John P. Newnham

Effects of frequent ultrasound during pregnancy : a randomised controlled trial

Despite widespread application of ultrasound imaging and Doppler blood flow studies, the effects of their frequent and repeated use in pregnancy have not been evaluated in controlled trials. From 2834 women with single pregnancies at 16-20 weeks gestation, 1415 were selected at random to receive ultrasound imaging and continuous-wave Doppler flow studies at 18, 24, 28, 34, and 38 weeks gestation (the intensive group) and 1419 to receive single ultrasound imaging at 18 weeks (the regular group). Outcome data was obtained from 99% of women who entered the study. The only difference between the two groups was significantly higher intrauterine growth restriction in the intensive group, when expressed both as birthweight < 10th centile (relative risk 1.35; 95% confidence interval 1.09 to 1.67; p = 0.006) and birthweight < 3rd centile (relative risk 1.65; 95% confidence intervals 1.09 to 2.49; p = 0.020). While it is possible that this finding was a chance effect, it is also plausible that frequent exposure to ultrasound may have influenced fetal growth. Repeated prenatal ultrasound imaging and Doppler flow examinations should be restricted to those women to whom the information is likely to be of clinical benefit.

The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health

A general characteristic of fetal endocrine maturation across different species is the enhanced activity of the fetal hypothalamic-pituitary-adrenal (HPA) axis during late gestation. Precocious activation of this axis may occur when the fetus is exposed to an adverse intra-uterine environment, such as hypoxemia. HPA development is associated with increased levels of ACTH(1-39) and adrenal corticosteroids (cortisol in sheep and human) in the fetal circulation, and increased expression of mRNA encoding corticotrophin releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and key steroidogenic enzymes in the fetal adrenal. At term, increased levels of cortisol act on the placenta/trophoblast derived cells to increase expression of prostaglandin synthase Type II (PGHS-II). In human gestation, cortisol also decreases expression of 15-hydroxyprostaglandin dehydrogenase (PGDH) in chorionic trophoblast cells. Increased synthesis and decreased metabolism of prostaglandin (PG) results, during late gestation, in enhanced output of primary PG, which in turn increases the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) in the human fetal membranes. Increased chorionic 11 beta HSD-1 results in increased local generation of cortisol from cortisone, with further paracrine/autocrine stimulation of PG output. Increased fetal cortisol contributes to the maturation of organ systems required for postnatal extra-uterine survival. However, excessive levels of feto-placental glucocorticoid, derived from maternal administration of synthetic corticosteroids or sustained endogenous fetal cortisol production, results in intrauterine growth restriction. Fetal sheep, exposed to maternal betamethasone in late gestation, develop insulin resistance and exaggerated adrenal responses to HPA stimulation by 6-12 months postnatal life. Thus, the level of fetal HPA activity is crucial not only for determining gestation length, but may also predict pathophysiologic adjustments in later life.

Pre-pregnancy body mass index and pregnancy outcomes.

Objective: To determine the effect of maternal pre‐pregnancy BMI on pregnancy outcomes.

Antenatal endotoxin and glucocorticoid effects on lung morphometry in preterm lambs.

In utero inflammation may accelerate fetal lung maturation but may also play a role in the pathogenesis of chronic lung disease. We examined the impact of endotoxin, a potent proinflammatory stimulus, on structural and functional maturation of preterm sheep lungs. Date bred ewes received 20 mg Escherichia coli endotoxin or saline by ultrasound guided intra-amniotic injection at 119 d gestation. A comparison group of animals received 0.5 mg/kg betamethasone, a known maturational agent, at 118 d gestation. Lambs were delivered by cesarean section at 125 d (term = 150 d) and ventilated for 40 min. Lung function data are reported elsewhere. Total and differential white cell counts were performed on amniotic fluid and fetal lung fluid samples. Morphometric analyses were performed on inflation fixed right upper lobes. Total cell count increased slightly but not significantly in both amniotic fluid and fetal lung fluid. Both endotoxin and betamethasone had similar effects on alveolarization: average alveolar volume increased by approximately 20% and total alveolar number decreased by almost 30%. Both treatments led to thinning of alveolar walls, although this was statistically significant in the betamethasone-treated group only. Although antenatal endotoxin leads to striking improvements in postnatal lung function, this may be at the expense of normal alveolar development.

Prenatal inflammation and lung development

Prenatal exposure of very low birth weight infants to chronic indolent chorioamnionitis with organisms such as mycoplasma and ureaplasma is frequent. Chorioamnionitis is inconsistently associated with changed risks of respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), probably because the diagnosis of chorioamnionitis does not quantify the extent or duration of the fetal exposures to infection and inflammation. The correlations between prenatal exposures and postnatal lung disease also are confounded by the imprecision of the diagnoses of RDS and BPD. In animal models, chorioamnionitis caused by pro-inflammatory mediators or live ureaplasma induces lung maturation, but also causes alveolar simplification and vascular injury. Intra-amniotic endotoxin administration also modulates the fetal innate immune system, resulting in maturation of monocytes to alveolar macrophages and the induction or paralysis of inflammatory responses depending on exposure history. Prenatal inflammation can have profound effects on the fetal lung and subsequent immune responses.

Maternal cigarette smoking during pregnancy, low birth weight and subsequent blood pressure in early childhood

Given the widely acknowledged inverse relationship between birth weight and blood pressure, a raised blood pressure in the offspring of smoking mothers as compared to those whose mothers did not smoke, would be anticipated by virtue of the reduction in birth weight associated with smoking during pregnancy. The objective of the present study was to test the hypothesis that maternal cigarette smoking during pregnancy has an effect on blood pressure in childhood independent of its effect on birth weight. Data was obtained from a prospective cohort study of 1708 pregnant women and their singleton offspring, delivered live at term, in Perth, Western Australia, commenced at 16 weeks gestation with serial blood pressure measurements through early childhood. Statistically significant associations were found between maternal smoking during pregnancy and systolic blood pressure at age six, between birth weight and systolic blood pressure at ages three and six, and between maternal smoking during pregnancy and birth weight. The relationship between birth weight and blood pressure in early childhood differed significantly on the basis of maternal cigarette smoking or not during pregnancy. This differential relationship persisted after adjustment for the childs current weight and socio-economic status. We concluded that intra-uterine exposure to maternal cigarette smoking increased childrens blood pressure at age one through to age six. This was not wholly attributable to an effect on birth weight or confounding of the association between birth weight and subsequent blood pressure by the childs current weight or socio-economic factors. Furthermore, maternal smoking during pregnancy does not account for the acknowledged elevation in blood pressure associated with low birth weight. The present study is an exploration of a possible causal pathway underlying the birth weight/blood pressure association rather than simply a confirmation of such an association which has been detailed in many other papers.

Decreased Indicators of Lung Injury with Continuous Positive Expiratory Pressure in Preterm Lambs

Continuous positive airway pressure (CPAP) is being used clinically to avoid mechanical ventilation of preterm infants as a strategy to minimize lung injury. There is little experimental information about how CPAP might minimize lung injury after preterm birth. We induced preterm labor in antenatal glucocorticoid-treated sheep carrying twins at 133 d gestation with an inhibitor of progesterone synthesis. The lambs delivered spontaneously approximately 2 d later and were randomized to three groups: no ventilation (n = 4), conventional mechanical ventilation to a target Pco2 of 40 mm Hg (n = 5), or CPAP using a bubble CPAP device set to deliver 5 cm H2O pressure (n = 6). The CPAP lambs breathed without distress and maintained Pco2 values of approximately 60 mm Hg. At 2 h of age, the lungs of the CPAP lambs held 74 ± 4 mL/kg air at 40 cm H2O pressure, which was more than the 60 ± 3 mL/kg for the ventilated lambs (p < 0.05). Lymphocyte and monocyte numbers in alveolar washes were equivalent in the unventilated, ventilated, and CPAP lambs. However, no neutrophils were found in the unventilated lambs, and the ventilated lambs had 6.6 times more neutrophils in alveolar washes than did the CPAP lambs (p < 0.05). The cells in alveolar wash from CPAP lambs contained less hydrogen peroxide than did the cells from ventilated lambs (p < 0.05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life.

Predictors of body mass index and associations with cardiovascular risk factors in Australian children: a prospective cohort study

OBJECTIVE:To examine predictors of body mass index (BMI) at the age of 8 y in a prospective study of Australian children.DESIGN:Longitudinal survey of a cohort of Australian children followed from the 16th week of gestation to 8 y.SUBJECTS:In total, 741 boys and 689 girls who attended the survey as 8 y olds.MEASUREMENTS:Weight and height, blood pressure measured by automated oscillometry, fasting blood lipids and glucose. Questionnaire assessment of activity and diet.RESULTS:Proportions of overweight including obesity in boys and girls were, respectively, 22 and 25% at 1 y, 14 and 14% at 3 y, 13 and 18% at 5 y and 15 and 20% at 8 y. At the age of 1, 3, 6 and 8 y, children with overweight including obesity showed significantly more adverse cardiovascular risk factors. Blood pressure (BP) was significantly higher by 2/3 mmHg (systolic/diastolic) at 1 y, 3/2 mmHg at 3 y, 4/2 mmHg at 5 y and 6/2 mmHg at 8 y; HDL was significantly lower (P=0.002) by 8% and triglycerides were significantly higher by 27% (P<0.001). In multivariate regression, BMI at the age of 8 y was significantly predicted positively by birth weight, mothers BMI and hours spent in watching television at the time of the survey of 6 y olds. Mothers being ex-smokers or non smokers and children being ‘slightly active’ and ‘active’ negatively predicted BMI in 8 y olds. In a subset of 298 children with information about fathers, paternal BMI was an additional independent predictor. Maternal or paternal overweight including obesity each independently increased risk of overweight including obesity at the age of 8 y three-fold. A food factor with consumption of cereals and breads as the major components derived from a Food Frequency Questionnaire in a subset of 340 children was also an independent negative predictor of BMI in multivariate models.CONCLUSION:The increasing rate of overweight including obesity, particularly in girls, is associated with an increase in cardiovascular risk factors very early in life. Improvement of health-related behaviours within the family and a focus on promotion of activity in children should be priorities in achieving weight control.

Repeated prenatal corticosteroid administration delays myelination of the corpus callosum in fetal sheep

Glucocorticoids regulate oligodendrocyte maturation and the myelin biosynthetic pathways. Synthetic glucocorticoids, the corticosteroids have been successfully used in clinical practice as a single course to enhance lung maturation and reduce mortality and morbidity in preterm infants with no long‐term neurologic or cognitive side effects. However, a trend has arisen to use repeated courses despite an absence of safety data from clinical trials. We examined the effects of clinically appropriate, maternally administrated, repeated courses of corticosteroids on myelination of the corpus callosum using sheep as a large animal model. The corpus callosum is a major white matter tract that undergoes protracted myelination, underpins higher order cognitive processing and developmental damage to which is associated with, for example, cerebral palsy, mental retardation and attention deficit hyperactivity disorder. Pregnant ewes were given saline or betamethasone (0.5 mg/kg) at 104, 111, 118 and 124 days gestation, stages equivalent to the third trimester in humans. Lambs were delivered at 145 days (term), perfused and the corpus callosum examined light and electron microscopically. Total axon numbers were unaffected (P>0.05). However, myelination was significantly delayed. Myelinated axons were 5.7% in the experimental group and 9.2% in controls (P<0.05); conversely, unmyelinated axons were 88.3 and 83.7% (P<0.05). Myelinated axon diameter and myelin sheath thickness were also reduced (0.68 vs. 0.94 and 0.11 vs. 0.14 μm, P<0.05). Our data suggest that repeated prenatal corticosteroid administration delays myelination of the corpus callosum and that further safety data are needed to evaluate clinical practice.

Treatment of Periodontal Disease During Pregnancy: A Randomized Controlled Trial

OBJECTIVE: To investigate whether treating periodontal disease prevents preterm birth and other major complications of pregnancy. METHODS: This single-center trial was conducted across six obstetric sites in metropolitan Perth, Western Australia. Pregnant women identified by history to be at risk (n=3,737) were examined for periodontal disease. Approximately 1,000 women with periodontal disease were allocated at random to receive periodontal treatment commencing around 20 weeks of gestation (n=542) or 6 weeks after the pregnancy was completed (controls; n=540). The treatment included mechanical removal of oral biofilms together with oral hygiene instruction and motivation at a minimum of three weekly visits, with further visits if required. RESULTS: There were no differences between the control and treatment groups in preterm birth (9.3% compared with 9.7%, odds ratio [OR] 1.05, 95% confidence interval [CI 0.7–1.58], P=.81), birth weight (3,450 compared with 3,410 g, P=.12), preeclampsia (4.1% compared with 3.4%, OR 0.82, 95% CI 0.44–1.56, P=.55), or other obstetric endpoints. There were four unexplained stillbirths in the control group and no pregnancy losses in the treated group (P=.12). Measures of fetal and neonatal well-being were similar in the two groups, including abnormalities in fetal heart rate recordings (P=.26), umbilical artery flow studies (P=.96), and umbilical artery blood gas values (P=.37). The periodontal treatment was highly successful in improving health of the gums (P<.01). CONCLUSION: The evidence provided by the present study does not support the hypothesis that treatment of periodontal disease during pregnancy in this population prevents preterm birth, fetal growth restriction, or preeclampsia. Periodontal treatment was not hazardous to the women or their pregnancies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00133926. LEVEL OF EVIDENCE: I