Michael Geary

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.

Intrauterine growth and its relationship to size and shape at birth

Birth size and shape are commonly used as indicators of fetal growth. Epidemiologic studies have suggested a relationship between birth size and the risk of developing cardiovascular disease in later life. Certain “growth phenotypes” have been linked to the development of certain components of cardiovascular disease, particularly babies who display disproportional growth in utero. These observations are based on retrospective analysis of historical data sets. If the “Fetal Origins of Adult Disease” hypothesis is to be generalisable to the present day, then it is essential to establish whether these “growth phenotypes” exist within the normal distribution of birth size. The UCL Fetal Growth Study is a prospective study of antenatal fetal growth assessed by ultrasound at 20 and 30 wk gestation in 1650 low risk, singleton, white pregnancies. Measures of birth size were obtained and analyzed by principal components to explain shape at birth. Birth measures were also related to antenatal growth measurements to determine the strength of ultrasound evaluation in determining subsequent growth.There was significant sexual dimorphism in all measures at birth, with males heavier, longer, and leaner than females. From 20 wk of gestation onwards, males had a significantly larger head size than females. Parity, maternal height, and body mass index were important determinants of birth weight (p < 0.001). Cigarette smoking influenced birth weight, length, and head circumference (p < 0.001) but had no effect on placental size. Principal component analysis revealed that proportionality was the predominant size/shape at birth (55% of variance explained). A further 18% of variance was explained by a contrast between weight, head circumference, and length versus three skinfolds. Anthropometric measures as assessed by ultrasound at 20 and 30 wk gestation were poor predictors of birth length, weight, and head circumference (adjusted R2 18, 40, and 28% at 30 wk gestation scan, respectively). These predictions were not improved by including growth patterns between 20 and 30 wk. There is sexual dimorphism in a number of anthropometric measures at birth and in utero. These sex differences are important determinants of body size and shape. In a low risk population delivering at term, body shape was largely determined by proportionality between anthropometric measures. The low correlations between antenatal measures and birth size suggest that it is unwise to ascribe birth shape phenotypes to adverse events at any particular stage of gestation. The weak relationship also suggests that routine antenatal scans around 30 wk of gestation to predict growth problems are unlikely to be of benefit in the majority of cases.

Successful reduction of massive postpartum haemorrhage by use of guidelines and staff education

We reviewed all cases of massive primary postpartum haemorrhage greater than 1000 mL over a six month period in 1999 to establish the incidence, identify aetiological factors and implement change. Fifty‐four cases (1.7%) were identified. We classified four as ‘near‐miss’ maternal mortality. Over 60% were delivered by caesarean section. Seventy‐six percent were due to uterine atony, 9% due to genital tract trauma and 15% were associated with significant antepartum haemorrhage from placenta praevia or abruption. No obvious labour or delivery risk factors were identified but deviation from hospital guidelines was common. Following revision of the guidelines, dissemination to staff and use of practice drills, we repeated the study on a prospective basis over the same time period in 2002. There was a significant reduction in the incidence of massive postpartum haemorrhage to 0.45%, and 100% adherence to the guidelines which resulted in a significant reduction in maternal morbidity. We believe that this approach can be replicated in other units.

Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth

Objective To determine 1. the relationship between maternal serum leptin concentrations and maternal anthropometry and 2. the relationship between cord serum leptin concentrations at birth and neonatal anthropometry.

Effect of early maternal iron stores on placental weight and structure

BACKGROUND Large placental size and low birthweight have been implicated as factors predicting high blood pressure in adulthood. Maternal anaemia has been suggested as a link. We investigated the interaction between maternal iron status and other factors known to influence birthweight and placental size. METHODS In a prospective study of 1650 low-risk, singleton, caucasian pregnancies, we related placental size and birthweight to maternal iron status, socioeconomic status, and parity. Placental morphology was assessed in 17 randomly chosen primigravid pregnancies. FINDINGS Parity was an important determinant of birthweight (mean standard deviation score -0.13 [SD 0.90] para 0; -0.24 [0.90] para 1; 0.32 [1.1] para 2; 0.21 [1.1] para > or = 3; p<0.0001) and placental weight (mean 655 g [SD 130]; 679 g [122]; 675 g [139]; 694 g [157], respectively; p=0.01). Cigarette smoking influenced birthweight only. Socioeconomic status had little effect after correction for parity. In addition to parity, the factors influencing placental weight were maternal height, weight, and serum ferritin concentration at booking, but not haemoglobin concentration. Serum ferritin concentrations were associated with folate intake and parity. In the placental morphology subset, serum ferritin concentration was inversely related to overall measures of peripheral villous capillarization. Haemoglobin concentration showed no such association. INTERPRETATION These findings show a relation between maternal anaemia and placental size and birthweight across the normal range for these measures. Low ferritin concentrations in early pregnancy were associated with increased placental vascularisation at term. The association between ferritin concentration and folate supplementation emphasises the importance of preconceptional health, particularly in women at high risk of iron deficiency.

Intra‐amniotic inflammation in human gastroschisis: possible aetiology of postnatal bowel dysfunction

Objective To assess amniotic fluid for evidence of an inflammatory exudate in association with fetal gastroschisis.

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.

Shoulder dystocia — is it predictable?

An unmatched comparative study is described to determine if routine clinical indicators are useful predictors for shoulder dystocia. Parity, maternal weight gain during pregnancy, and a history of a previous large baby and increased operative vaginal delivery rate were more often associated with shoulder dystocia. No other significant associations were found. However, shoulder dystocia can not be predicted accurately antepartum using routinely available clinical factors.

Definition of intertwin birth weight discordance.

OBJECTIVE: To establish the level of birth weight discordance at which perinatal morbidity increases in monochorionic and dichorionic twin pregnancy. METHODS: This prospective multicenter cohort study included 1,028 unselected twin pairs recruited over a 2-year period. Participants underwent two weekly ultrasonographic surveillance from 24 weeks of gestation with surveillance of monochorionic twins two-weekly from 16 weeks. Analysis using Cox proportional hazards compared a composite measure of perinatal morbidity (including any of the following: mortality, respiratory distress syndrome, hypoxic–ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, or sepsis) at different degrees of birth weight discordance with adjustment for chorionicity, gestational age, twin–twin transfusion syndrome, birth order, gender, and growth restriction. RESULTS: Perinatal outcome data were recorded for 977 patients (100%) who continued the study with both fetuses alive beyond 24 weeks, including 14 cases of twin–twin transfusion syndrome. Adjusting for gestation at delivery, twin order, gender, and growth restriction, perinatal mortality, individual morbidity, and composite perinatal morbidity were all seen to increase with birth weight discordance exceeding 18% for dichorionic pairs (hazard ratio 2.2, 95% confidence interval [CI] 1.6–2.9, P<.001) and 18% for monochorionic twins without twin–twin transfusion syndrome (hazard ratio 2.6, 95% CI 1.6–4.3, P<.001). A minimum twofold increase in risk of perinatal morbidity persisted even when both twin birth weights were appropriate for gestational age. CONCLUSION: The threshold for birth weight discordance established by this prospective study is 18% both for dichorionic twin pairs and for monochorionic twins without twin–twin transfusion syndrome. This threshold is considerably lower than that defined by many retrospective series as pathologic. We suggest that an anticipated difference of 18% in birth weight should prompt more intensive fetal monitoring. LEVEL OF EVIDENCE: II

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES:Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).METHODS:ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitages trend test.RESULTS:Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.CONCLUSIONS:Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.