Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes.

BACKGROUND: The aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelines and interventions aimed at limiting GWG in women with overweight or obesity. We explored relationships between maternal BMI, total GWG (as a continuous variable and as 'excessive' GWG), and pregnancy outcomes (including infant birthweight measures and caesarean birth). METHODS: Analysis of individual participant data (IPD) from the i-WIP (International Weight Management in Pregnancy) Collaboration, from randomised trials of diet and/or physical activity interventions during pregnancy reporting GWG and maternal and neonatal outcomes. Women randomised to the control arm of 20 eligible randomised trials (4370 of 8908 participants) from the i-WIP dataset of 36 randomised trials (total 12,240 women). The main research questions were to characterise the relationship between maternal BMI and (a) total GWG, (b) the risk of 'excessive' GWG (using the Institute of Medicine's guidelines), and (c) adverse pregnancy outcomes as mediated via GWG versus other pathways to determine the extent to which the observed effect of maternal BMI on pregnancy outcomes is mediated via GWG. We utilised generalised linear models and regression-based mediation analyses within an IPD meta-analysis framework. RESULTS: Mean GWG decreased linearly as maternal BMI increased; however, the risk of 'excessive' GWG increased markedly at BMI category thresholds (i.e. between the normal and overweight BMI category threshold and between the overweight and obese BMI category threshold). Increasing maternal BMI was associated with increased risk of all pregnancy outcomes assessed; however, there was no evidence that this effect was mediated via effects on GWG. CONCLUSIONS: There is evidence of a meaningful relationship between maternal BMI and GWG and between maternal BMI and adverse pregnancy outcomes. There is no evidence that the effect of maternal BMI on outcomes is via an effect on GWG. Our analyses also cast doubt on the existence of a relationship between 'excessive' GWG and adverse pregnancy outcomes. Our findings challenge the practice of actively managing GWG throughout pregnancy.

Fetal Growth and Adiposity of Infants Born Large for Gestational Age in Three Harmonized Randomized Trials.

OBJECTIVE: Infants born large for gestational age (LGA) are at an increased risk of short- and longer-term adverse outcomes. Understanding fetal growth and adiposity and their trajectories may help inform interventions to prevent birth of LGA infants. We aimed to compare fetal growth and adiposity measures of infants born LGA with those born not LGA, to determine whether the discrepancy at birth was primarily due to larger size throughout gestation, or instead to different trajectories of fetal growth. STUDY DESIGN: This was a secondary analysis of secondary outcomes of fetal growth and adiposity from three harmonized randomized trials-the LIMIT, GRoW, and Optimise randomized trials. These trials recruited women in early pregnancy, and a singleton gestation, from three major public metropolitan Adelaide maternity hospitals. Maternal body mass index (BMI) ranged from 18.5 to ≥40.0 kg/m2. Data were obtained from enrolled women who underwent research ultrasounds at 28 and 36 weeks' gestation. Outcome measures were ultrasound measures of fetal biometry and adiposity. RESULTS: Infants born LGA had larger fetal biometry measures, and higher growth trajectories, from 20 weeks' gestation. Fetal adiposity measures were consistently larger among infants born LGA and these differences increased over time. We did not find evidence that the differences in biometry and adiposity measurements varied according to maternal BMI. CONCLUSION: Infants born LGA had larger fetal biometry measures at all time points from 20 weeks' gestation, compared with infants born not LGA suggesting any interventions to prevent LGA likely need to commence earlier in pregnancy or prior to conception. KEY POINTS: · Infants born LGA had larger fetal biometry measures from 20 weeks' gestation.. · Infants born LGA had larger fetal adiposity measures.. · Interventions to prevent LGA need to start earlier in pregnancy or prior to conception..

Effects of an antenatal dietary intervention in women with obesity or overweight on child outcomes at 8-10 years of age: LIMIT randomised trial follow-up.

BACKGROUND: The LIMIT randomised controlled trial looked at the effect of a dietary and lifestyle intervention compared with routine antenatal care for pregnant women with overweight and obesity on pregnancy outcomes. While women in the intervention group improved diet and physical activity with a reduction of high birth weight, other outcomes were similar. We have followed the children born to women in this study at birth, 6 and 18 months and 3-5 years of age and now report follow-up of children at 8-10 years of age. METHODS: Children at 8-10 years of age who were born to women who participated in the LIMIT randomised trial, and whose mother provided consent to ongoing follow-up were eligible for inclusion. The primary study endpoint was the incidence of child BMI z-score > 85th centile for child sex and age. Secondary study outcomes included a range of anthropometric measures, neurodevelopment, child dietary intake, and physical activity. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Outcome assessors were blinded to the allocated treatment group. RESULTS: We assessed 1,015 (Lifestyle Advice n = 510; Standard Care n = 505) (48%) of the 2,121 eligible children. BMI z-score > 85th percentile was similar for children of women in the dietary Lifestyle Advice Group compared with children of women in the Standard Care Group (Lifestyle Advice 479 (45%) versus Standard Care 507 (48%); adjusted RR (aRR) 0.93; 95% CI 0.82 to 1.06; p = 0.302) as were secondary outcomes. We observed that more than 45% of all the children had a BMI z-score > 85th percentile, consistent with findings from follow-up at earlier time-points, indicating an ongoing risk of overweight and obesity. CONCLUSIONS: Dietary and lifestyle advice for women with overweight and obesity in pregnancy has not reduced the risk of childhood obesity, with children remaining at risk of adolescent and adult obesity. Other strategies are needed to address the risk of overweight and obesity in children including investigation of preconception interventions to assess whether this can modify the effects of maternal pre-pregnancy BMI. The LIMIT randomised controlled trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Data processing choices can affect findings in differential methylation analyses: an investigation using data from the LIMIT RCT.

Objective: A wide array of methods exist for processing and analysing DNA methylation data. We aimed to perform a systematic comparison of the behaviour of these methods, using cord blood DNAm from the LIMIT RCT, in relation to detecting hypothesised effects of interest (intervention and pre-pregnancy maternal BMI) as well as effects known to be spurious, and known to be present. Methods: DNAm data, from 645 cord blood samples analysed using Illumina 450K BeadChip arrays, were normalised using three different methods (with probe filtering undertaken pre- or post- normalisation). Batch effects were handled with a supervised algorithm, an unsupervised algorithm, or adjustment in the analysis model. Analysis was undertaken with and without adjustment for estimated cell type proportions. The effects estimated included intervention and BMI (effects of interest in the original study), infant sex and randomly assigned groups. Data processing and analysis methods were compared in relation to number and identity of differentially methylated probes, rankings of probes by p value and log-fold-change, and distributions of p values and log-fold-change estimates. Results: There were differences corresponding to each of the processing and analysis choices. Importantly, some combinations of data processing choices resulted in a substantial number of spurious 'significant' findings. We recommend greater emphasis on replication and greater use of sensitivity analyses.

Maternal and neonatal outcomes following the introduction of the Fetal Pillow at a tertiary maternity hospital: A retrospective cohort study.

BACKGROUND: Caesarean birth at full cervical dilatation can be technically challenging and may be associated with increased risks of maternal and neonatal morbidity, often secondary to difficulties in delivering a deeply impacted fetal head. The Fetal Pillow is a device designed to elevate an impacted fetal head out of the pelvis and reduce birth trauma. AIMS: To evaluate birth outcomes following the introduction of the Fetal Pillow at a tertiary maternity hospital. MATERIALS AND METHODS: This retrospective cohort study included all caesarean births at full cervical dilatation where the Fetal Pillow was utilised and compared with caesarean births where the Fetal Pillow was not used from October 2018 to December 2019. Maternal outcomes included uterine incision extension, blood loss, high dependency unit admission and postoperative length of stay. Neonatal outcomes included Apgar scores, resuscitation, cord arterial blood pH and lactate, nursery admission, birth trauma, jaundice and seizures. RESULTS: There were 53 caesarean births where the Fetal Pillow was utilised and 48 where it was not. Baseline characteristics were similar between groups with mean maternal age across both groups of 30.4 (±5.3) years, mean gestational age at birth of 39.5 (±1.2) weeks and mean infant birth weight of 3543 (±441) g. There were no statistically significant differences between the two study groups for the maternal and neonatal outcomes considered. CONCLUSIONS: There was no evidence that use of the Fetal Pillow to elevate an impacted fetal head during caesarean birth when cervical dilatation is >7 cm was associated with a reduced rate of adverse maternal and neonatal outcomes.

Childhood follow-up of the GRoW randomized trial: Metformin in addition to dietary and lifestyle advice for pregnant women with overweight or obesity.

BACKGROUND: Metformin for women with overweight or obesity during pregnancy has been evaluated in randomized trials to reduce adverse pregnancy and birth outcomes. The effect on longer-term child health remains of interest. OBJECTIVES: To evaluate the effect of in-utero exposure to metformin on child health compared with no exposure. METHODS: We assessed children born to 513 women who participated in the Metformin in addition to dietary and lifestyle advice for pregnant women with overweight or obesity: the GRoW randomized trial, where women were randomized to receive either metformin or placebo during pregnancy. Child weight, height, anthropometry, diet, physical activity and neurodevelopment were assessed at six and 18 months and three to five years of age. The main outcome was BMI z-score > 85th centile for age and sex. RESULTS: The number of children with BMI >85th centile was similar between treatment groups at all time points. At 18 months and three to five years of age, more than half of the children had a BMI z-score > 85th centile, indicating a high risk of childhood obesity. CONCLUSIONS: We did not show evidence of the benefit of metformin for children of women with overweight or obesity during pregnancy adding to the growing literature on the lack of effect of pregnancy interventions in reducing longer-term risks of childhood obesity.

Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women: The LIMIT Randomised Controlled Trial.

BACKGROUND: To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation. METHODS: We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI ≥25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes. RESULTS: No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI. CONCLUSION: We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation. CLINICAL TRIALS REGISTRATION: ACTRN12607000161426.

Maternal overweight and obesity during pregnancy: strategies to improve outcomes for women, babies, and children.

INTRODUCTION: Women with overweight and obesity, and their children, are at increased risk of adverse pregnancy, birth, and longer term health outcomes, believed to be compounded by excessive gestational weight gain (GWG). Research to date has focused on interventions to reduce excessive GWG through changes to maternal diet and/or lifestyle. AREAS COVERED: Current clinical recommendations for GWG vary according to a woman's early pregnancy body mass index, based on assumptions that associations between GWG and adverse pregnancy outcomes are causal in nature, and modifiable. While there are small differences in GWG following pregnancy interventions, there is little evidence for clinically relevant effects on pregnancy, birth, and longer term childhood outcomes. This review considers interventional studies targeting women with overweight or obesity to reduce GWG in an effort to improve maternal and infant health, and the current evidence for interventions prior to conception. EXPERT OPINION: GWG is not modifiable via diet and lifestyle change, and continued efforts to find the 'right' intervention for women with overweight and obesity during pregnancy are unjustified. Researchers should focus on gathering evidence for interventions prior to pregnancy to optimize maternal health and weight to improve pregnancy, birth, and longer term health outcomes associated with obesity.

The effects of dietary and lifestyle interventions among pregnant women with overweight or obesity on early childhood outcomes: an individual participant data meta-analysis from randomised trials.

BACKGROUND: The impact of maternal obesity extends beyond birth, being independently associated with an increased risk of child obesity. Current evidence demonstrates that women provided with a dietary intervention during pregnancy improve their dietary quality and have a modest reduction in gestational weight gain. However, the effect of this on longer-term childhood obesity-related outcomes is unknown. METHODS: We conducted an individual participant data meta-analysis from RCTs in which women with a singleton, live gestation between 10+0 and 20+0 weeks and body mass index (BMI) ≥ 25 kg/m2 in early pregnancy were randomised to a diet and/or lifestyle intervention or continued standard antenatal care and in which longer-term maternal and child follow-up at 3-5 years of age had been undertaken. The primary childhood outcome was BMI z-score above the 90th percentile. Secondary childhood outcomes included skinfold thickness measurements and body circumferences, fat-free mass, dietary and physical activity patterns, blood pressure, and neurodevelopment. RESULTS: Seven primary trials where follow-up of participants occurred were identified by a systematic literature search within the International Weight Management in Pregnancy (i-WIP) Collaborative Group collaboration, with six providing individual participant data. No additional studies were identified after a systematic literature search. A total of 2529 children and 2383 women contributed data. Approximately 30% of all child participants had a BMI z-score above the 90th percentile, with no significant difference between the intervention and control groups (aRR 0.97; 95% CI 0.87, 1.08; p=0.610). There were no statistically significant differences identified for any of the secondary outcome measures. CONCLUSIONS: In overweight and obese pregnant women, we found no evidence that maternal dietary and/or lifestyle intervention during pregnancy modifies the risk of early childhood obesity. Future research may need to target the pre-conception period in women and early childhood interventions. TRIAL REGISTRATION: PROSPERO, CRD42016047165.

Barriers to and facilitators for addressing overweight and obesity before conception: A qualitative study.

BACKGROUND: Obesity is a significant global health issue, especially for reproductive-aged women. Women who enter pregnancy overweight or obese are at increased risk of a range of adverse reproductive, maternal, and child health outcomes. The preconception period has been recognised as a critical time to intervene to improve health outcomes for women and their children. Despite this recognition, adequate information is significantly lacking in relation to women's health experiences, behaviours, and information preferences to inform the development of high-quality preconception intervention strategies. AIM: This study aimed to examine women's perspectives of barriers, enablers, and strategies for addressing overweight and obesity before conception. METHOD: Using a qualitative research design, twelve multiparous women, aged between 32 and 43 years, who considered themselves to be overweight or obese were interviewed. Data were analysed using thematic analysis. FINDINGS: Three themes were identified in relation to barriers: lack of information and knowledge, time constraints, and affordability. The following four themes emerged with respect to enablers and strategies: knowledge provision, accountability and motivation, regular contact, and habit formation. CONCLUSION: Key factors to incorporate in women-centred interventions for preconception weight loss include multi-faceted knowledge provision and practical affordable methods for supporting healthy behaviours. Interventions should integrate techniques for ensuring regular contact with support networks, to enhance accountability, motivation, and facilitate habit formation. Further research is now being conducted by our team to co-design interventions and strategies informed by these findings.

Skin and subcutaneous fascia closure at caesarean section to reduce wound complications: the closure randomised trial.

BACKGROUND: Wound infection is a common complication following caesarean section. Factors influencing the risk of infection may include the suture material for skin closure, and closure of the subcutaneous fascia. We assessed the effect of skin closure with absorbable versus non-absorbable suture, and closure versus non-closure of the subcutaneous fascia on risk of wound infection following Caesarean section. METHODS: Women undergoing caesarean birth at an Adelaide maternity hospital were eligible for recruitment to a randomised trial using a 2 × 2 factorial design. Women were randomised to either closure or non-closure of the subcutaneous fascia and to subcuticular skin closure with an absorbable or non-absorbable suture. Participants were randomised to each of the two interventions into one of 4 possible groups: Group 1 - non-absorbable skin suture and non-closure of the subcutaneous fascia; Group 2 - absorbable skin suture and non-closure of the subcutaneous fascia; Group 3 - non-absorbable skin suture and closure of the subcutaneous fascia; and Group 4 - absorbable skin suture and closure of the subcutaneous fascia. The primary outcomes were reported wound infection and wound haematoma or seroma within the first 30 days after birth. RESULTS: A total of 851 women were recruited and randomised, with 849 women included in the analyses (Group 1: 216 women; Group 2: 212 women; Group 3: 212 women; Group 4: 211 women). In women who underwent fascia closure, there was a statistically significant increase in risk of wound infection within 30 days post-operatively for those who had skin closure with an absorbable suture (Group 4), compared with women who had skin closure with a non-absorbable suture (Group 3) (adjusted RR 2.17; 95% CI 1.05, 4.45; p = 0.035). There was no significant difference in risk of wound infection for absorbable vs non-absorbable sutures in women who did not undergo fascia closure. CONCLUSION: The combination of subcutaneous fascia closure and skin closure with an absorbable suture may be associated with an increased risk of reported wound infection after caesarean section. TRIAL REGISTRATION: Prospectively registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12608000143325 , on the 20th March, 2008.

Relief of pain due to uterine cramping/involution after birth.

BACKGROUND: Women may experience differing types of pain and discomfort following birth, including cramping pain (often called after-birth pain) associated with uterine involution, where the uterus contracts to reduce blood loss and return the uterus to its non-pregnant size. This is an update of a review first published in 2011. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological pain relief/analgesia for the relief of after-birth pains following vaginal birth. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (31 October 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials comparing two different types of analgesia or analgesia versus placebo or analgesia versus no treatment, for the relief of after-birth pains following vaginal birth. Types of analgesia included pharmacological and non-pharmacological. Quasi-randomised trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, conducted 'Risk of bias' assessment, extracted data and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: In this update, we include 28 studies (involving 2749 women). The evidence identified in this review comes from middle- to high-income countries. Generally the trials were at low risk of selection bias, performance bias and attrition bias, but some trials were at high risk of bias due to selective reporting and lack of blinding. Our GRADE certainty of evidence assessments ranged from moderate to very low certainty, with downgrading decisions based on study limitations, imprecision, and (for one comparison) indirectness. Most studies reported our primary outcome of adequate pain relief as reported by the women. No studies reported data relating to neonatal adverse events, duration of hospital stay, or breastfeeding rates. Almost half of the included studies (11/28) excluded breastfeeding women from participating, making the evidence less generalisable to a broader group of women. Non-steroidal anti-inflammatory drugs (NSAIDs) compared to placebo NSAIDs are probably better than placebo for adequate pain relief as reported by the women (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.45 to 1.91; 11 studies, 946 women; moderate-certainty evidence). NSAIDs may reduce the need for additional pain relief compared to placebo (RR 0.15, 95% CI 0.07 to 0.33; 4 studies, 375 women; low-certainty evidence). There may be a similar risk of maternal adverse events (RR 1.05, 95% CI 0.78 to 1.41; 9 studies, 598 women; low-certainty evidence). NSAIDs compared to opioids NSAIDs are probably better than opioids for adequate pain relief as reported by the women (RR 1.33, 95% CI 1.13 to 1.57; 5 studies, 560 women; moderate-certainty evidence) and may reduce the risk of maternal adverse events (RR 0.62, 95% CI 0.43 to 0.89; 3 studies, 255 women; low-certainty evidence). NSAIDs may be better than opioids for the need for additional pain relief, but the wide CIs include the possibility that the two classes of drugs are similarly effective or that opioids are better (RR 0.37, 95% CI 0.12 to 1.12; 2 studies, 232 women; low-certainty evidence). Opioids compared to placebo Opioids may be better than placebo for adequate pain relief as reported by the women (RR 1.26, 95% CI 0.99 to 1.61; 5 studies, 299 women; low-certainty evidence). Opioids may reduce the need for additional pain relief compared to placebo (RR 0.48, 95% CI 0.28 to 0.82; 3 studies, 273 women; low-certainty evidence). Opioids may increase the risk of maternal adverse events compared with placebo, although the certainty of evidence is low (RR 1.59, 95% CI 0.99 to 2.55; 3 studies, 188 women; low-certainty evidence). Paracetamol compared to placebo Very low-certainty evidence means we are uncertain if paracetamol is better than placebo for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events (2 studies, 123 women). Paracetamol compared to NSAIDs Very low-certainty evidence means we are uncertain if there are any differences between paracetamol and NSAIDs for adequate pain relief as reported by the women, or the risk of maternal adverse events. No data were reported about the need for additional pain relief comparing paracetamol and NSAIDs (2 studies, 112 women). NSAIDs compared to herbal analgesia We are uncertain if there are any differences between NSAIDs and herbal analgesia for adequate pain relief as reported by the women, the need for additional pain relief, or risk of maternal adverse events, because the certainty of evidence is very low (4 studies, 394 women). Transcutaneous nerve stimulation (TENS) compared to no TENS Very low-certainty evidence means we are uncertain if TENS is better than no TENS for adequate pain relief as reported by the women. No other data were reported comparing TENS with no TENS (1 study, 32 women). AUTHORS' CONCLUSIONS: NSAIDs may be better than placebo and are probably better than opioids at relieving pain from uterine cramping/involution following vaginal birth. NSAIDs and paracetamol may be as effective as each other, whereas opioids may be more effective than placebo. Due to low-certainty evidence, we are uncertain about the effectiveness of other forms of pain relief. Future trials should recruit adequate numbers of women and ensure greater generalisability by including breastfeeding women. In addition, further research is required, including a survey of postpartum women to describe appropriately their experience of uterine cramping and involution. We identified nine ongoing studies, which may help to increase the level of certainty of the evidence around pain relief due to uterine cramping in future updates of this review.

Effect of metformin in addition to an antenatal diet and lifestyle intervention on fetal growth and adiposity: the GRoW randomised trial.

BACKGROUND: The infants born to women who are overweight or obese in pregnancy are at an increased risk of being born macrosomic or large for gestational age. Antenatal dietary and lifestyle interventions have been shown to be ineffective at reducing this risk. Our aim was to examine the effects of metformin in addition to a diet and lifestyle intervention on fetal growth and adiposity among women with a BMI above the healthy range. METHODS: Women who had a body mass index ≥25 kg/m2 in early pregnancy, and a singleton gestation, were enrolled in the GRoW trial from three public maternity hospitals in metropolitan Adelaide. Women were invited to have a research ultrasounds at 28 and 36 weeks' gestation at which ultrasound measures of fetal biometry and adiposity were obtained. Fetal biometry z-scores and trajectories were calculated. Measurements and calculations were compared between treatment groups. This secondary analysis was pre-specified. RESULTS: Ultrasound data from 511 women were included in this analysis. The difference in femur length at 36 weeks' gestation was (0.07 cm, 95% CI 0.01-0.14 cm, p = 0.019) and this was was statistically significant, however the magnitude of effect was small. Differences between treatment groups for all other fetal biometry measures, z-scores, estimated fetal weight, and adiposity measures at 28 and 36 weeks' gestation were similar. CONCLUSIONS: The addition of metformin to dietary and lifestyle advice in pregnancy for overweight and obese women has no clinically relevant effect on ultrasound measures of fetal biometry or adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12612001277831 ).

Gestational Weight Gain-Re-Examining the Current Paradigm.

Our aim was to investigate the underlying assumptions of the current gestational weight gain (GWG) paradigm, specifically that-(1) GWG is modifiable through diet and physical activity; (2) optimal GWG and risk of excess GWG, vary by pre-pregnancy body mass index (BMI) category and (3) the association between GWG and adverse pregnancy outcomes is causal. Using data from three large, harmonized randomized controlled trials (RCTs) of interventions to limit GWG and improve pregnancy outcomes and with appropriate regression models, we investigated the link between diet and physical activity and GWG; the relationships between pre-pregnancy BMI, GWG and birth weight z-score; and the evidence for a causal relationship between GWG and pregnancy outcomes. We found little evidence that diet and physical activity in pregnancy affected GWG and that the observed relationships between GWG and adverse pregnancy outcomes are causal in nature. Further, while there is evidence that optimal GWG may be lower for women with higher BMI, target ranges defined by BMI categories do not accurately reflect risk of adverse outcomes. Our findings cast doubt upon current advice regarding GWG, particularly for overweight and obese women and suggest that a change in focus is warranted.

Effects of an antenatal dietary intervention in women with obesity or overweight on child outcomes at 3-5 years of age: LIMIT randomised trial follow-up.

While the effects of an antenatal dietary intervention for women with obesity or overweight on pregnancy and newborn health have been extensively studied, the longer-term effects into childhood are unknown. We followed children born to women who participated in the LIMIT randomised trial, where pregnant women were randomised to an antenatal dietary and lifestyle intervention or standard antenatal care. Our aim was to assess the effect of the intervention, on child outcomes at 3-5 years of age on children whose mothers provided consent. We assessed 1418 (Lifestyle Advice n = 727; Standard Care n = 691) (66.9%) of the 2121 eligible children. There were no statistically significant differences in the incidence of child BMI z-score >85th centile for children born to women in the Lifestyle Advice Group, compared with the Standard Care group (Lifestyle Advice 444 (41.73%) versus Standard Care 417 (39.51%); adjusted relative risk (aRR) 1.05; 95% confidence intervals 0.93-1.19; p = 0.42). There were no significant effects on measures of child growth, adiposity, neurodevelopment, or dietary intake. There is no evidence that an antenatal dietary intervention altered child growth and adiposity at age 3-5 years. This cohort of children remains at high risk of obesity, and warrants ongoing follow-up.

A Randomised Trial to Optimise Gestational Weight Gain and Improve Maternal and Infant Health Outcomes through Antenatal Dietary, Lifestyle and Exercise Advice: The OPTIMISE Randomised Trial.

There are well-recognised associations between excessive gestational weight gain (GWG) and adverse pregnancy outcomes, including an increased risk of pre-eclampsia, gestational diabetes and caesarean birth. The aim of the OPTIMISE randomised trial was to evaluate the effect of dietary and exercise advice among pregnant women of normal body mass index (BMI), on pregnancy and birth outcomes. The trial was conducted in Adelaide, South Australia. Pregnant women with a body mass index in the healthy weight range (18.5-24.9 kg/m2) were enrolled in a randomised controlled trial of a dietary and lifestyle intervention versus standard antenatal care. The dietitian-led dietary and lifestyle intervention over the course of pregnancy was based on the Australian Guide to Healthy Eating. Baseline characteristics of women in the two treatment groups were similar. There was no statistically significant difference in the proportion of infants with birth weight above 4.0 kg between the Lifestyle Advice and Standard Care groups (24/316 (7.59%) Lifestyle Advice versus 26/313 (8.31%) Standard Care; adjusted risk ratio (aRR) 0.91; 95% confidence interval (CI) 0.54 to 1.55; p = 0.732). Despite improvements in maternal diet quality, no significant differences between the treatment groups were observed for total GWG, or other pregnancy and birth outcomes.

Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy.

BACKGROUND: Multiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe. Since publication of this new review in Issue 10, 2017, we have now moved one study (El-Refaie 2016) from included to studies awaiting classification, pending clarification about the study data. OBJECTIVES: To assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi-randomised or cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence. MAIN RESULTS: We included 16 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4548 women. The risk of bias for the majority of included studies was low, with the exception of three studies that had inadequate blinding, or significant loss to follow-up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM progesterone versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low-quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by dose There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.90, 95% CI 0.66 to 1.23; women = 1503; studies = 5; I2 = 36%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.53, 95% CI 0.79 to 2.97; women = 1345; studies = 3; low-quality evidence); infant birthweight less than 2500 g (average RR 0.95, 95% CI 0.84 to 1.07; infants = 2640; studies = 3; I2 = 66%, moderate-quality evidence)). No childhood outcomes were reported in the trials. For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (8%) (RR 0.92, 95% CI 0.86 to 0.98; women = 1919; studies = 5; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.70, 95% CI 0.52 to 0.94; infants = 2695; studies = 4). AUTHORS' CONCLUSIONS: Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes. Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).

Nutrition During Pregnancy, Lactation and Early Childhood and its Implications for Maternal and Long-Term Child Health: The Early Nutrition Project Recommendations.

BACKGROUND: A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). METHODS: Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. FINDINGS: Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. INTERPRETATION: We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases.

Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: the GRoW randomised, double-blind, placebo-controlled trial.

BACKGROUND: Maternal overweight and obesity are associated with well recognised pregnancy complications. Antenatal dietary and lifestyle interventions have a modest effect on gestational weight gain without affecting pregnancy outcomes. We aimed to assess the effects on maternal and infant outcomes of antenatal metformin given in addition to dietary and lifestyle advice among overweight and obese pregnant women. METHODS: GRoW was a multicentre, randomised, double-blind, placebo-controlled trial in which pregnant women at 10-20 weeks' gestation with a BMI of 25 kg/m2 or higher were recruited from three public maternity units in Adelaide, SA, Australia. Women were randomly assigned (1:1) via a computer-generated schedule to receive either metformin (to a maximum dose of 2000 mg per day) or matching placebo. Participants, their antenatal care providers, and research staff (including outcome assessors) were masked to treatment allocation. All women received an antenatal dietary and lifestyle intervention. The primary outcome was the proportion of infants with birthweight greater than 4000 g. Secondary outcomes included measures of maternal weight gain, maternal diet and physical activity, maternal pregnancy and birth outcomes, maternal quality of life and emotional wellbeing, and infant birth outcomes. Outcomes were analysed on an intention-to-treat basis (including all randomly assigned women who did not withdraw consent to use their data, and who did not have a miscarriage or termination of pregnancy before 20 weeks' gestation, or a stillbirth). The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12612001277831. FINDINGS: Of 524 women who were randomly assigned between May, 28 2013 and April 26, 2016, 514 were included in outcome analyses (256 in the metformin group and 258 in the placebo group). Median gestational age at trial entry was 16·29 weeks (IQR 14·43-18·00) and median BMI was 32·32 kg/m2 (28·90-37·10); 167 (32%) participants were overweight and 347 (68%) were obese. There was no significant difference in the proportion of infants with birthweight greater than 4000 g (40 [16%] with metformin vs 37 [14%] with placebo; adjusted risk ratio [aRR] 0·97, 95% CI 0·65 to 1·47; p=0·899). Women receiving metformin had lower average weekly gestational weight gain (adjusted mean difference -0·08 kg, 95% CI -0·14 to -0·02; p=0·007) and were more likely to have gestational weight gain below recommendations (aRR 1·46, 95% CI 1·10 to 1·94; p=0·008). Total gestational weight gain, pregnancy and birth outcomes, maternal diet and physical activity, and maternal quality of life and emotional wellbeing did not differ significantly between groups. Similar numbers of women in both treatment groups (76% [159/208] in the metformin group and 73% [144/196] in the placebo group) reported side-effects including nausea, diarrhoea, and vomiting. Two stillbirths (placebo group) and one neonatal death (metformin group) occurred; none of the perinatal deaths were determined to be attributable to participation in the trial. INTERPRETATION: For pregnant women who are overweight or obese, metformin given in addition to dietary and lifestyle advice initiated at 10-20 weeks' gestation does not improve pregnancy and birth outcomes. FUNDING: Australian National Health and Medical Research Council.

Prenatal Diet and Child Growth at 18 Months.

OBJECTIVE: Our objective was to evaluate the effect of an antenatal dietary and lifestyle intervention in pregnant women who are overweight or obese on child outcomes at age 18 months. METHODS: We conducted a follow-up study of children at 18 months of age who were born to women who participated in the Limiting Weight Gain in Overweight and Obese Women during Pregnancy to Improve Health Outcomes randomized trial. The primary follow-up study outcome was prevalence of child BMI z scores >85th percentile. Secondary study outcomes included a range of anthropometric measures, neurodevelopment, general health, and child feeding. Intention to treat principles were used in analyses, according to the treatment group allocated at randomization. RESULTS: A total of 1602 children were assessed at age 18 months (lifestyle advice, n = 816; standard care, n = 786), representing 75.0% of the eligible sample (n = 2136). There were no statistically significant differences in the prevalence of child BMI z scores >85th percentile for children born to women in the lifestyle advice group, compared with the standard care group (lifestyle advice, 505 [47.11%] versus standard care, 483 [45.36%]; adjusted relative risk: 1.04; 95% confidence interval: 0.94 to 1.16; P = .45). There was no evidence of effects on child growth, adiposity, neurodevelopment, or dietary and physical activity patterns. CONCLUSIONS: There is no evidence that providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention altered 18-month child growth and adiposity.