Obstetric and neonatal outcomes in pregnant women with idiopathic polyhydramnios: a systematic review and meta-analysis.

Although the assessment of the amniotic fluid volume in pregnancy is part of the fetal wellbeing surveillance, the impact of idiopathic polyhydramnios (IP) on maternal and perinatal outcomes in unknown. The aim of this meta-analysis was to investigate the association of IP with different maternal and perinatal outcomes. We screened five electronic databases until December 2023 and performed data extraction and quality assessment using ROBINS-E in duplicates. Pooled risk ratios and 95% confidence intervals (95% CI) were calculated with a random effects model. 38 studies were included. Patients with IP were at increased risk of perinatal complications including preterm delivery (RR 1.96, 95% CI 1.35-2.86; I2 = 92%), placental abruption (RR 3.20, 95% CI 2.20-4.65; I2 = 2%), delivery via caesarean section (RR 1.60, 95% CI 1.39-1.84; I2 = 95%) and postpartum haemorrhage (RR 1.98, 95% CI 1.22-3.22; I2 = 84%). Similarly, IP was associated with increased risk of adverse perinatal outcomes including low APGAR score (RR 3.0, 95% CI 1.23-7.35; I2 = 95%), stillbirth (RR 4.75, 95% CI 2.54-8.86; I2 = 9%) and perinatal mortality (RR 4.75, 95% CI 2.67-8.48; I2 = 37%). This meta-analysis suggests that pregnant women with IP may be at increased risk of perinatal complications and adverse neonatal outcomes. However, data remains inconclusive considering the low quality and high heterogeneity of included studies.PROSPERO registration number: CRD42022359944.

Maternal cardiovascular adaptation to pregnancy in obese pregnant women.

INTRODUCTION: Obesity is known to be associated with cardiovascular compromise and a major risk factor for the development of hypertensive disorders in pregnancy. However, little is known about the effect of obesity on maternal cardiac function. The aim of this study was to investigate the effect of obesity on the maternal cardiovascular system. MATERIAL AND METHODS: This was a prospective, observational, longitudinal study. Pregnant women with booking body mass index (BMI) ≥30 kg/m2 were compared with pregnant women with normal booking BMI 20-24.9 kg/m2. Participants were seen at three time points during pregnancy; 12-14, 20-24 and 30-32 weeks. At all visits, maternal blood pressure (BP) was measured, and cardiac geometry and function were assessed using two-dimensional trans-thoracic echocardiography. Multilevel linear mixed-effects models were used for all the comparisons. RESULTS: Fifty-nine pregnant women with obesity were compared with 14 pregnant women with normal BMI. In women with obesity, the maternal BP, heart rate and cardiac output were higher and peripheral vascular resistance was lower (p < 0.01 for all comparisons) compared with normal BMI women. Women with obesity had altered cardiac geometry with higher left ventricular end diastolic diameter, intraventricular septal thickness, posterior wall diameter, relative wall thickness and left ventricular mass (p < 0.001 for all comparisons). There was also evidence of impaired diastolic indices in the obese group with a lower E/A ratio, tissue Doppler imaging E' lateral and medial and higher left atrial volume (p < 0.01 for all comparisons). Finally, women with obesity had reduced longitudinal function, as assessed by mitral plane annular systolic excursion, between the second and third trimester of pregnancy, indicating possible early cardiac dysfunction in this group. CONCLUSIONS: Obesity is associated with maternal hyperdynamic circulation, altered cardiac geometry and suboptimal diastolic function, compared with normal BMI pregnant women, and these factors may contribute to the increased risk of complications in obese pregnant women.

Impact of maternal bariatric surgery on offspring perinatal cardiac function: A prospective study.

OBJECTIVE: To assess perinatal cardiac function in offspring of women with previous bariatric surgery and examine its association with maternal glucose control. DESIGN: Prospective study. SETTING: Maternity unit, UK. POPULATION: Fifty-four fetuses/neonates; 29 of post-bariatric surgery women and 25 of women without surgery. METHODS: Prospective, longitudinal observational study of pregnant women with and without previous bariatric surgery, matched for early pregnancy body mass index. Cardiac function of all offspring was assessed by two-dimensional conventional, spectral tissue Doppler and speckle-tracking echocardiography at 35-37 weeks of gestation and at 5-7 weeks of age. Maternal glycated haemoglobin (HbA1c) was measured at 27-30 weeks of gestation. Maternal demographics and fetal/infant cardiac function indices were compared between the groups. Correlation coefficient (r) is reported. MAIN OUTCOME MEASURES: Fetal/infant cardiac function indices. RESULTS: Compared with no-bariatric neonates, offspring of post-bariatric women were smaller at birth (birthweight centiles: 64.96 ± 36.41 versus 40.17 ± 27.99; p = 0.007). There were no significant differences in fetal/infant cardiac function indices and perinatal cardiac changes, between groups. There was a positive correlation between maternal HbA1c and fetal left ventricular (LV) longitudinal strain (r = 0.33) and LV longitudinal strain rate (r = 0.29), suggesting an inverse relation between HbA1c and fetal LV systolic function, but this was mainly seen in offspring of women with no previous bariatric surgery (r = 0.56 and r = 0.50, respectively). CONCLUSIONS: Maternal bariatric surgery does not appear to inadvertently affect the offspring cardiac performance. We found an inverse correlation between maternal HbA1c levels and fetal LV systolic function but this was mainly seen in the no-bariatric pregnancies.

Risk factors for a serious adverse outcome in neonates: a retrospective cohort study of vaginal births.

OBJECTIVE: To investigate the hypothesis that risk factors in addition to an abnormal fetal heart rate pattern (aFHRp) are independently associated with adverse neonatal outcomes of labour. DESIGN: Observational prospective cohort study. SETTING: 17 UK maternity units. SAMPLE: 585 291 pregnancies between 1988 and 2000 inclusive. METHODS: Adjusted odds ratios (OR) with 95% confidence intervals (95% CI) were estimated from multivariable logistic regression. MAIN OUTCOME MEASURES: Adverse neonatal outcome at term (5-minute Apgar score <7, and a composite measure comprising 5-minute Apgar score <7, resuscitation by intubation and/or perinatal death). RESULTS: Analysis was based on 302 137 vaginal births at 37-42 weeks inclusive. We found a higher odds of Apgar score at 5 minutes <7 with suspected fetal growth restriction (OR 1.34, 95% CI 1.16-1.53), induction of labour (OR 1.41, 95% CI 1.25-1.58), nulliparity (OR 1.48, 95% CI 1.34-1.63), booking body mass index ≥30 (OR 1.18, 95% CI 1.02-1.37), maternal age <25 (OR 1.23, 95% CI 1.10-1.39), black ethnicity (OR 1.21, 95% CI 1.03-1.43), early-term birth at 37-38 weeks (OR 1.13, 95% CI 1.02-1.25), late-term birth at 41-42 weeks (OR 1.14, 95% CI 1.01-1.28), use of oxytocin (OR 1.27, 95% CI 1.14-1.41), maternal pyrexia (OR 1.87, 95% CI 1.46-2.40), aFHRp and presence of meconium (aFHRp without meconium: OR 2.40, 95% CI 2.15-2.69; meconium without aFHRp: OR 2.20, 195% CI.94-2.49; both aFHRp and meconium: OR 4.26, 95% CI 3.74-4.87). The results were similar when the composite adverse outcome was considered. CONCLUSIONS: A range of risk factors, including suspicion of fetal growth restriction, maternal pyrexia and presence of meconium, are implicated in poor birth outcomes in addition to aFHRp. Interpretation of the fetal heart rate pattern alone is insufficient as a basis for decisions about escalation and intervention.

Gestational Weight Gain in Pregnancies Following Bariatric Surgery.

INTRODUCTION: To compare the gestational weight gain (GWG) between women with previous bariatric surgery and those without and investigate whether GWG correlates with birthweight (BW) or delivery of a small-for-gestational-age (SGA) neonate. MATERIALS AND METHODS: Prospective, longitudinal study, include 100 pregnant women with previous bariatric surgery and 100 without weight loss surgery, but with similar early-pregnancy body mass index (BMI). In a sub-study, 50 of the post-bariatric women were also matched to 50 women without surgery, but early-pregnancy BMI similar to the pre-surgery BMI of the post-bariatric ones. All women had their weight/BMI measured at 11-14 and 35-37 weeks of gestation, and the difference in maternal weight/BMI between the two time points was expressed as GWG/BMI gain. Associations between maternal GWG/BMI gain and birthweight (BW) were examined. RESULTS: Compared to no bariatric women with similar early-pregnancy BMI, post-bariatric women had similar GWG (p = 0.46), and the number of women with appropriate, insufficient, and excessive weight gain was comparable between groups (p = 0.76). However, post-bariatric women delivered smaller babies (p < 0.001), and GWG was not a significant predictor of BW or of delivering a SGA neonate. Compared to no bariatric women with similar pre-surgery BMI, post-bariatric ones had higher GWG (p < 0.01) but still delivered smaller neonates (p = 0.001). CONCLUSIONS: Post-bariatric women seem to have similar or greater GWG compared to women without surgery matched for early-pregnancy or pre-surgery BMI, respectively. Maternal GWG was not associated with BW or higher prevalence of SGA neonates seen in women with previous bariatric surgery.

Maternal cardiovascular adaptation to pregnancy in women with previous bariatric surgery.

BACKGROUND: Obesity in pregnancy is associated with substantial risks, notably hypertensive disorders. Bariatric surgery achieves sustained weight loss and has several cardiovascular benefits, including positive effects on blood pressure, cardiac geometry, and both systolic and diastolic function. Pregnancy following bariatric surgery is also associated with improved outcomes, including a reduced risk of hypertensive disorders. The underlying mechanisms, however, remain uncertain. Maternal cardiovascular adaptation plays a vital role in maintaining a healthy pregnancy, and maladaptation has been associated with adverse pregnancy outcomes. However, to date, the maternal cardiovascular adaptation to pregnancy after bariatric surgery has not been investigated. OBJECTIVE: To investigate the maternal cardiovascular adaptation to pregnancy in women with previous bariatric surgery compared with women with a similar early-pregnancy body mass index, age, and race but no history of weight loss surgery. STUDY DESIGN: This was a prospective, observational, longitudinal study including pregnant women with (n=41) and without (n=41) a history of bariatric surgery. The participants were seen at 3 time points; at 12 to 14, 20 to 24, and 30 to 32 weeks of pregnancy. At each visit, the blood pressure was measured and the maternal cardiovascular system was assessed using transthoracic echocardiography. Two-dimensional speckle tracking was performed to assess the global longitudinal and circumferential strain on a subset of patients (15 in each group). Offline analysis was performed according to the European and American echocardiography guidelines. Multilevel linear mixed-effect models were used for all the comparisons. RESULTS: Compared with the no-surgery group, women with previous bariatric surgery, had lower systolic and diastolic blood pressure, heart rate, and cardiac output across all the trimesters (P<.01 for all comparisons), with an evidence of more favorable diastolic indices, including a higher E-wave/A-wave ratio across the mitral valve (P<.001), higher mitral velocity at the lateral and medial annulus (E') (P=.01 and P=.03, respectively), and a lower left atrial volume (P<.05). Furthermore, women with previous bariatric surgery demonstrated lower global longitudinal (P<.01) and circumferential strain (P=.02), which is suggestive of better systolic function. CONCLUSION: Our findings indicate better cardiovascular adaptation to pregnancy in women with previous bariatric surgery than in pregnant women of a similar early-pregnancy body mass index but no history of surgery.

Effect of postbariatric maternal weight loss and surgery to conception interval on perinatal outcomes of nulliparous women.

BACKGROUND: Bariatric surgery is associated with an increased risk of delivering a small neonate. The role of maternal weight loss and surgery to conception interval is unclear. OBJECTIVES: To investigate the effect of maternal weight loss, as a result of bariatric surgery, and surgery to conception interval on fetal growth and birthweight (BW). SETTING: Inner London Teaching Hospital METHODS: We studied prospectively nulliparous women with previous bariatric surgery. Information on type, time, and presurgery weight was obtained. Surgery-to-conception interval was calculated as the time between surgery and conception, defined as the fourteenth day of the pregnancy dated by first trimester ultrasound scan. In the first trimester, maternal weight was measured. Assessment of maternal weight change between presurgery and first trimester of pregnancy was defined as total weight loss (TWL) (%). Fetal ultrasound scans were performed twice; 30-32 and 35-37 weeks' gestation and estimated fetal weight (EFW) was calculated. Fetal growth rate was calculated as the ratio of EFW increase (in grams) between 30-32 and 35-37 weeks divided by the time interval (in days) between the 2 examinations. BW was recorded. RESULTS: The study included 54 pregnant women, 26 with a restrictive procedure (gastric band or vertical sleeve gastrectomy) and 28 with a gastric bypass. Surgery to conception interval was not a significant predictor of the offspring's growth. Maternal TWL was a significant predictor of fetal growth rate (P = .04) and predictor of BW (P = .005), even after adjustment for confounders. CONCLUSIONS: Maternal weight loss, as a result of bariatric surgery, has an inverse correlation with fetal growth rate and BW.

Fetal fractional limb volumes in pregnancies following bariatric surgery.

INTRODUCTION: Obesity rates have reached an epidemic level and bariatric surgery is the most effective method of sustainable weight loss. Pregnancy following bariatric surgery is associated with an increased prevalence of small babies. The objective of the study is to compare the fetal fat distribution, as assessed by fractional arm and thigh volume using three-dimensional ultrasonography, in pregnancies following maternal bariatric surgery with those without such history. MATERIAL AND METHODS: This is a prospective, longitudinal, observational study conducted in a Maternity Unit in the UK. The study included 189 pregnant women; 63 with previous bariatric surgery [27 restrictive (13 with gastric band, 14 with sleeve gastrectomy) and 36 malabsorptive procedures] and 126 with no previous surgery but similar maternal booking body mass index. Fetal arm and thigh volume were obtained at 30-33 and 35-37 weeks' gestation and fractional limb volumes were calculated using a commercially available software. Women underwent a 75 g, 2 h oral glucose tolerance test at 28-31 weeks of gestation. RESULTS: Overall, adjusted fetal arm and thigh volume were smaller in the post-bariatric, compared to the no surgery, group and this was more marked in women who had undergone a previous sleeve gastrectomy (P < .001 and P = .002, respectively) or a malabsorptive procedure (P < .001 for both). There was a strong positive correlation between maternal fasting/post-prandial (2 h) glucose levels, at the time of the oral glucose tolerance test, and arm and thigh volume at both 30-33 and 35-37 weeks (P < .01 for all). CONCLUSIONS: The study has demonstrated that in the third trimester of pregnancy, fetuses of women with previous bariatric surgery have smaller fractional limb volumes, therefore less soft tissue, compared to fetuses of women without such surgery and this may be related to the lower maternal glucose levels seen in the former pregnancies.

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.

BACKGROUND: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. OBJECTIVE: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. STUDY DESIGN: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. RESULTS: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69). CONCLUSION: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.

Longitudinal metabolic and gut bacterial profiling of pregnant women with previous bariatric surgery.

OBJECTIVE: Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development. DESIGN: A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed. RESULTS: Previous malabsorptive, but not restrictive, procedures induced significant changes in maternal metabolic pathways involving branched-chain and aromatic amino acids with decreased circulation of leucine, isoleucine and isobutyrate, increased excretion of microbial-associated metabolites of protein putrefaction (phenylacetlyglutamine, p-cresol sulfate, indoxyl sulfate and p-hydroxyphenylacetate), and a shift in the gut microbiota. The urinary concentration of phenylacetylglutamine was significantly elevated in malabsorptive patients relative to controls (p=0.001) and was also elevated in urine of neonates born from these mothers (p=0.021). Furthermore, the maternal metabolic changes induced by malabsorptive surgery were associated with reduced maternal insulin resistance and fetal/birth weight. CONCLUSION: Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

Maternal, neonatal insulin resistance and neonatal anthropometrics in pregnancies following bariatric surgery.

OBJECTIVE: An increasing number of women present pregnant having undergone bariatric surgery, a popular treatment for sustainable weight loss. The aim of the study was to investigate the effect, if any, of bariatric surgery on maternal and neonatal insulin resistance (IR) and neonatal body fat composition. METHODS: Maternal IR, at 28 weeks of gestation during 2-hour 75 g oral glucose tolerance test (OGTT), neonatal IR, from umbilical cord venous blood, and neonatal birthweight and body fat composition (calculated by measuring skin folds) at birth were evaluated in 41 post-bariatric and 82 pregnant women with similar early pregnancy body mass index but no history of such surgery. Insulin resistance was assessed using the homeostasis model assessment of IR (HOMA-IR). RESULTS: In the post-bariatric surgery group, compared to the no surgery group, maternal HOMA-IR (1.15 [1.04-2.07] vs 2.20 [1.53-3.38]; p < 0.01), neonatal birthweight (p < 0.01) and body fat (p < 0.01) were significantly lower whereas neonatal cord HOMA-IR was similar (1.29 [0.65-2.39] vs 1.19 [0.46-1.93]; p = 0.49). In the no surgery group, there was a positive correlation between maternal and neonatal HOMA-IR (p = 0.03) and between neonatal HOMA-IR and body fat (p < 0.01). However, no such significant correlations were detected in the post-bariatric surgery group. CONCLUSION: Pregnancy following bariatric surgery is associated with a reduction in maternal IR and altered neonatal body composition with significantly lower birthweight and adiposity but no improvement in cord IR.

Inverse correlation between maternal plasma asymmetric dimethylarginine (ADMA) and birthweight percentile in women with impaired placental perfusion: circulating ADMA as an NO-independent indicator of fetal growth restriction?

L-Arginine (Arg) is the enzymatic precursor of nitric oxide (NO) which has multiple biological functions. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO. We hypothesized that the ADMA and SDMA have additional biological functions in pregnancy, beyond NO synthesis, and may play a role in the regulation of birthweight (BW). To investigate this issue, we measured the plasma concentration of ADMA, SDMA, Arg and the NO metabolites nitrite and nitrate, at 23-25 weeks of gestation in women with normal placental function (Group 1) and in women with impaired placental perfusion; 19 of these women had normal outcome (Group 2), 14 had a fetus that was growth restricted (Group 3), and 10 women eventually developed preeclampsia (Group 4). BW percentile was found to inversely correlate with maternal plasma ADMA concentration in Group 3 (r = - 0.872, P < 0.001) and in Group 4 (r = - 0.800, P < 0.05). But, BW percentile did not correlate with the maternal plasma concentration of Arg, SDMA, nitrate or nitrite. Our results suggest that maternal plasma ADMA concentration is an important indicator of fetal growth restriction in women with impaired placental perfusion independent of NO.

Birth weight in relation to health and disease in later life: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Birth weight, a marker of the intrauterine environment, has been extensively studied in epidemiological research in relation to subsequent health and disease. Although numerous meta-analyses have been published examining the association between birth weight and subsequent health-related outcomes, the epidemiological credibility of these associations has not been thoroughly assessed. The objective of this study is to map the diverse health outcomes associated with birth weight and evaluate the credibility and presence of biases in the reported associations. METHODS: An umbrella review was performed to identify systematic reviews and meta-analyses of observational studies investigating the association between birth weight and subsequent health outcomes and traits. For each association, we estimated the summary effect size by random-effects and fixed-effects models, the 95 % confidence interval, and the 95 % prediction interval. We also assessed the between-study heterogeneity, evidence for small-study effects and excess significance bias. We further applied standardized methodological criteria to evaluate the epidemiological credibility of the statistically significant associations. RESULTS: Thirty-nine articles including 78 associations between birth weight and diverse outcomes met the eligibility criteria. A wide range of health outcomes has been studied, ranging from anthropometry and metabolic diseases, cardiovascular diseases and cardiovascular risk factors, various cancers, respiratory diseases and allergies, musculoskeletal traits and perinatal outcomes. Forty-seven of 78 associations presented a nominally significant summary effect and 21 associations remained statistically significant at P < 1 × 10-6. Thirty associations presented large or very large between-study heterogeneity. Evidence for small-study effects and excess significance bias was present in 13 and 16 associations, respectively. One association with low birth weight (increased risk for all-cause mortality), two dose-response associations with birth weight (higher bone mineral concentration in hip and lower risk for mortality from cardiovascular diseases per 1 kg increase in birth weight) and one association with small-for-gestational age infants with normal birth weight (increased risk for childhood stunting) presented convincing evidence. Eleven additional associations had highly suggestive evidence. CONCLUSIONS: The range of outcomes convincingly associated with birth weight might be narrower than originally described under the "fetal origin hypothesis" of disease. There is weak evidence that birth weight constitutes an effective public health intervention marker.

Insulin-like growth factor axis in pregnancies affected by fetal growth disorders.

BACKGROUND: Insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their binding proteins (IGFBPs) are expressed in the placenta and known to regulate fetal growth. DNA methylation is an epigenetic mechanism which involves addition of methyl group to a cytosine base in the DNA forming a methylated cytosine-phosphate-guanine (CpG) dinucleotide which is known to silence gene expression. This silences gene expression, potentially altering the expression of IGFs and their binding proteins. This study investigates the relationship between DNA methylation of components of the IGF axis in the placenta and disorders in fetal growth. Placental samples were obtained from cord insertions immediately after delivery from appropriate, small (defined as birthweight <10th percentile for the gestation [SGA]) and macrosomic (defined as birthweight > the 90th percentile for the gestation [LGA]) neonates. Placental DNA methylation, mRNA expression and protein levels of components of the IGF axis were determined by pyrosequencing, rtPCR and Western blotting. RESULTS: In the placenta from small for gestational age (SGA) neonates (n = 16), mRNA and protein levels of IGF1 were lower and of IGFBPs (1, 2, 3, 4 and 7) were higher (p < 0.05) compared to appropriately grown neonates (n = 37). In contrast, in the placenta from large for gestational age (LGA) neonates (n = 20), mRNA and protein levels of IGF1 was not different and those of IGFBPs (1, 2, 3 and 4) were lower (p < 0.05) compared to appropriately grown neonates. Compared to appropriately grown neonates, CpG methylation of the promoter regions of IGF1 was higher in SGA neonates. The CpG methylation of the promoter regions of IGFBP1, IGFBP2, IGFBP3, IGFBP4 and IGFBP7 was lower in the placenta from SGA neonates as compared to appropriately grown neonates, but was unchanged in the placenta from LGA neonates. CONCLUSIONS: Our results suggest that changes in CpG methylation contribute to the changes in gene expression of components of the IGF axis in fetal growth disorders. Differential methylation of the IGF1 gene and its binding proteins is likely to play a role in the pathogenesis of SGA neonates.

First-trimester fetal growth discordance and development of preeclampsia in dichorionic twin pregnancies.

OBJECTIVE: To investigate the relation between first-trimester fetal growth discrepancy, as assessed by crown-rump length (CRL) at 11+0 to 13+6 weeks of gestation, and subsequent development of preeclampsia (PE) in dichorionic diamniotic (DCDA) twin pregnancies. The association between inter-twin CRL and birth weight (BW) discrepancy was also investigated. METHODS: This was a retrospective, case-control study of DCDA twin pregnancies. Inter-twin CRL discrepancy was calculated as 100×(larger CRL-smaller CRL)/larger CRL. BW discordance was calculated as 100×(larger BW-smaller BW)/larger BW. RESULTS: The study included 299 DCDA pregnancies that remained normotensive and 35 that subsequently developed PE. There was no significant difference in the inter-twin CRL discrepancy between pregnancies complicated by PE and those that were not [3.2%, interquartile range (IQR): 0.5-4.5% vs. 3.3%, IQR: 1.4-5.5%; P=0.17]. There was a positive correlation between inter-twin CRL and BW discrepancy but only in pregnancies that remained normotensive (P<0.001). In women that subsequently developed PE, there was no association between inter-twin CRL and BW discordance (P=0.54). CONCLUSIONS: In unselected DCDA twins, first-trimester CRL discrepancy is not different between pregnancies that subsequently develop PE and those that remain normotensive. Furthermore, in pregnancies that are complicated by PE, the association between inter-twin CRL and BW discrepancy appears to be lost.

First-trimester maternal serum vitamin D and mode of delivery.

Low maternal vitamin D levels have been associated with adverse pregnancy outcome. A recent study has suggested that low maternal vitamin D levels at the time of delivery are also associated with an almost fourfold increase in caesarean section risk. The aim of the present study was to investigate whether there is a difference in maternal serum 25-hydroxyvitamin D (25(OH)D) levels at 11-13 weeks' gestation according to the mode of delivery. Maternal serum 25(OH)D levels were measured at 11-13 weeks' gestation in 995 singleton pregnancies resulting in the birth of phenotypically normal neonates at term. The measured 25(OH)D levels were adjusted for maternal age, BMI, racial origin, smoking, method of conception and season of blood testing, and the adjusted levels (multiple of the median; MoM) were compared between those who subsequently delivered vaginally and those that delivered by caesarean section. Delivery was vaginal in 79·6 % of cases, by emergency caesarean section in 11·6 % and by elective caesarean section in 8·8 %. The median 25(OH)D level in our population was 46·82 (interquartile range (IQR) 27·75-70·13) nmol/l. The adjusted maternal median 25(OH)D levels in the emergency and elective caesarean section groups (0·99, IQR 0·71-1·46 MoM and 0·96, IQR 0·73-1·27 MoM, respectively) were not significantly different from the vaginal delivery group (0·99, IQR 0·71-1·33 MoM; P = 0·53 and P = 0·81, respectively). First-trimester maternal serum 25(OH)D levels are similar between women who subsequently have a vaginal delivery and those who deliver by elective or emergency caesarean section.