Fionnuala McAuliffe

Baf60c is essential for function of BAF chromatin remodelling complexes in heart development

Tissue-specific transcription factors regulate several important aspects of embryonic development. They must function in the context of DNA assembled into the higher-order structure of chromatin. Enzymatic complexes such as the Swi/Snf-like BAF complexes remodel chromatin to allow the transcriptional machinery access to gene regulatory elements. Here we show that Smarcd3, encoding Baf60c, a subunit of the BAF complexes, is expressed specifically in the heart and somites in the early mouse embryo. Smarcd3 silencing by RNA interference in mouse embryos derived from embryonic stem cells causes defects in heart morphogenesis that reflect impaired expansion of the anterior/secondary heart field, and also results in abnormal cardiac and skeletal muscle differentiation. An intermediate reduction in Smarcd3 expression leads to defects in outflow tract remodelling reminiscent of human congenital heart defects. Baf60c overexpressed in cell culture can mediate interactions between cardiac transcription factors and the BAF complex ATPase Brg1, thereby potentiating the activation of target genes. These results reveal tissue-specific and dose-dependent roles for Baf60c in recruiting BAF chromatin remodelling complexes to heart-specific enhancers, providing a novel mechanism to ensure transcriptional regulation during organogenesis.

Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomised control trial

Objective To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group. Design Randomised controlled trial. Setting Maternity hospital in Dublin, Ireland. Participants 800 women without diabetes, all in their second pregnancy between January 2007 to January 2011, having previously delivered an infant weighing greater than 4 kg. Intervention Women were randomised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy. Main outcomes The primary outcome measure was difference in birth weight. The secondary outcome measure was difference in gestational weight gain. Results No significant difference was seen between the two groups in absolute birth weight, birthweight centile, or ponderal index. Significantly less gestational weight gain occurred in women in the intervention arm (12.2 v 13.7 kg; mean difference −1.3, 95% confidence interval −2.4 to −0.2; P=0.01). The rate of glucose intolerance was also lower in the intervention arm: 21% (67/320) compared with 28% (100/352) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L (P=0.02). Conclusion A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia. It did, however, have a significant positive effect on gestational weight gain and maternal glucose intolerance. Trial registration Current Controlled Trials ISRCTN54392969.

Optimizing the definition of intrauterine growth restriction: the multicenter prospective PORTO Study

OBJECTIVE The objective of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction (IUGR) (PORTO Study), a national prospective observational multicenter study, was to evaluate which sonographic findings were associated with perinatal morbidity and mortality in pregnancies affected by growth restriction, originally defined as estimated fetal weight (EFW) <10th centile. STUDY DESIGN Over 1100 consecutive ultrasound-dated singleton pregnancies with EFW <10th centile were recruited from January 2010 through June 2012. A range of IUGR definitions were used, including EFW or abdominal circumference <10th, <5th, or <3rd centiles, with or without oligohydramnios and with or without abnormal umbilical arterial Doppler (pulsatility index >95th centile, absent or reversed end-diastolic flow). Adverse perinatal outcome, defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death was documented for all cases. RESULTS Of 1116 fetuses, 312 (28%) were admitted to neonatal intensive care unit and 58 (5.2%) were affected by adverse perinatal outcome including 8 mortalities (0.7%). The presence of abnormal umbilical Doppler was significantly associated with adverse outcome, irrespective of EFW or abdominal circumference measurement. The only sonographic weight-related definition consistently associated with adverse outcome was EFW <3rd centile (P = .0131); all mortalities had EFW <3rd centile. Presence of oligohydramnios was clinically important when combined with EFW <3rd centile (P = .0066). CONCLUSION Abnormal umbilical artery Doppler and EFW <3rd centile were strongly and most consistently associated with adverse perinatal outcome. Our data call into question the current definitions of IUGR used. Future studies may address whether using stricter IUGR cutoffs comparing various definitions and management strategies has implications on resource allocation and pregnancy outcome.

Fetal cardiac effects of maternal hyperglycemia during pregnancy.

Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy.A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis.

Prediction and prevention of the macrosomic fetus

Fetal macrosomia is associated with significant maternal and neonatal morbidity. In the long term, infants who are large for gestational age are more likely than other infants to be obese in childhood, adolescence and early adulthood, and are inherently at higher risk of cardiovascular and metabolic complications in adulthood. With over one billion adults in the world now overweight and more than 600 million clinically obese, preventing the vicious cycle effect of fetal macrosomia and childhood obesity is an increasingly pertinent issue. Fetal growth is determined by a complex interplay of various genetic and environmental influences. Consequently the prediction of pregnancies at risk of pathological overgrowth is difficult. Many risk factors for fetal macrosomia, such as maternal obesity and advanced maternal age, are also conversely associated with intrauterine growth restriction. Sonographic detection of fetal macrosomia is notoriously fraught with difficulties, with dozens of formulas for estimated fetal weight proposed but few with sufficient sensitivity to alter clinical practice. This calls into question policies of elective delivery based on projected estimated fetal weight cut-offs alone. More recently the identification of markers of fetal adiposity and maternal serum biomarkers are being investigated to improve the antenatal detection of the large for gestational age fetus. Prevention of fetal macrosomia is entirely dependent upon correct identification of those at risk. Maternal weight, gestational weight gain and glycaemic control are the risk factors for fetal macrosomia that are most amenable to intervention, and have potential maternal health benefits beyond pregnancy and childbirth. The ideal method of optimising maternal weight and glucose homeostasis is yet to be elucidated, though a number of promising advances are recently being reported. In this review we outline the contemporary evidence for the prediction and prevention of fetal macrosomia, which is indeed a contemporary dilemma.

Respiratory function in singleton and twin pregnancy

Objective Singleton pregnancy causes important changes in respiratory function. The incidence of twin pregnancies is increasing, but it is not known whether affected women suffer greater respiratory compromise. The aim of this study was to determine if changes in respiratory function during pregnancy in healthy women were greater in those with a twin pregnancy compared with those with a singleton pregnancy.

Oxytocin bolus versus oxytocin bolus and infusion for control of blood loss at elective caesarean section: double blind, placebo controlled, randomised trial.

Objectives To determine the effects of adding an oxytocin infusion to bolus oxytocin on blood loss at elective caesarean section. Design Double blind, placebo controlled, randomised trial, conducted from February 2008 to June 2010. Setting Five maternity hospitals in the Republic of Ireland. Participants 2069 women booked for elective caesarean section at term with a singleton pregnancy. We excluded women with placenta praevia, thrombocytopenia, coagulopathies, previous major obstetric haemorrhage (>1000 mL), or known fibroids; women receiving anticoagulant treatment; those who did not understand English; and those who were younger than 18 years. Intervention Intervention group: intravenous slow 5 IU oxytocin bolus over 1 minute and additional 40 IU oxytocin infusion in 500 mL of 0.9% saline solution over 4 hours (bolus and infusion). Placebo group: 5 IU oxytocin bolus over 1 minute and 500 mL of 0.9% saline solution over 4 hours (placebo infusion) (bolus only). Main outcomes Major obstetric haemorrhage (blood loss >1000 mL) and need for an additional uterotonic agent. Results We found no difference in the occurrence of major obstetric haemorrhage between the groups (bolus and infusion 15.7% (158/1007) v bolus only 16.0% (159/994), adjusted odds ratio 0.98, 95% confidence intervals 0.77 to 1.25, P=0.86). The need for an additional uterotonic agent in the bolus and infusion group was lower than that in the bolus only group (12.2% (126/1033) v 18.4% (189/1025), 0.61, 0.48 to 0.78, P<0.001). Women were less likely to have a major obstetric haemorrhage in the bolus and infusion group than in the bolus only group if the obstetrician was junior rather than senior (0.57, 0.35 to 0.92, P=0.02). Conclusion The addition of an oxytocin infusion after caesarean delivery reduces the need for additional uterotonic agents but does not affect the overall occurrence of major obstetric haemorrhage. Trial Registration Current Controlled Trials ISRCTN17813715.

Effect of pregestational diabetes mellitus on fetal cardiac function and structure.

OBJECTIVE Fetuses of diabetic pregnancy experience cardiomyopathy, the intracardiac cause of which is understood poorly. The aim of this study was to assess the interrelation between cardiac functional and structural changes in fetuses of mothers with pregestational diabetes mellitus. STUDY DESIGN Twenty-six mothers with pregestational diabetes mellitus were recruited prospectively to have a fetal echocardiogram at 13, 20, and 36 weeks of gestation to assess cardiac function and structure. For comparison, 30 healthy control subjects were recruited at each gestational age. RESULTS In the first trimester, there was evidence of poorer fetal cardiac diastolic function among the diabetic cohort (lower left early/atrial ratio, longer isovolumetric relaxation time and higher left myocardial performance index; P < .05). In the third trimester, the fetal interventricular septum and the right ventricular free wall were thicker in the diabetic cohort (P < .05). CONCLUSION In fetuses of pregestational diabetic pregnancy, sonographic evidence of altered cardiac function is evident before ultrasound evidence of cardiac structural changes. This suggests that altered cardiac function may precede cardiac structural changes in fetuses of pregestational diabetic pregnancy.

An investigation into the relationship between the metabolic profile of follicular fluid, oocyte developmental potential, and implantation outcome

OBJECTIVE To determine whether metabolomic analysis of follicular fluid could prove a useful noninvasive technique for the selection of viable oocytes and embryos. DESIGN Metabolomic analysis based on proton nuclear magnetic resonance ((1)H NMR) performed on follicular fluid collected from in vitro fertilization (IVF) patients. SETTING A university research center and a private fertility clinic. PATIENT(S) Fifty-eight women undergoing IVF treatment. INTERVENTION(S) Follicular fluid collected at the time of oocyte retrieval. MAIN OUTCOME MEASURE(S) Metabolomic profile, assessment of oocyte developmental potential and embryo viability. RESULT(S) The metabolomic profile of follicular fluid from follicles where the oocyte resulted in a fertilized egg that failed to cleave (n = 9) was distinctly different from that where oocytes developed into early cleavage-stage embryos. Discriminating metabolites included glucose, lactate, choline/phosphocholine, and lipoproteins. Comparison of follicular fluid from women who subsequently had a positive β human chorionic gonadotropin (n = 10) to those who were unsuccessful in achieving a pregnancy (n = 12) revealed metabolic differences that were correlated to cycle outcome. CONCLUSION(S) Differences in the metabolite composition of follicular fluid correlate with the developmental competence of the human oocyte. Therefore, metabolomic profiling of follicular fluid may prove to be an important technique in gamete/embryo selection.

Probiotics in obese pregnancy do not reduce maternal fasting glucose: a double-blind, placebo-controlled, randomized trial (Probiotics in Pregnancy Study)

BACKGROUND Recent studies have reported beneficial effects of probiotics on maternal glycemia in healthy pregnant women. Obesity significantly increases risk of impaired glucose tolerance in pregnancy, but glycemic effects of probiotics in this specific obstetric group require additional investigation. OBJECTIVE The aim of the Probiotics in Pregnancy Study was to investigate the effect of a probiotic capsule on maternal fasting glucose in obese pregnant women. DESIGN In this placebo-controlled, double-blind, randomized trial, 175 pregnant women with an early pregnancy body mass index (BMI; in kg/m²) from 30.0 to 39.9 were recruited from antenatal clinics at the National Maternity Hospital, Dublin, Ireland. Exclusion criteria were BMI <30.0 or >39.9, prepregnancy or gestational diabetes, age <18 y, multiple pregnancy, and fetal anomaly. Women were randomly assigned to receive either a daily probiotic or a placebo capsule from 24 to 28 wk of gestation in addition to routine antenatal care. The primary outcome was the change in fasting glucose between groups from preintervention to postintervention. Secondary outcomes were the incidence of gestational diabetes and neonatal anthropometric measures. RESULTS In 138 women who completed the study (63 women in the probiotic group; 75 women in the placebo group), mean (±SD) early pregnancy BMI was 33.6 ± 2.6, which differed significantly between probiotic (32.9 ± 2.4) and placebo (34.1 ± 2.7) groups. With adjustment for BMI, the change in maternal fasting glucose did not differ significantly between treated and control groups [-0.09 ± 0.27 compared with -0.07 ± 0.39 mmol/L; P = 0.391; B = -0.05 (95% CI: -0.17, 0.07)]. There were also no differences in the incidence of impaired glycemia (16% in the probiotic group compared with 15% in the placebo group; P = 0.561), birth weight (3.70 kg in the probiotic group compared with 3.68 kg in the placebo group; P = 0.723), or other metabolic variables or pregnancy outcomes. A secondary analysis of 110 women, excluding antibiotic users and poor compliers, also revealed no differences in maternal glucose or other outcomes between groups. CONCLUSION Probiotic treatment of 4 wk during pregnancy did not influence maternal fasting glucose, the metabolic profile, or pregnancy outcomes in obese women.