GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking^1–4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high⁵, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Restricted fetal growth is associated with increased risk for the future development of Type 2 diabetes in humans. The study aim was to assess the glucose tolerance of old (seventeen months) male rats, which were growth restricted in early life due to maternal protein restriction during gestation and lactation. Rat mothers were fed diets containing either 20% or 8% protein and all offspring weaned onto a standard rat diet. In old‐age fasting plasma glucose concentrations were significantly higher in the low protein offspring: 8.4 (1.3)mmol/l v. 5.3 (1.3)mmol/l (p = 0.005), Areas under the curves were increased by 67% for glucose (p = 0.01) and 81% for insulin (p = 0.01) in these rats in intravenous glucose tolerance tests, suggesting (a degree of) insulin resistance. These results show that early growth retardation due to maternal protein restriction leads to the development of diabetes in old male rat offspring. The diabetes is predominantly associated with insulin resistance.

Associations between low birth weight and higher adrenal androgen secretion before puberty have yet only been reported in case-control studies in girls. We examined the influence of birth weight and early postnatal weight gain on overnight-fasting adrenal androgen and cortisol levels in 770 children from a large normal United Kingdom birth cohort at age 8 yr. In univariate analyses, adrenal androgen levels were inversely related to birth weight sd score in each sex [dehydroepiandrosterone sulfate in boys: regression coefficient (B) = -2.5 microg/dl/SD; 95% confidence interval (CI), -4.7 to -0.2; in girls: B = -3.8 microg/dl/SD; 95% CI, -6.2 to -1.4; androstenedione in boys: B = -0.15 nmol/liter/sd, 95% CI, -0.25 to -0.6; in girls: B = -0.13 nmol/liter/SD; 95% CI, -0.24 to -0.02). In multivariate analyses, both lower birth weight and larger current body weight predicted higher adrenal androgen levels (P < 0.005 for all comparisons). Allowing for current weight, children who showed rapid postnatal weight gain between 0 and 3 yr had higher dehydroepiandrosterone sulfate (P = 0.002) and androstenedione (P = 0.004) levels at 8 yr. In contrast, cortisol levels were unrelated to birth weight or current body size. In summary, the relationship between lower birth weight and higher childhood adrenal androgen levels was continuous throughout the range of normal birth weights, and was similar in boys and girls. Adrenal androgen levels were highest in small infants who gained weight rapidly during early childhood. We suggest that higher adrenal androgen secretion could contribute to links between early growth and adult disease risks, possibly by enhancing insulin resistance and central fat deposition.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study of over 23 000 diabetes-free pregnancies has shown that at a population level an unequivocal linear relationship exists between maternal glucose concentrations around the beginning of the third trimester of pregnancy and the risk of their baby being born above the ninetieth centile for weight. With the rising incidence of gestational diabetes (GDM) across the developed world, largely paralleling the increased prevalence of obesity, there has been a sharp increase in the risk of pregnancy complications developing related to the birth of macrosomic babies. The associated additional long-term complications of GDM pregnancies means that in the future there is likely to be a large increase in the incidence of type 2 diabetes and associated conditions in both the mothers and their affected offspring. The present review seeks to highlight recent advances and remaining gaps in knowledge about GDM in terms of its genetics (where some of the recently discovered polymorphic risk factors for type 2 diabetes have also proved to be risk factors for GDM) and its treatment by diet, exercise and drugs.

In rats, maternal anaemia during pregnancy causes hypertension in the adult offspring, although the mechanism is unknown. The present study investigated the renal morphology of adult rats born to mothers who were Fe-deficient during pregnancy. Rats were fed either a control (153 mg Fe/kg diet, n 7) or low-Fe (3 mg/kg diet, n 6) diet from 1 week before mating and throughout gestation. At delivery, the Fe-restricted (IR) mothers were anaemic; the IR pups were also anaemic and growth-retarded at 2 d of age. At 3 and 16 months, systolic blood pressure in the IR offspring (163 (sem 4) and 151 (sem 4) mmHg respectively, n 13) was greater than in control animals (145 (sem 3) and 119 (sem 4) mmHg respectively, n 15, P<0·05). At post mortem at 18 months, there was no difference in kidney weight between treatment groups, although relative kidney weight as a fraction of body weight in the IR offspring was greater than in control animals (P<0·05). Glomerular number was lower in the IR offspring (11·4 (sem 1·1) per 4mm², n 13) compared with control rats (14·8 (sem 0·7), n 15, P<0·05). Maternal treatment had no effect on glomerular size, but overall, female rats had smaller and more numerous glomeruli per unit area than male rats. When all animals were considered, inverse relationships were observed between glomerular number and glomerular size (r−0·73, n 28, P<0·05), and glomerular number and systolic blood pressure at both 3 months (r−0·42, n 28, P<0·05) and 16 months of age (r−0·64, n 28, P<0·05). Therefore, in rats, maternal Fe restriction causes hypertension in the adult offspring that may be due, in part, to a deficit in nephron number.