposure alters hypothalamic-pituitary-adrenal axis function, signalling elements and associated behaviours in a rodent model

Alcohol consumption throughout pregnancy has been associated with mental illness, hyperactivity and social difficulties in offspring. This may be due in part to programmed disruption of the hypothalamic-pituitary-adrenal axis (HPA) activity and responsiveness. However, it is unknown if the HPA is affected and similar behavioural outcomes occur following alcohol exposure limited to the time around conception, the periconceptional (PC) period. Female Sprague-Dawley rats were treated with PC:EtOH (12.5 % v/v EtOH liquid diet) or a control diet from four days before conception, until embryonic day 4. Offspring at 3-months of age underwent the forced swim test (FST) and social interaction test. HPA reactivity tests (combined dexamethasone suppression test (DST) and corticotropin-releasing hormone test (CST), 30-minute restraint stress) were performed at 5 months of age and then pituitary and adrenal glands were collected for expression of genes involved in HPA regulation.PC:EtOH exposure significantly increased immobility (p < 0.05) in both sexes in the FST. PC:EtOH also increased the duration of affiliative behaviour (p < 0.05) within the social interaction test in female offspring. PC:EtOH programmed HPA hyperactivity in both sexes during the DST/CST test (p < 0.05); however, there was no impact of PC:EtOH on plasma corticosterone concentration in response to restraint stress. There was no significant impact of PC:EtOH on mRNA expression in glucocorticoid signalling genes in the pituitary gland or the steroidogenic pathway in the adrenal gland.This study suggests that alcohol exposure, even when limited to a short period around conception, can program mental illness-like phenotypes, and this was associated with alterations in HPA responsiveness. This study further highlights that consumption of alcohol even prior to implantation may impact the long-term health of offspring.

Paternal programming of offspring health

In recent years, a new focus of the Developmental Origins of Health and Disease hypothesis has emerged examining the potential role that paternal health may play in embryo development, fetal growth and long-term offspring health. While the association between male health and sperm quality has been studied in detail, our understanding of the long-term paternal effects on offspring health remains limited. As with studies aimed at understanding maternal programming, animal models are an essential tool with which to define the underlying mechanisms linking paternal health to post-fertilisation development and offspring well-being. Here, new insights into the genetic and epigenetic nature of the sperm, as well as the role seminal plasma plays in modulating the maternal reproductive environment, are demonstrating the significant role a father's wellbeing at the time of conception has for programming the health of his offspring. In this article we will outline the current understanding of the impact of male health on semen quality, reproductive fitness and post-fertilisation offspring development and explore the mechanisms underlying the paternal programming of offspring health.

Maternal oxycodone treatment causes pathophysiological changes in the mouse placenta

IntroductionPregnant women are increasingly being prescribed and abusing opioid drugs. As the primary communication organ between mother and conceptus, the placenta may be vulnerable to opioid effects but also holds the key to better understanding how these drugs affect long-term offspring health. We hypothesized that maternal treatment with oxycodone (OXY), the primary opioid at the center of the current crisis, deleteriously affects placental structure and gene expression patterns. MethodsFemale mice were treated daily with 5 mg OXY/kg or saline solution (Control, CTL) for two weeks prior to breeding and until placenta were collected at embryonic age 12.5. A portion of the placenta was fixed for histology, and the remainder was frozen for RNA isolation followed by RNAseq. ResultsMaternal OXY treatment reduced parietal trophoblast giant cell (pTGC) area and decreased the maternal blood vessel area within the labyrinth region. OXY exposure affected placental gene expression profiles in a sex dependent manner with female placenta showing up-regulation of many placental enriched genes, including Ceacam11, Ceacam14, Ceacam12, Ceacam13, Prl7b1, Prl2b1, Ctsq, and Tpbpa. In contrast, placenta of OXY exposed males had alteration of many ribosomal proteins. Weighted correlation network analysis revealed that in OXY female vs. CTL female comparison, select modules correlated with OXY-induced placental histological changes. Such associations were lacking in the male OXY vs. CTL male comparison. DiscussionResults suggest OXY exposure alters placental histology. In response to OXY exposure, female placenta responds by upregulating placental enriched transcripts that are either unchanged or downregulated in male placenta. Such changes may shield female offspring from developmental origins of health and disease-based diseases.

Fetal circulating human resistin increases in diabetes during pregnancy and impairs placental mitochondrial biogenesis

BackgroundDiabetes during pregnancy affects placental mitochondrial content and function, which has the potential to impact fetal development and the long-term health of offspring. Resistin is a peptide hormone originally discovered in mice as an adipocyte-derived factor that induced insulin resistance. In humans, resistin is primarily secreted by monocytes or macrophages. The regulation and roles of human resistin in diabetes during pregnancy remain unclear.MethodsFetal resistin levels were measured in cord blood from pregnancies with (n = 42) and without maternal diabetes (n = 81). Secretion of resistin from cord blood mononuclear cells (CBMCs) was measured. The actions of human resistin in mitochondrial biogenesis were determined in placental trophoblastic cells (BeWo cells) or human placental explant.ResultsConcentrations of human resistin in cord sera were higher in diabetic pregnancies (67 ng/ml) compared to healthy controls (50 ng/ml, P < 0.05), and correlated (r = 0.4, P = 0.002) with a measure of maternal glycemia (glucose concentration 2 h post challenge). Resistin mRNA was most abundant in cord blood mononuclear cells (CBMCs) compared with placenta and mesenchymal stem cells (MSCs). Secretion of resistin from cultured CBMCs was increased in response to high glucose (25 mM). Exposing BeWo cells or human placental explant to resistin decreased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial abundance, and ATP production.ConclusionsResistin is increased in fetal circulation of infants exposed to the diabetic milieu, potentially reflecting a response of monocytes/macrophages to hyperglycemia and metabolic stresses associated with diabetes during pregnancy. Increased exposure to resistin may contribute to mitochondrial dysfunction and aberrant energy metabolism characteristic of offspring exposed to diabetes in utero.

Delivery mode and future infectious morbidity of the offspring: a sibling analysis.

Cesarean delivery (CD) has been recently suggested to be associated with offspring's long-term health implications. We aimed to investigate the association between delivery mode and long-term infectious morbidity of the offspring while employing sibling matched analysis to maximize confounder control. A retrospective population-based cohort study was performed, which included all sibling deliveries occurring between 1991 and 2014 at a regional tertiary medical center. Offsprings were followed up until the age of 18years. The study included 13,516 individuals (6758 sibling pairs): the first born was via vaginal delivery and the second via CD. Each siblings pair was considered a matched set, with the aim to perform a within-family analysis. A Kaplan-Meier survival curve was used to compare the cumulative infectious morbidity incidence and a multivariable Cox survival hazards regression model to control for confounders. Crude rates of total infectious hospitalizations were found to be significantly higher in the CD group (OR 1.25; 95% CI 1.12-1.40). Specifically, bronchiolitis (OR 2.02, 95% CI 1.56-2.63), otitis (OR 1.52, 95% CI 1.21-1.9), and gastroenteritis (OR 1.41, 95% CI 1.05-1.9) were all found to be significantly more common in the CD group. The survival curve demonstrated significantly higher cumulative infection-related hospitalization rates in the CD group (log-rank p < 0.001). The Cox model, adjusted for several confounders, confirmed the significant association between CD and offspring's infection-related morbidity (adjusted HR 1.25; 95% CI 1.02-1.53). CD appears to be independently associated with later offspring infection-related morbidity, even while rigorously adjusting for confounders.

Role of metformin in epigenetic regulation of placental mitochondrial biogenesis in maternal diabetes

Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.

Sleep-disordered breathing in pregnancy: a developmental origin of offspring obesity?

Sleep-disordered breathing (SDB) worsens over pregnancy, and obstructive sleep apnea is associated with serious maternal complications. Intrauterine exposures that provoke insulin resistance (IR), inflammation, or oxidative stress may have long-term offspring health consequences. In obesity, worsening maternal SDB appears to be an exposure that increases the risk for both small- or large-for-gestational-age (SGA, LGA, respectively), suggesting distinct outcomes linked to a common maternal phenotype. The aim of this paper is to systematically review and link data from both mechanistic rodent models and descriptive human studies to characterize the impact of maternal SDB on fetal development. A systematic review of the literature was conducted using PubMed, Embase, and CINAHL (01/2000-09/2019). Data from rodent (9 studies) and human models (48 studies, 5 meta-analyses) were included and reviewed using PRISMA guidelines. Evidence from rodent models suggests that intermittent maternal hypoxia results in mixed changes in birth weight (BW) followed by accelerated postnatal growth, while maternal sleep fragmentation results in normal BW followed by later metabolic derangement. Human studies support that maternal SDB is associated with both SGA and LGA, both of which may predispose offspring to later obesity. Evidence also suggests a link between SDB, inflammation, and oxidative stress that may impact maternal metabolism and/or placental function. SDB is common in pregnancy and affects fetal growth and development. Given that SDB has significant potential to adversely influence the intrauterine metabolic environment, larger, prospective studies in humans are urgently needed to fully elucidate the effects of this exposure on offspring metabolic risk.

Clinical Implications

Clinical Implications

Association of maternal BMI during early pregnancy with infant anemia: a large Chinese birth cohort

BackgroundInfant anemia is prevalent in low- and middle-income countries. Maternal body mass index (BMI) is associated with serum ferritin in cord blood, but as yet has not been linked to infant anemia. The objective of this study was to examine the association of maternal BMI during early pregnancy with infant hemoglobin levels and anemia at 6 and 12 months in a Chinese birth cohort.MethodsThe prospective cohort included 17,193 mother-infant pairs. Maternal weight and height prior to 20 gestational weeks as well as infant hemoglobin at 6 and 12 months were measured following standard procedures, and BMI was calculated as weight in kilograms divided by the square of height in meters. Women were categorized into underweight, normal weight (reference), overweight, and obesity. Infant anemia was defined as hemoglobin < 11.0 g/dl. Fractional polynomial regression was used to examine the relation between maternal BMI and infant hemoglobin, joinpoint regression to identify breakpoints, and logistic regression to estimate odds ratios (ORs).ResultsIn the cohort, 1160 (6.8%) were anemic at 6 months and 904 (5.3%) at 12 months. An inverse U-shaped relation of maternal BMI with infant hemoglobin was found at 6 months, at their maximum at maternal BMI of 22.4 kg/m2, and a similar relationship found again at 12 months. Maternal obesity rather than underweight was associated with an increased risk of anemia for infants at 6 months (adjusted OR 1.39, 95% CI 1.02, 1.88), but not at 12 months. Maternal anemia during mid-pregnancy augmented the risk at 6 months (adjusted OR 2.91, 95% CI 1.14, 7.46), but did not mediate the association (Z = − 1.102, P = 0.270).ConclusionsMaternal BMI during early pregnancy is correlated with infant hemoglobin in an inverse U-shaped profile, and obesity increases infant anemia risk that is aggravated by maternal anemia during pregnancy. This study enriched the epidemiological evidence on the adverse effect of high maternal BMI on long-term health of offspring. Optimizing maternal weight in obstetric care is necessary to improve offspring health.

An evaluation of the benefits and harms of antenatal corticosteroid treatment for women at risk of imminent preterm birth or prior to elective Caesarean-section: Study protocol for an individual participant data meta-analysis

Background: Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. Methods: This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The individual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial individually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Discussion: Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. PROSPERO registration: CRD42020167312 (03/02/2020)

Pre-pregnancy obesity and childhood malignancies: A population-based cohort study.

Exploring the effect of maternal obesity during pregnancy on the long-term health of offspring is of great importance. The aim of this study was to evaluate the association between maternal pre-pregnancy obesity and future risk of childhood malignancies. A population-based cohort analysis comparing the risk for long-term childhood malignancies (up to the age of 18 years) in children born (1991-2014) to mothers with and without pre-pregnancy obesity (body mass index>30) was conducted in July 2017. Childhood malignancies were predefined based on ICD-9 codes, as recorded in the hospital medical files. Children with congenital malformations and multiple gestations were excluded from the analysis. The Kaplan-Meier survival curve was constructed to compare cumulative oncological morbidity in both groups over time. The Cox proportional hazards model was used to control for confounders. During the study period, 241273 infants met the inclusion criteria; 3268 were born to mothers with pre-pregnancy obesity. Children of obese women had significantly increased risk for several childhood malignancies (including brain tumors) as well as increased risk for total hospitalizations with malignancy diagnoses, even after controlling for several confounders (adjusted HR 1.90, 95% CI 1.07-3.37, P=0.028). Cumulative incidence of oncological morbidity was also significantly increased over time in the studied group (log-rank P=0.023). Maternal pre-pregnancy obesity is significantly associated with an increased long-term risk for general childhood malignancies, and specifically brain tumors in the offspring. These results are important when counseling mothers regarding potential future risks and recommended lifestyle modifications.

An evaluation of the benefits and harms of antenatal corticosteroid treatment for women at risk of imminent preterm birth or prior to elective Caesarean-section: Study protocol foran individual participant data meta-analysis.

Background: Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. Methods: This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The individual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial individually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Discussion: Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. PROSPERO registration: CRD42020167312 (03/02/2020).

Mechanisms of intergenerational transmission of polycystic ovary syndrome.

Developmental origins of adult disease (DoHAD) refers to critical gestational ages during human fetal development and beyond when the endocrine metabolic status of the mother can permanently program the physiology and/or morphology of the fetus, modifying its susceptibility to disease after birth. The aim of this review is to address how DoHAD plays an important role in the phenotypic expression of polycystic ovary syndrome (PCOS), the most common endocrinopathy of women characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. Clinical studies of PCOS women are integrated with findings from relevant animal models to show how intergenerational transmission of these central components of PCOS are programmed through an altered maternal endocrine-metabolic environment that adversely affects the female fetus and long-term offspring health. Prenatal testosterone treatment in monkeys and sheep have been particularly crucial in our understanding of developmental programming of PCOS because organ system differentiation in these species, as in humans, occurs during fetal life. These animal models, along with altricial rodents, produce permanent PCOS-like phenotypes variably characterized by LH hypersecretion from reduced steroid-negative feedback, hyperandrogenism, ovulatory dysfunction, increased adiposity, impaired glucose-insulin homeostasis and other metabolic abnormalities. The review concludes that DoHAD underlies the phenotypic expression of PCOS through an altered maternal endocrine-metabolic environment that can induce epigenetic modifications of fetal genetic susceptibility to PCOS after birth. It calls for improved maternal endocrine-metabolic health of PCOS women to lower their risks of pregnancy-related complications and to potentially reduce intergenerational susceptibility to PCOS and its metabolic derangements in offspring.