Intrauterine growth retardation has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Bilateral uterine artery ligation was performed on day 19 of gestation (term is 22 days) in the pregnant rat; sham-operated pregnant rats served as controls. Birth weights of intrauterine growth-retarded (IUGR) animals were significantly lower than those of controls until ϳ7 weeks of age, when IUGR rats caught up to controls. Between 7 and 10 weeks of age, the growth of IUGR rats accelerated and surpassed that of controls, and by 26 weeks of age, IUGR rats were obese (P < 0.05 vs. controls). No significant differences were observed in blood glucose and plasma insulin levels at 1 week of age. However, between 7 and 10 weeks of age, IUGR rats developed mild fasting hyperglycemia and hyperinsulinemia (P < 0.05 vs. controls). At age 26 weeks, IUGR animals had markedly elevated levels of glucose (P < 0.05 vs. controls). IUGR animals were glucose-intolerant and insulin-resistant at an early age. First-phase insulin secretion in response to glucose was also impaired early in life in IUGR rats, before the onset of hyperglycemia. There were no significant differences in ␤-cell mass, islet size, or pancreatic weight between IUGR and control animals at 1 and 7 weeks of age. However, in 15-week-old IUGR rats, the relative ␤-cell mass was 50% that of controls, and by 26 weeks of age, ␤-cell mass was less than one-third that of controls (P < 0.05). The data presented here support the hypothesis that an abnormal intrauterine milieu can induce permanent changes in glucose homeostasis after birth and lead to type 2 diabetes in adulthood. Diabetes 50:2279 -2286, 2001 I ntrauterine growth retardation is a common complication of pregnancy and a significant cause of perinatal morbidity and mortality. Barker et al. (1,2) first introduced the hypothesis that an adverse intrauterine environment could induce disease in later life. He proposed that low-birth weight infants were at increased risk for developing obesity, hypertension, and type 2 diabetes. Several subsequent studies have lent support to Barker's hypothesis (3-6). However, multiple problems associated with these population-based studies, such as the lack of association of gestational age with birth weight, inadequate recording of confounding variables, and loss to follow-up, have dampened enthusiasm for the universal acceptance of Barker's hypothesis. Experiments using animal models of intrauterine growth retardation can circumvent some of these difficulties and elucidate the underlying cellular and molecular mechanisms. To that end, we have developed a model of intrauterine growth retardation in the rat induced by bilateral uterine artery ligation (7,8). Blood flow to the fetus is not ablated, but reduced to a similar degree to that observed in human pregnancies complicated by uteroplacental insuffici...

Intrauterine growth retardation (IUGR) has been linked to the onset of diseases in adulthood, including type 2 diabetes, and has been proposed to result from altered gene regulation patterns due to epigenetic modifications of developmental genes. To determine whether epigenetic modifications may play a role in the development of adult diabetes following IUGR, we used a rodent model of IUGR that expresses lower levels of Pdx1, a pancreatic and duodenal homeobox 1 transcription factor critical for beta cell function and development, which develops diabetes in adulthood. We found that expression of Pdx1 was permanently reduced in IUGR beta cells and underwent epigenetic modifications throughout development. The fetal IUGR state was characterized by loss of USF-1 binding at the proximal promoter of Pdx1, recruitment of the histone deacetylase 1 (HDAC1) and the corepressor Sin3A, and deacetylation of histones H3 and H4. Following birth, histone 3 lysine 4 (H3K4) was demethylated and histone 3 lysine 9 (H3K9) was methylated. During the neonatal period, these epigenetic changes and the reduction in Pdx1 expression could be reversed by HDAC inhibition. After the onset of diabetes in adulthood, the CpG island in the proximal promoter was methylated, resulting in permanent silencing of the Pdx1 locus. These results provide insight into the development of type 2 diabetes following IUGR and we believe they are the first to describe the ontogeny of chromatin remodeling in vivo from the fetus to the onset of disease in adulthood.

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Objective The aim of this study was to examine the association between biological, behavioural and lifestyle risk factors and risk of miscarriage.Design Population-based case-control study.Setting Case-control study nested within a population-based, two-stage postal survey of reproductive histories of women randomly sampled from the UK electoral register.Population Six hundred and three women aged 18-55 years whose most recent pregnancy had ended in first trimester miscarriage (<13 weeks of gestation; cases) and 6116 women aged 18-55 years whose most recent pregnancy had progressed beyond 12 weeks (controls).Methods Women were questioned about socio-demographic, behavioural and other factors in their most recent pregnancy.Main outcome measure First trimester miscarriage.Results After adjustment for confounding, the following were independently associated with increased risk: high maternal age; previous miscarriage, termination and infertility; assisted conception; low pre-pregnancy body mass index; regular or high alcohol consumption; feeling stressed (including trend with number of stressful or traumatic events); high paternal age and changing partner. Previous live birth, nausea, vitamin supplementation and eating fresh fruits and vegetables daily were associated with reduced risk, as were feeling well enough to fly or to have sex. After adjustment for nausea, we did not confirm an association with caffeine consumption, smoking or moderate or occasional alcohol consumption; nor did we find an association with educational level, socio-economic circumstances or working during pregnancy.Conclusions The results confirm that advice to encourage a healthy diet, reduce stress and promote emotional wellbeing might help women in early pregnancy (or planning a pregnancy) reduce their risk of miscarriage. Findings of increased risk associated with previous termination, stress, change of partner and low pre-pregnancy weight are noteworthy, and we recommend further work to confirm these findings in other study populations.Keywords Diet, miscarriage, paternal factors, pregnancy history, stress, termination, UK population.Please cite this paper as: Maconochie N, Doyle P, Prior S, Simmons R. Risk factors for first trimester miscarriage-results from a UK-population-based case-control study.