孕前超重/肥胖与婴儿不良出生结局关系前瞻性队列研究

  目的  探讨妇女连续两次妊娠间孕前体重变化与早产、低出生体重、巨大儿、小于胎龄儿及大于胎龄儿的关系。  方法  基于广东省妇幼卫生信息系统,收集2015 — 2020年具有两次分娩记录的6 589名孕妇及其分娩婴儿的资料,将生育间体质指数（BMI）变化分为4组（< – 1、 – 1～、1～、 ≥ 3）,使用logistic回归模型分析两次妊娠间孕前BMI变化与不良出生结局的关联。  结果   本研究纳入的6 589名孕产妇及其子女早产、低出生体重儿、巨大儿、小于胎龄儿、大于胎龄儿的发生率分别为5.6 %、4.7 %、2.4 %、11.4 %和5.4 %。logistic回归结果显示,相对于BMI变化 − 1～的参照组,BMI变化1～组发生巨大儿风险增加66 %（OR = 1.66,95 % CI = 1.13～2.24）,BMI变化 ≥ 3组发生巨大儿、大于胎龄儿的风险分别增加131 %（OR = 2.31,95 % CI = 1.42～3.70）、87 %（OR = 1.87,95 % CI = 1.33～2.60）。BMI每增加1,小于胎龄儿风险降低7 %（OR = 0.93,95 % CI = 0.89～0.97）。各组发生早产、低出生体重的风险与对照组相比差异均无统计学意义（P > 0.05）。  结论  两次妊娠间体重的增长与巨大儿及大于胎龄儿的风险增加相关。应加强对妇女妊娠期及分娩后的体重管理,以降低二胎巨大儿、大于胎龄儿的发生风险。     

Fetal origins of obesity

The worldwide epidemic of obesity continues unabated. Obesity is notoriously difficult to treat, and, thus, prevention is critical. A new paradigm for prevention, which evolved from the notion that environmental factors in utero may influence lifelong health, has emerged in recent years. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and BMI attained in later life. Although the data are limited by lack of information on potential confounders, these associations seem robust. Possible mechanisms include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, and pancreatic structure and function. Additionally, lower birth weight seems to be associated with later risk for central obesity, which also confers increased cardiovascular risk. This association may be mediated through changes in the hypothalamic pituitary axis, insulin secretion and sensing, and vascular responsiveness. The combination of lower birth weight and higher attained BMI is most strongly associated with later disease risk. We are faced with the seeming paradox of increased adiposity at both ends of the birth weight spectrum-higher BMI with higher birth weight and increased central obesity with lower birth weight. Future research on molecular genetics, intrauterine growth, growth trajectories after birth, and relationships of fat and lean mass will elucidate relationships between early life experiences and later body proportions. Prevention of obesity starting in childhood is critical and can have lifelong, perhaps multigenerational, impact.     

Fetal and infant origins of asthma

Previous studies have suggested that asthma, like other common diseases, has at least part of its origin early in life. Low birth weight has been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults, and increased risks of respiratory symptoms in early childhood. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by adaptation mechanisms in fetal life and infancy in response to various adverse exposures. Various pathways leading from adverse fetal and infant exposures to growth adaptations and respiratory health outcomes have been studied, including fetal and early infant growth patterns, maternal smoking and diet, children’s diet, respiratory tract infections and acetaminophen use, and genetic susceptibility. Still, the specific adverse exposures in fetal and early postnatal life leading to respiratory disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms may underlie the complex associations of low birth weight with respiratory disease in later life. New well-designed epidemiological studies are needed to identify the specific underlying mechanisms. This review is focused on specific adverse fetal and infant growth patterns and exposures, genetic susceptibility, possible respiratory adaptations and perspectives for new studies.     

Fetal origins of insulin resistance and obesity

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.     

Fetal alcohol syndrome: the origins of a moral panic

Since its discovery almost 30 years ago, the fetal alcohol syndrome (FAS) has been characterized in the USA, as a major threat to public health. In part because FAS resonated with broader social concerns in the 1970s and 1980s about alcohol's deleterious effect on American society and about a perceived increase in child abuse and neglect, it quickly achieved prominence as a social problem. In this paper, we demonstrate that, as concern about this social problem escalated beyond the level warranted by the existing evidence, FAS took on the status of a moral panic. Through examples taken from both the biomedical literature and the media about drinking during pregnancy, we illustrate the evolution of this development, and we describe its implications, particularly how it has contributed to a vapid public policy response.     

Early origins and adult correlates of psychosomatic distress

Previous studies have demonstrated associations between fetal insults and psychological and developmental outcomes in children and adolescents. It is not clear whether psychosomatic problems in adults also have early origins. This study involved full-term live-born singletons free of congenital anomaly in the 1970 British Birth Cohort Study. Birthweight, gestational age, maternal smoking, parental social class and birth order were recorded around the time of birth. Psychological and somatic distresses were measured by the Malaise Inventory at age 26. A number of socio-behavioural covariates were also measured at this time. Multiple (least square) regression analysis showed that birthweight standardised for gestational age had a "reverse J" relation with psychological distress (p < 0.05); gestational age was inversely related to psychological distress (each p < 0.05); levels of maternal smoking were positively related to both psychological distress and somatic distress (each p < 0.01). Logistic regression analyses of high levels of psychological distress and somatic distress gave similar results. The findings were not strongly affected by adjustment for various adult correlates. In supplementary analyses multiple imputation was used to handle loss to follow-up and missing values at age 26. Approximately, the same patterns of associations were found. The results support the hypothesis of a biological link between perinatal factors and psychological distress in adults. The strengths of the associations were compared with those between the outcome and adult correlates.     

Nutrition and the early origins of adult disease

There is now overwhelming evidence that much of our predisposition to adult illness is determined by the time of birth. These diseases appear to result from interactions between our genes, our intrauterine environment and our postnatal lifestyle. Those at greatest risk are individuals in communities making a rapid transition from lives of 'thrift' to a lives of 'plenty'. From a global perspective, such origins of diabetes, coronary heart disease and stroke, should render research in these fields as one of the highest priorities in human health care. Prevention will be enhanced by elucidation of the mechanisms by which the fetus is programmed by the mother for the life she expects it to live. At the present time, there is evidence that fetal nutrition and premature exposure to cortisol are effective intrauterine triggers, but a multitude of alternative pathways require investigation. It is also likely that programming extends across generations, and may involve the embryo and perhaps the oocyte. An oocyte that becomes an adult human develops in the uterus of its grandmother, so further research is required to describe the role of environments of grandmothers and mothers in predisposing offspring to health or illness in adult life.     

Fetal alcohol exposure and adult tumorigenesis.

Adult rats exposed to prenatal alcohol were evaluated for their susceptibility to either hormone- or chemical-inducing tumors. In the first study, rats exposed to prenatal alcohol displayed an increased propensity to beta-estradiol (E2)-induced adenohypophyseal prolactinoma. The susceptibility was manifest as a potentiated increase in anterior pituitary weight as well as in serum prolactin levels after 1 and 3 weeks but not 5 weeks of hormone treatment. Two weeks after withdrawing the E2-implant, the prolactinoma underwent involution and serum prolactin reversed to baseline levels. The high concentrations of serum corticosterone were also reduced but did not return to baseline levels after E2 removal. In the second study, nitrosomethylbenzylamine (NMBA) was utilized to induce esophageal cancer in adult rats. There were no significant differences in tumor incidence or size between the prenatal alcohol-exposed and the pair-fed cohorts. However, the NMBA-treated prenatal alcohol-exposed rats displayed a marked decrease in thymus: body wt ratio as well as adrenal gland hyperplasia. The results suggest that no single mechanism can account for the variable susceptibility displayed by the prenatal alcohol-exposed rats to chemical carcinogens. Some of the observed changes, however, may be attributable to the long-lasting adverse effects of prenatal alcohol exposure on the well-being of the adult host.     

Historic and early life origins of hypertension in Africans

Cardiovascular disease (CVD) causes 12.4 million deaths annually, most (9.6 million) occurring in developing countries. Hypertension, the most common CVD, arises within the context of obesity, but the underlying mechanisms remain obscure. Obesity and salt intake are two important risk factors for hypertension and are the focus of this paper. Traditional African populations show a low prevalence of hypertension, but hypertension is more common in migrant African populations in the West than in other ethnic groups. One explanation is genetic, but no causative gene has been confidently identified. Nongenetic susceptibilities such as fetal programming are an alternative explanation. Hypothetically, fetal programming induced by transient stimuli permanently alters fetal structure and function at the cellular, organ and whole-body levels. Birth weight is inversely related to blood pressure and hypertension risk, suggesting that susceptibility to hypertension risk factors such as obesity and salt sensitivity are themselves programmed. In support of this hypothesis, obesity (especially central obesity) is also inversely related to size at birth. Likewise, salt sensitivity might derive from undernutrition in utero, reducing the nephron number and resetting the pressure-natriuresis curve rightward. However, no robust human data or evidence of enhanced salt sensitivity among African-origin populations exist. In the United States, blacks have a greater prevalence of low birth weight than whites, suggesting that the higher prevalence of hypertension among blacks is related to fetal programming. Nevertheless, we need to be scrupulous in ascribing risk to the myriad other confounders of this relationship, including environmental and behavioral correlates of ethnicity, before concluding that excess risk of hypertension in Africans is programmed in utero.