Amy L. Wooldridge

Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep

Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming.

Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep.

Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents.

In utero programming of allergic susceptibility

Background: Around 30-40% of the worlds population will experience allergy, the most common and earliest-onset noncommunicable disease. With a steady rise in the incidence of allergic disease over recent decades, up to 18% of children will suffer a respiratory, food or skin allergy before their 18th birthday. There is compelling evidence that the risk of developing allergy is influenced by early life events and particularly in utero exposures. Methods: A comprehensive literature review was undertaken which outlines prenatal risk factors and potential mechanisms underlying the development of allergy in childhood. Results: Exposures including maternal cigarette smoking, preterm birth and Caesarean delivery are implicated in predisposing infants to the later development of allergy. In contrast, restricted growth in utero, a healthy maternal diet and a larger family size are protective, but the mechanisms here are unclear and require further investigation. Conclusion: To ameliorate the allergy pandemic in young children, we must define prenatal mechanisms that alter the programming of the fetal immune system and also identify specific targets for antenatal interventions.

Development of an experimental model of maternal allergic asthma during pregnancy

We studied the effects of preconceptional allergen sensitisation and repeated airway allergen challenges during pregnancy on maternal immune and airway functions during pregnancy, and maternal, fetal and placental phenotype in late pregnancy in sheep. This protocol induced maternal responses consistent with an allergic asthmatic phenotype. During pregnancy, lung resistance and the eosinophil influx induced by allergen challenges increased progressively in allergic sheep, and in late pregnancy airway smooth muscle content was greater in allergic than control ewes. Effects on fetal growth and development were consistent with those of maternal asthma in humans. Maternal allergic asthma decreased relative fetal weight by 12%, reduced fetal lung expression of surfactant protein B, and altered placental morphology. This provides an animal model in which to identify mechanisms underlying fetal effects of maternal asthma in pregnancy, including fetal physiological responses to exacerbations, and to evaluate responses to clinically used treatments and novel interventions.

Placental restriction in multi-fetal pregnancies increases spontaneous ambulatory activity during daylight hours in young adult female sheep.

Intrauterine growth restriction (IUGR) has adverse effects on metabolic health and early life, whereas physical activity is protective against later development of metabolic disease. Relationships between birth weight and physical activity in humans, and effects of IUGR on voluntary activity in rodents, are mixed and few studies have measured physical activity in a free-ranging environment. We hypothesized that induced restriction of placental growth and function (PR) in sheep would decrease spontaneous ambulatory activity (SAA) in free-ranging adolescent and young adult progeny from multi-fetal pregnancies. To test this hypothesis, we used Global Positioning System watches to continuously record SAA between 1800 and 1200 h the following day, twice during a 16-day recording period, in progeny of control (CON, n=5 males, 9 females) and PR pregnancies (n=9 males, 10 females) as adolescents (30 weeks) and as young adults (43 weeks). PR reduced size at birth overall, but not in survivors included in SAA studies. In adolescents, SAA did not differ between treatments and females were more active than males overall and during the day (each P<0.001). In adults, daytime SAA was greater in PR than CON females (P=0.020), with a similar trend in males (P=0.053) and was greater in females than males (P=0.016). Adult SAA was negatively correlated with birth weight in females only. Contrary to our hypothesis, restricted placental function and small size at birth did not reduce progeny SAA. The mechanisms for increased daytime SAA in adult female PR and low birth weight sheep require further investigation.

Placental restriction in multi-fetal pregnancies and between-twin differences in size at birth alter neonatal feeding behaviour in the sheep

Most individuals whose growth was restricted before birth undergo accelerated or catch-up neonatal growth. This is an independent risk factor for later metabolic disease, but the underlying mechanisms are poorly understood. This study aimed to test the hypothesis that natural and experimentally induced in utero growth restriction increase neonatal appetite and milk intake. Control (CON) and placentally restricted (PR) ewes carrying multiple fetuses delivered naturally at term. Outcomes were compared between CON (n=14) and PR (n=12) progeny and within twin lamb pairs. Lamb milk intake and feeding behaviour and ewe milk composition were determined using a modified weigh-suckle-weigh procedure on days 15 and 23. PR lambs tended to have lower birth weights than CON (-15%, P=0.052). Neonatal growth rates were similar in CON and PR, whilst heavier twins grew faster in absolute but not fractional terms than their co-twins. At day 23, milk protein content was higher in PR than CON ewes (P=0.038). At day 15, PR lambs had fewer suckling bouts than CON lambs and in females light twins had more suckling attempts than their heavier co-twins. Birth weight differences between twins positively predicted differences in milk intakes. Lactational constraint and natural prenatal growth restriction in twins may explain the similar milk intakes in CON and PR. Within twin comparisons support the hypothesis that prenatal constraint increases lamb appetite, although this did not increase milk intake. We suggest that future mechanistic studies of catch-up growth be performed in singletons and be powered to assess effects in each sex.

Pre-birth origins of allergy and asthma

Allergy is a chronic disease that can develop as early as infancy, suggesting that early life factors are important in its aetiology. Variable associations between size at birth, a crude marker of the fetal environment, and allergy have been reported in humans and require comprehensive review. Associations between birth weight and allergy are however confounded in humans, and we and others have therefore begun exploring the effects of early life events on allergy in experimental models. In particular, we are using ovine models to investigate whether and how a restricted environment before birth protects against allergy, whether methyl donor availability contributes to allergic protection in IUGR, and why maternal asthma during pregnancy is associated with increased risks of allergic disease in children. We found that experimental intrauterine growth restriction (IUGR) in sheep reduced cutaneous responses to antigens in progeny, despite normal or elevated IgE responses. Furthermore, maternal methyl donor supplementation in late pregnancy partially reversed effects of experimental IUGR, consistent with the proposal that epigenetic pathways underlie some but not all effects of IUGR on allergic susceptibility. Ovine experimental allergic asthma with exacerbations reduces relative fetal size in late gestation, with some changes in immune populations in fetal thymus suggestive of increased activation. Maternal allergic asthma in mice also predisposes progeny to allergy development. In conclusion, these findings in experimental models provide direct evidence that a perturbed environment before birth alters immune system development and postnatal function, and provide opportunities to investigate underlying mechanisms and develop and evaluate interventions.

Relationship between birth weight or fetal growth rate and postnatal allergy: a systematic review protocol

REVIEW QUESTION/OBJECTIVE The objective of this systematic review is to synthesize the best available evidence on the relationship between size at birth or fetal growth and postnatal allergy. Specifically, this review aims to assess evidence regarding relationships between absolute birth weight at term, birth weight corrected for gestational age, expressed as relative to population or customized growth data, or fetal growth measures and physician-diagnosed or parent- and self-reported postnatal clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis).The specific review question is: what is the association between the absolute birth weight at full-term or birth weight relative to population or customized data and corrected for gestational age or direct measures of fetal growth, and physician-diagnosed or parent- and self-reported clinical allergic disease (eczema/atopic dermatitis, hay fever/rhinitis, allergic asthma or anaphylaxis)?