Jane E. Harding

The developmental origins of adult disease (Barker) hypothesis

Many studies have provided evidence for the hypothesis that size at birth is related to the risk of developing disease in later life. In particular, links are well established between reduced birthweight and increased risk of coronary heart disease, diabetes, hypertension and stroke in adulthood. These relationships are modified by patterns of postnatal growth. The most widely accepted mechanisms thought to underlie these relationships are those of fetal programming by nutritional stimuli or excess fetal glucocorticoid exposure. It is suggested that the fetus makes physiological adaptations in response to changes in its environment to prepare itself for postnatal life. These changes may include epigenetic modification of gene expression. Less clear at this time are the relevance of fetal programming phenomena to twins and preterm babies, and whether any of these effects can be reversed after birth. Much current active research in this field will be of direct relevance to future obstetric practice.

Cardiovascular risk factors after antenatal exposure to betamethasone : 30-year follow-up of a randomised controlled trial

BACKGROUND Antenatal betamethasone treatment is widely used for the prevention of neonatal respiratory distress syndrome in preterm infants and substantially reduces neonatal mortality and morbidity. Fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms of the fetal origins of adult disease hypothesis. We assessed whether antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome affects cardiovascular risk factors at 30 years of age. METHODS We followed up at age 30 years 534 individuals whose mothers participated in a double-blind, placebo-controlled, randomised trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Mothers received two doses of betamethasone or placebo given by intramuscular injection 24 h apart. Follow-up assessments included anthropometry; measurement of blood pressure, blood lipids (after overnight fasting), and early morning cortisol levels; and a 75 g oral glucose tolerance test. FINDINGS There were no differences between those exposed to betamethasone and to placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease. After a 75 g oral glucose tolerance test, participants exposed to betamethasone had higher plasma insulin concentrations at 30 min (60.5 vs 52.0 mIU/L; ratio of geometric means 1.16 [95% CI 1.03 to 1.31], p=0.02) and lower glucose concentrations at 120 min (4.8 vs 5.1 mmol/L; difference -0.26 mmol/L [-0.53 to 0.00], p=0.05) than did those exposed to placebo. INTERPRETATION Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no clinical effect on cardiovascular risk factors at 30 years of age. Thus, obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Customised birthweight centiles predict SGA pregnancies with perinatal morbidity

Objectives  To determine the following: (1) the proportion of babies reclassified as small or appropriately grown using customised and population centiles; and (2) the relative risks of perinatal morbidity, including abnormal umbilical Doppler studies, in babies classified as small for gestational age (SGA) and appropriate for gestational age (non‐SGA) using the two centile calculations.

FETAL GROWTH AND PLACENTAL FUNCTION

Fetal growth is largely determined by the availability of nutrients to the fetus. The fetus is at the end of a supply line that ensures delivery of nutrients from the maternal/uterine circulation to the fetus via the placenta. However, this supply line can not be regarded as a linear relationship. Maternal undernutrition will not only reduce global nutrient availability but will also influence the maternal and fetal somatotrophic axis. Both endocrine systems react in a very similar way to limited substrate supply. The hormones of the fetal somatotrophic axis, and in particular insulin-like growth factor (IGF)-1, are important regulators of fetal growth. Placental function is pivotal to materno-fetal nutrient and metabolite transfer. Placental function in turn, is heavily influenced by the maternal and fetal growth hormone (GH)-IGF-1 system. The placenta itself is also an active endocrine organ and it produces a large number of hormones including GH and IGF-1 as well their corresponding receptors. Thus the placenta can no longer be considered merely a passive conduit for fetal nutrition. Rather, it is actively involved in the integration of nutritional and endocrine signals from the maternal and fetal somatotrophic axes.

The Physiology and Pathophysiology of Intrauterine Growth Retardation

Insulin-like growth factor I (IGF-I) is the primary hormone influencing fetal growth in later gestation. The regulation of fetal IGF-I in utero is primarily influenced by placental glucose transfer, which regulates fetal insulin release. Furthermore, insulin has direct adipogenic effects on the fetus; fetal growth hormone (GH) may also have additional modes of action on fetal growth. Swallowed amniotic fluid contains IGF-I and may influence gastrointestinal maturation and fetal growth. Furthermore, both fetal and maternal IGF-I can influence placental metabolism. Experimentally, the maternal administration of GH and IGF-I can affect placental function and thus influence fetal growth; this may suggest therapeutic approaches to the treatment of intrauterine growth retardation (IUGR) in utero. Both experimental and clinical evidence support our hypothesis that IUGR is a multihormone relative resistance syndrome; relative resistance to insulin, IGF-I and GH can be demonstrated. Such resistance may be the basis of altered programming by which fetal growth retardation is associated with postnatal growth failure and a greater propensity to develop cardiovascular and metabolic disease in later life.

Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep

ABSTRACT: The influence of fetal glucose and amino acid supply on the regulation of fetal plasma IGF-I levels was investigated in fetuses from starved ewes. Paired maternal and fetal blood samples were taken during an initial 2-d control period, after 48 h of maternal starvation, during a 24-h fetal infusion of glucose (n = 6) or an amino acid mixture (Synthamin 17, n = 5) with continued starvation, and after 48 h of maternal refeeding. After 48 h of starvation, maternal and fetal plasma IGF-I, insulin, and blood glucose fell significantly in both groups compared with control values (IGF-I for glucose group: maternal, −18.53 ± 6.60; fetal, −5.23 ± 1.81 nmol/L; amino acid group: maternal, −18.2 ± 6.97, fetal, −5.12 ± 1.61 nmol/L; both p < 0.05). Fetal glucose but not mixed amino acid infusion raised fetal plasma IGF-I, insulin, and blood glucose to near control values (glucose group fetal IGF-I, −1.77 ± 1.98; amino acid group, −5.93 ± 2.22 nmol/L; both p < 0.05). Maternal plasma IGF-I remained depressed during glucose infusion (−16.33 ± 8.32 nmol/L), but continued to fall in the amino acid group (−21.41 ± 8.20 nmol/L, p < 0.05). After 48 h of maternal refeeding, all values had returned to near control values for both groups (glucose group IGF-I: maternal, −5.2 ± 3.86; fetal, 0.01 ± 2.2 nmol/L; amino acid group: maternal, −11.66 ± 3.2; fetal, −0.70 ± 2.61 nmol/L). We conclude that in the ovine fetus glucose may have a more important role than amino acids in the regulation of fetal plasma IGF-I.

Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial

Abstract Objectives To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. Design Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Setting Tertiary obstetric hospital in Auckland, New Zealand. Participants 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). Interventions Mothers received two doses of betamethasone or placebo 24 hours apart. Main outcome measures Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. Results No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. Conclusions Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Periconceptional Undernutrition of Ewes Impairs Glucose Tolerance in Their Adult Offspring

Maternal undernutrition throughout pregnancy can have long-term effects on the health of adult offspring. Undernutrition around the time of conception alters growth, metabolism, and endocrinology of the sheep fetus, but the impact on offspring after birth is largely unknown. We determined the effect of maternal periconceptional undernutrition in sheep on glucose tolerance in the offspring before and after puberty. Undernourished (UN) ewes were fed individually to maintain weight loss of 10–15% bodyweight from 61 d before until 30 d after mating. Offspring (24 UN, 30 control) underwent an i.v. glucose tolerance test at 4 and 10 mo of age. Glucose tolerance was similar in both groups at 4 mo. Insulin area under the curve increased by 33% between 4 and 10 mo (101 ± 8 versus 154 ± 12 ng · min · mL−1, p < 0.0001). At 10 mo, UN offspring had a 10% greater glucose area under the curve than controls (809 ± 22 versus 712 ± 20 mM · min, p < 0.01), a reduced first phase insulin response (p = 0.003) which was particularly apparent in females and in singletons, and a decreased insulin:glucose ratio (p = 0.01). We conclude that maternal undernutrition around the time of conception results in impaired glucose tolerance in postpubertal offspring.

Incidence of Neonatal Hypoglycemia in Babies Identified as at Risk

OBJECTIVES Routine blood glucose screening is recommended for babies at risk of neonatal hypoglycemia. However, the incidence of hypoglycemia in those screened is not well described. We sought to determine the incidence of hypoglycemia in babies identified as being at risk, and also to determine differences in incidence between at risk groups. STUDY DESIGN Infants (n = 514) were recruited who were born in a tertiary hospital, ≥35 weeks gestation and identified as at risk of hypoglycemia (small, large, infant of a diabetic, late-preterm, and other). Blood glucose screening used a standard protocol and a glucose oxidase method of glucose measurement in the first 48 hours after birth. RESULTS One-half of the babies (260/514, 51%) became hypoglycemic (<2.6 mM), 97 (19%) had severe hypoglycemia (≤2.0 mM), and 98 (19%) had more than 1 episode. The mean duration of an episode was 1.4 hours. Most episodes (315/390, 81%) occurred in the first 24 hours. The median number of blood glucose measurements for each baby was 9 (range 1-22). The incidence and timing of hypoglycemia was similar in all at risk groups, but babies with a total of 3 risk factors were more likely to have severe hypoglycemia. CONCLUSIONS Hypoglycemia is common amongst babies recommended for routine blood glucose screening. We found no evidence that screening protocols should differ in different at risk groups, but multiple risk factors may increase severity. The significance of these hypoglycemic episodes for long-term outcome remains undetermined.

Periconceptional Undernutrition Alters Growth Trajectory and Metabolic and Endocrine Responses to Fasting in Late-Gestation Fetal Sheep

Maternal undernutrition during pregnancy can lead to impaired metabolic regulation in postnatal offspring. The extent to which such abnormalities are determined in early gestation, and may already be present in fetal life, is unknown. We studied the effect of periconceptional undernutrition on fetal growth and metabolism in late gestation. Ewes were either well fed throughout pregnancy (N) or undernourished to reduce ewe weight by 15% from 61 d before until 30 d after mating (UN). At 121 d, one cohort of ewes and their singleton fetuses (N, n = 10; UN, n = 10) were fasted for 72 h, given 25 g of glucose i.v. over 8 h, and refed. Fetal and placental weights were not different at 131 d. UN ewes had higher glucose, amino nitrogen, and Hb concentrations than N ewes. UN fetuses had higher glucose and lactate, and lower amino nitrogen and O2 concentrations and pH. UN ewes had higher insulin and lower IGF-I concentrations, and UN ewes and fetuses had higher placental lactogen concentrations. A second cohort (N, n = 8; UN, n = 10) were studied until term. Chest girth increment was reduced in UN fetuses until delivery, but birth weights were not significantly reduced. These findings suggest that fetal growth, metabolic and endocrine status, and placental function in late gestation are influenced by maternal nutrition in the periconceptional period, independent of fetal size. Metabolic and endocrine adaptations in the mother may mediate some of these effects. Such adaptations may allow continued fetal growth and survival in the face of a potentially adverse nutritional environment.