Andrew Bisits

A placental clock controlling the length of human pregnancy

We report the existence of a ‘placental clock’, which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16–20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.

Patterns of Plasma Corticotropin-Releasing Hormone, Progesterone, Estradiol, and Estriol Change and the Onset of Human Labor

CONTEXT Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Caseload midwifery care versus standard maternity care for women of any risk: M@NGO, a randomised controlled trial

BACKGROUND Women at low risk of pregnancy complications benefit from continuity of midwifery care, but no trial evidence exists for women with identified risk factors. We aimed to assess the clinical and cost outcomes of caseload midwifery care for women irrespective of risk factors. METHODS In this unblinded, randomised, controlled, parallel-group trial, pregnant women at two metropolitan teaching hospitals in Australia were randomly assigned to either caseload midwifery care or standard maternity care by a telephone-based computer randomisation service. Women aged 18 years and older were eligible if they were less than 24 weeks pregnant at the first booking visit. Those who booked with another care provider, had a multiple pregnancy, or planned to have an elective caesarean section were excluded. Women allocated to caseload care received antenatal, intrapartum, and postnatal care from a named caseload midwife (or back-up caseload midwife). Controls received standard care with rostered midwives in discrete wards or clinics. The participant and the clinician were not masked to assignment. The main primary outcome was the proportion of women who had a caesarean section. The other primary maternal outcomes were the proportions who had an instrumental or unassisted vaginal birth, and the proportion who had epidural analgesia during labour. Primary neonatal outcomes were Apgar scores, preterm birth, and admission to neonatal intensive care. We analysed all outcomes by intention to treat. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12609000349246. FINDINGS Publicly insured women were screened at the participating hospitals between Dec 8, 2008, and May 31, 2011. 1748 pregnant women were randomly assigned, 871 to caseload and 877 to standard care. The proportion of caesarean sections did not differ between the groups (183 [21%] in the caseload group vs 204 [23%] in the standard care group; odds ratio [OR] 0·88, 95% CI 0·70-1·10; p=0·26). The proportion of women who had elective caesarean sections (before onset of labour) differed significantly between caseload and standard care (69 [8%] vs 94 [11%]; OR 0·72, 95% CI 0·52-0·99; p=0·05). Proportions of instrumental birth were similar (172 [20%] vs 171 [19%]; p=0·90), as were the proportions of unassisted vaginal births (487 [56%] vs 454 [52%]; p=0·08) and epidural use (314 [36%] vs 304 [35%]; p=0·54). Neonatal outcomes did not differ between the groups. Total cost of care per woman was AUS

Rates of obstetric intervention among low-risk women giving birth in private and public hospitals in NSW: a population-based descriptive study

566·74 (95% 106·17-1027·30; p=0·02) less for caseload midwifery than for standard maternity care. INTERPRETATION Our results show that for women of any risk, caseload midwifery is safe and cost effective. FUNDING National Health and Medical Research Council (Australia).

The Doppler Assessment in multiple pregnancy randomised controlled trial of ultrasound biometry versus umbilical artery Doppler ultrasound and biometry in twin pregnancy

Objectives To compare the risk profile of women giving birth in private and public hospitals and the rate of obstetric intervention during birth compared with previous published rates from a decade ago. Design Population-based descriptive study. Setting New South Wales, Australia. Participants 691 738 women giving birth to a singleton baby during the period 2000 to 2008. Main outcome measures Risk profile of women giving birth in public and private hospitals, intervention rates and changes in these rates over the past decade. Results Among low-risk women rates of obstetric intervention were highest in private hospitals and lowest in public hospitals. Low-risk primiparous women giving birth in a private hospital compared to a public hospital had higher rates of induction (31% vs 23%); instrumental birth (29% vs 18%); caesarean section (27% vs 18%), epidural (53% vs 32%) and episiotomy (28% vs 12%) and lower normal vaginal birth rates (44% vs 64%). Low-risk multiparous women had higher rates of instrumental birth (7% vs 3%), caesarean section (27% vs 16%), epidural (35% vs 12%) and episiotomy (8% vs 2%) and lower normal vaginal birth rates (66% vs 81%). As interventions were introduced during labour, the rate of interventions in birth increased. Over the past decade these interventions have increased by 5% for women in public hospitals and by over 10% for women in private hospitals. Among low-risk primiparous women giving birth in private hospitals 15 per 100 women had a vaginal birth with no obstetric intervention compared to 35 per 100 women giving birth in a public hospital. Conclusions Low-risk primiparous women giving birth in private hospitals have more chance of a surgical birth than a normal vaginal birth and this phenomenon has increased markedly in the past decade.

Inflammatory aetiology of human myometrial activation tested using directed graphs.

Objective To assess the addition value of umbilical artery Doppler ultrasound added to standard ultrasound biometry measurements in the management of twin pregnancies.

Clinical Use of Doppler Ultrasound in Pregnancy: Information from Six Randomised Trials

There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-labouring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p = 0.925), progesterone withdrawal, as a primary event, is plausible (p = 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p = 0.091). DGraph, a software program that creates directed graphs, produced similar results (p = 0.684, p = 0.280, and p = 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible.

Rates of obstetric intervention and associated perinatal mortality and morbidity among low-risk women giving birth in private and public hospitals in NSW (2000-2008) : a linked data population-based cohort study

The objective of this report was to undertake an overview of the clinical utility of umbilical Doppler ultrasound in the management of high-risk pregnancies. The study is designed as a formal meta-analysis of 6 randomised trial reports selected by predetermined criteria and was performed at the Division of Reproductive Medicine, Newcastle University, Australia. A total of 6 randomised controlled trials amounted to 2,102 patients in the experimental (Doppler) group and 2,133 patients in the control group. All patients had high-risk pregnancies. The management of pregnancies with Doppler was compared to those with standard obstetric management (i.e. excluding Doppler). Main outcome measures were perinatal mortality in the form of intrauterine deaths as well as obstetric performance indicators including caesarean section, elective delivery, fetal distress in labour, antenatal admissions and admissions to Neonatal Intensive Care Unit. The meta-analysis shows a significant reduction in perinatal mortality in the groups in which Doppler was used. Typical odds ratio was 0.5 [95% confidence intervals (CI) 0.34, 0.73]. The specific reduction in perinatal mortality occurred in intrauterine deaths in otherwise normally formed fetuses. The typical odds ratio was 0.54 with 95% CI 0.32, 0.89. This meta-analysis shows a significant reduction in overall perinatal mortality, specifically in the form of intrauterine deaths in otherwise normally formed babies.

Lessons to be learnt in managing the breech presentation at term: an 11-year single-centre retrospective study.

Objectives To examine the rates of obstetric intervention and associated perinatal mortality and morbidity in the first 28 days among low-risk women giving birth in private and public hospitals in NSW (2000–2008). Design Linked data population-based retrospective cohort study involving five data sets. Setting New South Wales, Australia. Participants 691 738 women giving birth to a singleton baby during the period 2000–2008. Main outcome measures Rates of neonatal resuscitation, perinatal mortality, neonatal admission following birth and readmission to hospital in the first 28 days of life in public and private obstetric units. Results Rates of obstetric intervention among low-risk women were higher in private hospitals, with primiparous women 20% less likely to have a normal vaginal birth compared to the public sector. Neonates born in private hospitals were more likely to be less than 40 weeks; more likely to have some form of resuscitation; less likely to have an Apgar <7 at 5 min. Neonates born in private hospitals to low-risk mothers were more likely to have a morbidity attached to the birth admission and to be readmitted to hospital in the first 28 days for birth trauma (5% vs 3.6%); hypoxia (1.7% vs 1.2%); jaundice (4.8% vs 3%); feeding difficulties (4% vs 2.4%) ; sleep/behavioural issues (0.2% vs 0.1%); respiratory conditions (1.2% vs 0.8%) and circumcision (5.6 vs 0.3%) but they were less likely to be admitted for prophylactic antibiotics (0.2% vs 0.6%) and for socioeconomic circumstances (0.1% vs 0.7%). Rates of perinatal mortality were not statistically different between the two groups. Conclusions For low-risk women, care in a private hospital, which includes higher rates of intervention, appears to be associated with higher rates of morbidity seen in the neonate and no evidence of a reduction in perinatal mortality.

Women’s experiences of planning a vaginal breech birth in Australia

The 2000 publication of the Term Breech Trial significantly impacted obstetric practice in Australia with a rapid increase in delivery of term breech singletons by caesarean section. More reassuring data from European centres who continued to offer vaginal breech deliveries to carefully selected women have led to a softening of international guidelines which now support an individualised approach to management. The application of this principle to an Australian population, particularly in the wake of such a major change in obstetric practice, has not previously been demonstrated.