Pregnancy as a Window to Future Maternal and Child Health

Infertility

Infertility affects 11% of reproductive-aged women in the United States and may be the result of many different factors, either alone or in combination. However, the single most common endocrine disorder in women of reproductive age is polycystic ovary syndrome (PCOS), which often occurs with increased or excessive body weight and is known to increase women's subsequent risk for insulin resistance, metabolic syndrome, and type 2 diabetes. This raises the question of whether infertility per se or possibly its treatment increases a woman's risk of subsequent metabolic or vascular disease. Alternatively, infertility and subsequent vascular disease may represent different phenotypes of the same underlying disorder.

A longitudinal cohort study of over 28,000 women who received infertility treatments in Ontario from 1993 through 2011 and who were then followed through 2015 found that compared with the subset of women who subsequently gave birth, those women who did not subsequently become pregnant had a 19% higher rate of cardiovascular events across a median 8.4 years of follow-up. There was no correlation with the number or type of fertility treatment cycles. Although this study did not compare the prevalence of cardiovascular events with a control population with unimpaired fertility, a recent meta-analysis found no obvious association between exposure to fertility therapy and subsequent cardiovascular outcomes.

A recent report from the Framingham Heart Study Third Generation cohort reported that premenopausal women with self-reported prior infertility (14.2% of the cohort) had larger body mass indices (BMIs) and waist circumferences, as well as a trend toward increased rates of diabetes versus women without such a history. In addition, a recent report from the Women's Health Initiative noted that a history of “always, or sometimes, having irregular menses” was positively associated with postmenopausal coronary heart disease, whereas a history of infertility per se was not. These reports collectively suggest that women with a PCOS/metabolic syndrome phenotype represent the majority of the link between infertility and subsequent metabolic and vascular disease.

It is important to note that a history of infertility may also be a harbinger of other long-term health issues for women. Endometrial cancer is seen more commonly in women with PCOS, and both osteoporosis and dementia are more likely in women with premature ovarian failure. The details of a woman's fertility history should, therefore, be elicited by her primary care provider to determine whether her history is associated with increased risks for cardiovascular and metabolic diseases.

Parity

In addition to nulliparity, grand multiparity (≧5 births) is associated with an increased risk of subsequent cardiovascular disease. A longitudinal cohort of over 1.3 million women born in Sweden between 1932 and 1955 found that women with two births had the lowest risk of cardiovascular disease. Primiparous women (one birth) in this series had a modestly increased hazard ratio of 1.09 (95% CI, 1.03, 1.15) and grand multiparous women a somewhat higher hazard ratio of 1.47 (95% CI, 1.37, 1.57). Although these estimates attempted to control for socioeconomic factors and pregnancy-related complications, they cannot distinguish with certainty whether these associated risks are causal or correlational.

It has been proposed that the decrease in cardiovascular risk seen among women who have had an uncomplicated pregnancy compared with those who have not carried a pregnancy is related to long-standing changes in vascular structure and function associated with the physiologic cardiovascular changes of pregnancy. However, a recent study comparing the number of offspring and subsequent cardiovascular disease in both female and male parents found similar associations between the number of offspring and cardiovascular disease in both sexes, suggesting that the previous reports may be explained by unobserved behavioral and/or lifestyle factors rather than pregnancy-related changes in physiology.

Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a condition in which carbohydrate intolerance develops or is first diagnosed during pregnancy. The prevalence of GDM has increased over the past several decades. In 1980 it was estimated that 1% to 3% of pregnancies in the United States were complicated by GDM, whereas current estimates suggest a prevalence of 6% to 9%. This increase has paralleled the increasing prevalence of obesity in western societies.

It is well established that women diagnosed with gestational diabetes are at increased risk for development of subsequent type 2 diabetes. In fact, O'Sullivan and Mahan's 1964 description of gestational diabetes was based on its ability to predict future diabetes and without taking perinatal outcomes into account. Type 2 diabetes is a major disease burden, particularly in its advanced stages. Affected individuals are at increased risk for cardiovascular and peripheral vascular disease, retinopathy, neuropathy, and nephropathy.

One recent estimate suggests a 7.4-fold increased lifetime risk for type 2 diabetes in women with GDM. A review of 28 studies has demonstrated a rapid increase in the incidence of this disease in the first 5 years after delivery (17% to 50%) and a more gradual plateau thereafter to approximately 70% at 20-plus years ( Fig. 26.2 ). The variability in these estimates is a function of the different populations studied as well as the various definitions of GDM and type 2 diabetes employed.

Although these facts clearly demonstrate the importance of continued follow-up for women whose pregnancies were complicated by GDM, it is also likely that current progression rates to type 2 diabetes are higher. Several investigators from countries with single-payer health care systems have described a more rapid onset of type 2 diabetes within their respective populations over the past several decades. A study from Ontario found that women were developing type 2 diabetes more rapidly, reaching their threshold of 16% in 9 years if delivered in 1995 to 1996 versus 4.7 years if delivered in 1999 to 2001 ( Fig. 26.3 ). A Danish study has shown that, when controlled for years of follow-up, a GDM cohort that delivered in 1987 to 1996 had a higher rate of diabetes or impaired glucose tolerance than did a GDM cohort delivered in 1978 to 1985 (40.0% vs 27.0%, respectively), at least in part because the more recent cohort had significantly higher median BMIs (26.0 vs 22.9).

GDM results from the same spectrum of genetic and physiologic abnormalities that characterize type 2 diabetes outside of pregnancy. These include varying degrees of insulin resistance and relative insulin deficiency. These conditions are frequently accompanied by hypertension, high serum low-density lipoprotein (LDL) cholesterol, and low serum high-density lipoprotein (HDL) cholesterol; these collectively constitute the metabolic syndrome. They are all further compounded by high-calorie diets and sedentary lifestyles. The familial prevalence of GDM parallels that of type 2 diabetes.

Women with a history of GDM, by virtue of their increased risks of either having or acquiring the components of the metabolic syndrome, are at increased risk for cardiovascular disease. Approximately one-third of women with a history of GDM will have developed metabolic syndrome within 5 to 10 years of delivery. This is likely the sequela of the ongoing subclinical inflammation and vascular dysfunction that is frequently seen in otherwise euglycemic women following GDM pregnancies.

Women whose pregnancies are complicated by GDM must be provided with effective contraception after delivery. Their increased likelihood of developing clinically apparent diabetes outside of pregnancy makes it particularly important that subsequent pregnancies be planned to the extent possible and that diabetes screening tests be completed prior to conception.

Infants delivered following pregnancies complicated by GDM have long been recognized to be at increased risk for various neonatal complications, including operative delivery, birth trauma, neonatal hypoglycemia, hyperbilirubinemia, and polycythemia. However, offspring of pregnancies complicated by gestational diabetes are also at risk for chronic diseases later in life, including obesity and metabolic disease.