A systematic review on effects of early menopause reported that women with early-pregnancy miscarriage are more likely to develop CVD, specifically ischemic heart disease (IHD) in later life, implying lower protective effects of estrogens on serum lipids, and vessel wall anatomy as possible causes (21). Increased total serum cholesterol (22), triglycerides (TGs) (23), antithrombin III (24), factor VII, and fibrinogen (25) have also been speculated to be responsible (22, 26). Early miscarriage, either as a single or recurrent complication, carries a hazard ratio (HR) between 1.25 and 1.56 for subsequent IHD (27) (Table 2). This association was independent of maternal age, height, socioeconomic deprivation, chronic hypertension, and complications during the first pregnancy. The proportion of smokers was only marginally higher compared to women without miscarriage (28.4 vs. 26.8%). While the authors hypothesized that the association of IHD and miscarriage reflects common inherited thrombophilic defects, they did not find significant associations between miscarriage and family history of CVD or venous thrombotic embolism.

It has been long recognized that infant BW correlates with the mother’s subsequent risk for IHD and is “aggregated within families” possibly due to genetic, physiologic, environmental, epigenetic, and socioeconomic factors (30, 43–45). Delivering an FGR infant is associated with maternal coronary artery disease, cerebrovascular disease, or cardiac insufficiency with HRs ranging from 1.35 to 3.4 for severe early-onset FGR (Table 2) (28). Birth weight has an inverse linear association with maternal CVD mortality and is also related to grandparental CVD and CVD mortality (29). These BW associations across generations are independent of socioeconomic, environmental, or behavioral factors, body mass index (BMI), age, or smoking status. Familial aggregation of shared determinants for risk factors associated with pregnancy complications and CVD were postulated as a potential cause for these associations (46). Other hypothesized mechanisms are based on the observation that the impact of the mother is stronger than of the father: women at high risk of CVD may be unable to mount an adequate hemodynamic response leading to FGR and/or PE. This is supported by cardiac changes seen on maternal echocardiography showing increased cardiac chamber dimensions and left ventricular hypertrophy in the index pregnancy. The likelihood of developing FGR and/or PE is elevated by many maternal demographic and medical characteristics, such as hypertension, obesity, and age that are shared risk factors for CVD (47).

Adverse effects of FGR on cardiovascular health of the offspring were already suspected in 1977 by Forsdhal, who reported that Norwegian children, raised in poor provinces in the early twentieth century but became prosperous thereafter, suffered from excess rates of myocardial infarction as adults (48). In 1986, Barker and Osmond showed that the distribution of CVD in England was related to a person’s BW (49). Maternal hunger throughout pregnancy was linked to high blood pressure in the offspring; while third-trimester deprivation led to high levels of low-density lipoprotein, cholesterol, and fibrinogen (50). The Dutch Famine Birth Cohort Study considered long-term effects of prenatal starvation among women born before, during, or after the Hunger Winter when the average supply was <1,000 calories/day (51). Intra-family sibling analysis revealed that BW was decreased when famine exposure was in the third trimester but not when it was in the first trimester. However, the expected increase in BW of the offspring with birth order was reversed after maternal exposure in the first trimester (52). The results suggested that biologic effects depend on timing of gestational exposure and are still present in subsequent generations. People conceived during the famine had doubled rates of CVD, atherogenic plasma lipid profiles and were at increased risk of schizophrenia, depression, high stress responsiveness and performed worse on tasks that correlated with accelerated aging (53) (Table 3).

In most pregnancy studies, the effects of famine cannot be clearly separated from those of stress especially when studied in the context of war trauma. Following the Chernobyl disaster, the perceived level of stress was a better predictor of the offspring’s risk of cognitive disorders than the actual exposure to radiation (65). Conditions during and after famine periods varied between countries: in the Netherlands, World War II was followed by a period of abundance and in Russia, life conditions remained poor. The latter was not associated with adverse effects suggesting that it is beneficial when the postnatal environment matches the prenatal environment (66). There are also individual differences in susceptibility toward hunger and stress dependent on the individual genetic background (67). While starvation may play a minor role in high resourced countries, the first trimester is a vulnerable period as serious hyperemesis significantly increases the odds for cognitive and psychological diseases in the offspring (OR 3.6, p < 0.0001) (68).

Cardiovascular changes in FGR offspring are already present in utero, can persist after birth, and may produce aberrant cardiomyocyte growth in adult hearts with reversible myocardial hypertrophy (69). In humans, FGR induced cardiovascular remodeling at age 5 is ameliorated by breastfeeding but worsened by a high maternal BMI (70). Longitudinal growth analysis suggests that children with higher BP tended to be smaller during third trimester of fetal life but were normal size as infants. By contrast, children with increased aortic root diameter or left ventricular mass tend to be larger during fetal life, but of similar size during infancy (Table 3) (54). School age children with clustering of CVD risk factors had a smaller first-trimester fetal crown-rump length, lower second and third trimester estimated fetal weight but more rapid growth from 6 months onward. This suggests that even first-trimester fetal growth relates to subsequent cardiovascular risks (71). As adults, women rather than men with LBW (≤2.5 kg) have higher fasting plasma glucose, insulin, diabetes, and metabolic syndrome (Table 3). In both genders, height increased with BW, whereas BMI and waist circumference have a U-shaped association with BW (58).

Adequate nutrition and micronutrient density such as iron, copper, zinc, iodine, selenium, and vitamin A and D are prerequisite for fetal growth. In industrialized countries, food containing essential micronutrients is likely to be more expensive decreasing the dietary quality in low-income groups (72, 73). Even in countries without absolute food shortage (e.g., Sri Lanka) 25% of mothers and 33% of all children were malnourished and at risk of anemia, mental illness, or poor immune system (74). Exposure to unexpected contraction in the first trimester was associated with a decrease in BW which was stronger for women at home with <12 years’ education and associated with increased risks for FGR (OR 1.5; 95% CI 1.1–2) (75). In recognition of the important impact of maternal nutrition and the crucial importance of preventive care, reduction of poverty and hunger during pregnancy is a defined millennium goal of the United Nations.

Older studies have demonstrated that multiparity independently increases maternal CVD risks in later life (31) (Table 2). A “J” shaped association between number of children and CVD was observed, lowest among those with two children and increasing with each additional child beyond two by 30–47% for women and by 12% for men (32) (Table 2). Specifically, in women, the number of children was inversely correlated with high-density lipoprotein (HDL) cholesterol and positively associated with TGs and diabetes. It has been concluded that lifestyle risk factors combined with child rearing result in obesity and increased rates of CVD. The 9% increase in CVD risk in women with only one child has been attributed to coexisting fertility conditions such as polycystic ovary (PCO) (76).

Risk factors for HDP can be broadly categorized as personal, cardiovascular, metabolic, and prothrombotic (77). Approximately 80% of women with a history of PE have at least one risk factor of which the cardiovascular risk profile is most prevalent, followed by hyperhomocysteinemia, metabolic syndrome, and thrombophilia (78, 79). Both circulatory and metabolic risk profiles were associated with earlier onset PE; FGR was more likely in patients with a diastolic BP above 80 mmHg (80). All first-trimester prediction algorithms for PE identify surrogate markers of cardiovascular and metabolic health as independent contributors (77). The most recent and largest systematic review and meta-analysis on risk factors for PE in relation to clinical risk factors included more than 25 million pregnancies (81): women with antiphospholipid antibody syndrome had the highest rate of PE (17.3%, 95% CI 6.8–31.4%). Those with prior PE had the greatest relative risk (RR) of 8.4 (7.1–9.9). Chronic hypertension ranked second with a RR of 5.1 (4.0–6.5), pre-gestational diabetes had a RR of 3.7 (3.1–4.3), pre-pregnancy BMI > 30, and ART were other risk factors suggesting that the presence of any one might suffice to designate a woman as “high risk” and support clinical prediction for the use of early prevention (81). The parallel rise in PE and maternal long-term complications supports the concept that early-pregnancy risk profiles are causally linked to maternal long-term health. Accordingly, the American Heart Association guidelines on female CVD include GDM and HDP in their risk assessment (82). Although balanced diets and active lifestyles reduce the risk for DM in women with GDM, adoption of these health behaviors is low (83).

Placental invasion, size, and function are sensitive to maternal blood flow disturbances and the placenta modulates fetal responses to the environment. The “gateway” to the fetus modifies epigenetic marks and placental gene expression leading to gender-specific diseases (84). The placental lesions of PE and severe FGR, such as “atherosis in the placental bed,” are similar to atherosclerosis suggesting common genotypes, phenotypes, and earlier mortality (85). Mothers with PE have atherosclerotic disease such as angina pectoris, cardiac insufficiency, or renal disease within a mean interval of 11 years and earlier mortality is evident by 20 years after delivery in these women (86, 87).

Maternal placental syndromes combined with FGR increase the downstream risk for early hospitalization for heart failure, cardiac dysrhythmia, and CVD follows this pattern (34, 35) (Table 2) suggesting that dysfunction in both placental compartments amplifies the risks. Affected women should therefore have their blood pressure and weight assessed by 6 months postpartum, and a healthy lifestyle should be emphasized. Following coronary artery revascularization, middle-aged women are at higher risk for death than men. After a mean of 5 years, 41 deaths (2.2 per 100 person years) occurred in women compared to 1.1 in women without maternal placental syndrome (HR 1.96; 95% CI 1.29–2.99). The risk of death was significant in women with placental abruption (HR 2.79; 95% CI 1.31–5.96), placental infarction (HR 3.09; 95% CI 1.23–7.74), and PE (HR 1.61; 95% CI 1.00–2.58). Women with placental syndrome in two pregnancies had the highest HR of death of 4.31 (95% CI 1.71–10.89). This should be included in the informed consent process (33).

Children born to pre-eclamptic mothers are at increased risk for high BP, stroke, cognitive delay, and depression (Table 3) (55). As young adults, these children have a 2.5-fold increased risk of a QRISK Score above the 75th centile (95% CI 1.32–4.56, p = 0.004). Consideration of additional factors would allow identification of a cohort with hypertension (Table 3) (56). PE leads to a 40% elevated risk of later serious CVD (88); 30% of all 20-year old’s with high BP had mothers with PE (95% CI 1.3–7.0; p = 0.01) (56). The recognition of these associations by family practitioners and pediatricians raises the possibility of tailored interventions to prevent adult hypertensive disease. The discussion on the optimal management approach to HDP during pregnancy is ongoing (89, 90).

First-trimester pregnancy-associated plasma protein-A was one of the first serum biomarkers noted to correlate with placental function and fetal growth (91). Now, more complex first-trimester screening algorithms for PE and FGR offer individual risk prediction with up to 90 and 60% sensitivity, respectively (5, 92, 93); 91% of women that are test positive at the first-trimester screen have cardiovascular and metabolic conditions amenable to therapy (8). Since many of these risk profiles pre-date before or persist after pregnancy it appears that first-trimester screening for placental disease is not only cost-effective but could have therapeutic benefits that reach far beyond pregnancy (94).

Prematurity and low BW are endpoints of several potentially different etiologies (95). Women who had a preterm birth more frequently develop CVD and type 2 diabetes (4, 36). There is a negative correlation with gestational age at delivery and the rates of later maternal diseases. In a recent systematic review, SPB increased maternal risks of developing or dying from IHD, stroke, and overall CVD (28, 96) (Table 2).

Following preterm birth, the offspring is also at higher risk for elevated BP levels in adulthood and insulin resistance in infancy (97). It is unknown if this is attributable to interactions between peripartum exposure to inflammatory cytokines, cardiovascular effects of pulmonary dysmaturity, and placental dysfunction (98–100).

Acute stress responses activate the hypothalamus–pituitary–adrenal axis (HPA) and the immune system to enable the organism for environmental threats. However, prolonged activation of the stress response may have adverse consequences. Maternal stress, anxiety, and psychological maternal disease can evoke immediate changes in blood flow to the uterus, fetal heart rate, or fetal movements (FM). However, they also induce long-term changes in fetal growth, metabolism, behavior, and cognition. Since there are no direct neural connections between mother and fetus, acute and chronic responses are likely elicited by neuroendocrine, autonomic, or vasodilatory input. Low BW by itself is associated with “hostility” in adult life, e.g., a rival cynic personality with mistrust and negative affections, which again is combined with CVD (57) (Table 3).

It is fascinating to imagine that the fetus may actively contribute to its own epigenesis as FM between 20 and 38 weeks transiently stimulate maternal sympathetic arousal prepare women for nurturing without becoming desensitized (101). Listening to music and singing lullabies has been shown to reduce women’s experience of stress, anxiety, and depression and might simultaneously stimulate and be remembered by the fetus (102, 103).

The interplay of maternal stress on metabolic disorders in the next generation has been investigated: only 2/45 known type 2 diabetes susceptibility genes are associated with LBW, indicating that the association is mainly non-genetic. The developing fetal brain requires some, but not overwhelming stress. FGR is associated with poor school education, smoking, drinking habits, poor social activities of mothers, and poor maternal social support (59). Even exposure to modern media “attacks” seems to reduce BW by 50 g (104). Maternal exposure to the death of a close relative is also correlated to LBW, where deregulation of the HPA was most marked during the second trimester when spiral arteries invade trophoblastic cells (105). Endocrine factors, such as β-HCG or progesterone, play gender-specific roles for growth and disease. In a multivariable regression model, increase in maternal progesterone by 1 ng/ml during the first trimester increased girls’ BW by 10.2 g (95% CI 2.03–18.31); perceived worries (and smoking) predicted FGR in boys irrespective of progesterone levels (106). Fascinating reviews on maternal stress have been published (67, 107).

Maternal smoking is one of the commonest modifiable risk factors. It has been estimated that active or passive smoking during pregnancy is responsible for at least 20% of infants with LBW (108). The effect is dose dependent (adjusted OR 2.40 for 0–9, 2.68 for 10–15, 2.88 for >15 cigarettes daily). Parental smoking also increases CVD risk in the offspring (109). After puberty, the effect of parental smoking was positively associated with BMI (p < 0.001) with a significant dose response for each additional 10 cigarettes. The associations of maternal smoking were stronger than for paternal smoking. At age 32, offspring of at least one smoking parent had higher BMI and waist circumference. Adjusted weight at age 17 was 63.2 kg for offspring of non-smoking parents compared to 64.6 kg of at least one smoking parent and at age 32, 68.3 and 70.5 kg, respectively (60) (Table 3). In many countries, pregnant mothers are exposed to wood fuel smoke. The carbon monoxide depresses placental energy-dependent processes and amino-acid transport and exhibits a reduction of infants’ adjusted mean BW by −186 g (110). Variation in genes encoding enzymes modify the associations between maternal smoking and BW, but the contribution of epigenetic mechanisms, rather than genetic, underlie the long-term effects of smoke exposure as shown in aberrant placental metabolism, syncytial knot formation, or markers of placental oxidative damage (111).

Several studies have shown that breastfeeding is associated with decreased activation of the HPA axis, a blunted BP response to stress, and increased fat mobilization (122–124). In a prospective Danish cohort, an inverse association was observed for breastfeeding duration and weight retention up to 18 months correlating with anthropometric measures 7 years after delivery (37) (Table 2). In mothers, who already have symptoms of GDM, breastfeeding is protective against type 2 diabetes.

Infant feeding characteristics are associated with subsequent risk for maternal DM within 2 years (38) (Table 2). Potential mechanisms for these associations include prolactin-mediated preservation of pancreatic β-cells, less inflammation, and improved endothelial function. To estimate the effect of breastfeeding on maternal health, mice were randomly divided into lactated (L) and non-lactated (NL) animals (120). At 9 months, the NL group weighed significantly more compared with the L group had significantly higher systolic BP, lower ejection fraction, and higher renal artery resistive indices compared with L mice which all suggested that lactation has a direct beneficial effect. Large systematic reviews covering >9,000 abstracts and approximately 400 individual studies have demonstrated that breastfeeding reduces risks for type 2 diabetes, breast, and ovarian cancer. Early cessation or not breastfeeding was associated with a higher risk of postpartum depression. There was no relationship between a history of lactation and the risk of osteoporosis (125). Lactation duration was found to be inversely associated with common carotid intima-media thickness at 20 years; mean differences between a duration of ≥10 months compared with 0 to <1 month ranged from −0.062 mm for unadjusted models to −0.029 mm if adjusted for pre-pregnancy BMI, cardiometabolic risk factors, parity, smoking, and sociodemographics (p trend: 0.01) (38). It is not yet clear whether all observed associations between breastfeeding and maternal health are causal since breastfeeding women have a healthier lifestyle overall. Nevertheless, it was estimated that low breastfeeding rates in the US result in 4,981 excess cases of breast cancer, 53,847 cases of hypertension, and 13,946 cases of myocardial infarction. Suboptimal breastfeeding is therefore supposed to incur a total of $17.4 billion in cost to society/year resulting from premature death (95% CI $4.38 to 24.68 billion), $733.7 million in direct costs (95% CI $612.9 to 859.7 million), and $126.1 million indirect morbidity costs (95% CI $99.00 to 153.22 million). There was a non-significant difference in additional premature deaths before 70 years (126).

Infants benefit from breastfeeding due to protection from infections and biologic signals for promoting cellular growth and differentiation. Breastfeeding reduced the severity of respiratory problems in the first 27 weeks of life (RR 0.70; 95% CI 0.55–0.88) (127) and reduces risks for acute otitis media, non-specific gastroenteritis, lower respiratory tract infections, atopic dermatitis, asthma, obesity, type 1 and 2 diabetes, childhood leukemia, sudden infant death syndrome, and necrotizing enterocolitis (125). The American Academy of Pediatrics recommends exclusive breastfeeding for approximately 6 months, followed by continued breastfeeding with complementary foods for 1 year or longer (128). The American College of Obstetrics and Gynecology asks for a multidisciplinary approach involving practitioners, family members, and child care providers to support breastfeeding mainly for underserved women (129). Breastfeeding promotion is a practical, low-cost intervention to prevent CVD, obesity, and diabetes in high-risk women, with the potential for benefits that are complementary to lifestyle interventions targeting weight loss.

Overweight (BMI > 25 kg/m²) and obesity (BMI > 30 kg/m²) have become global risk factors for NCDs (130). Obesity before and during pregnancy leads to an increase of maternal mortality; more than 50% of all maternal deaths in Great Britain were overweight or obese (131). The accumulation of visceral fat tissue correlates with increasing insulin resistance and a metabolic syndrome (132). Pregnancy itself leads to obesity: approximately 75% of women are heavier 1-year postpartum than they were pre-pregnancy (133). Increased abdominal fat mass (134), which also characterizes aging (135), may affect long-term maternal health because abdominal fat mass predicts mortality better than weight or BMI (136). This is also the reason why a body fat index—a novel ultrasound index evaluating central maternal fat—seems to be more informative than BMI in terms of prediction of obstetric complications particularly for subsequent development of GDM. Also women with normal pre-pregnancy BMI need to be informed about the recommendations by the Institute of Medicine. Excess weight gain increases fat mass, especially in women with preconception obesity (137, 138). Excess pregnancy weight gain increases the risk for lifelong visceral fat retention (39, 137, 139, 140) (Table 2).

Mothers with excessive weight gain are less likely to breastfeed (141). In a cohort of 46,688 women, a BMI ≥ 30 kg/m² was associated with higher adjusted rates of cardiovascular events and related hospitalizations (142). Truncal obesity as defined by WC or waist/hip ratio has been shown to be more strongly related to certain cancer types than obesity as defined by BMI (143). Possible mechanisms that relate obesity to cancer risk include insulin resistance and chronic hyperinsulinemia, increased production of insulin-like growth factors, or high bioavailability of steroid hormones because adipose tissue-derived hormones and cytokines (adipokines), such as leptin, adiponectin, and inflammatory markers, may reflect mechanisms linked to tumor genesis.

Maternal obesity or pre-gestational DM is associated with fetal myocardial functional changes as early as the first trimester, which could explain the predisposition of offspring to CVD later in life (29, 41). Offspring of mothers with excessive weight gain and a BMI > 30 kg/m² are more frequently obese at age 16 compared to offspring of mothers with normal weight gain, even after adjusting for age, socioeconomic status, sex, or BW (144). As adults they demonstrate reduced life quality and life span (HR: 1.35; 95% CI 1.17–1.55) (145). These Scandinavian epidemiologic data match with animal experiments demonstrating that rats on a high-calorie diet before and during pregnancy demonstrate adipogenesis and are “programmed to early death, e.g., a shorter life” (146). Endothelial lesions, increased number of fat lobule in utero, as well as the U-shaped correlation of BW and obesity might play a role (3). Additionally, exposure to obesity and high-fat diet before, during, and after pregnancy promote appetite over satiety neurons in the hypothalamic arcuate nucleus leading to offspring hyperphagia and obesity (147). Finally, a high-caloric or high-fat maternal diet modulates the fetal gut microbiome and gut–brain axis causing a persistent predisposition to metabolic disease and obesity in the offspring (148, 149).

Maternal obesity is associated with sex-specific differences not only in fetal size but also in neurodevelopment reflected by gene expression signatures and the brain transcriptome. Especially male embryos of dams on the high-fat diet had a significantly lower BW than controls; dietary change in pregnancy resulted in significantly more dysregulated genes and pathways in male than in female brains (386 vs. 66, p < 0.001) (150).

Type 1 or type 2 diabetes may exist before pregnancy; GDM is defined as glucose intolerance first diagnosed in pregnancy and is associated with subsequent hyperinsulinemia, dyslipidemia, type 2 DM, hypertension, and CVD (151). Already in the 1950s, Pedersen et al. reported the association of GDM with DM and fetal macrosomia [c.f. (152)]. In the 1980s, Freinkel described the impact of GDM on fetal long-term health and together with Metzger on maternal glucose tolerance after birth; 30% of women with GDM have a persisting glucose tolerance and develop type 2 diabetes within 10 years (153–155). Worldwide, the incidence of GDM has increased to 7–14% (156). Weight gain above the IOM norms and GDM are associated: a case–control study of 800 women with excessive weight gain but normal glucose tolerance showed a 50% increase of GDM compared to controls with normal weight gain (118).

The hypothesis that pre-existing risk profiles play a role is supported by the fact that first-trimester prediction of GDM by history or biochemical–biophysical tests has sensitivities as high as 80% (7). The risk to develop overt DM increases with maternal age and accelerated almost 10-fold for women with GDM resulting in cumulative 15-year risk of 25% (156). A comprehensive systematic review including 205 relevant reports, 20 studies, 675,455 women, and 10,859 type 2 DM events confirmed the increase of type 2 DM compared to normoglcyemic women (40) (Table 2).

Fetal programming related to GDM and DM is complex since both, low and high BW are associated with the development of a metabolic risk profile in later life. A significant association between low (OR 2.15, 95% CI 1.29–3.50) and high BW (OR 1.97, 95% CI 1.12–3.45) and later development of GDM was shown with a U-shaped relation between BW and risk of GDM (61). In families or regions where GDM was not known before an “epigenetic mismatch” between prenatal and postnatal nutrition plays an increasing role.

The hypothesis “fetal origins of disease” was proposed to explain associations between low BW and impaired glucose tolerance or CVD (157–161). The thrifty phenotype hypothesis suggests that early malnutrition induces poor development of pancreatic β-cell mass and programs the metabolic syndrome (157–162). LBW was related to high concentrations of split proinsulin, a sign of beta-cell dysfunction, linked to later high blood pressure (163, 164) and to metabolic abnormalities in combination with low physical activity and/or high-energy intake (165). The British Maternal Nutrition Study correlated prenatal micronutrient deficiency with increased insulin resistance in childhood: the offspring of mothers with combined high folate and low vitamin B12 levels were insulin resistant (166). Similarly, prenatal famine exposure was associated with impaired glucose tolerance and insulin secretion in adulthood (167, 168). Before, it was already demonstrated that a pregnancy with a LBW child indicates a risk for significantly lower rates of insulin, C-peptide, and proinsulin responses than controls. Insulin sensitivity was increased in the FGR compared to the control group (169).

Children of mothers with GDM and fetal macrosomia are at higher risk of childhood obesity and its consequences (170). Metabolic markers such as insulin resistance and high TGs are present in 21% before puberty (171) and at age 11, maternal GDM with fetal macrosomia increased the risk of metabolic syndrome 3.6-fold over controls with isolated macrosomia (63). Similarly, as adults these children are at higher risk for DM and metabolic syndrome (171, 172). A large Danish study of women with DM confirmed that as adults the offspring was at increased risk for CVD (adjusted OR 1.46; 95% CI 1.16–1.83) and for insulin-dependent DM (adjusted OR 4.7; 95% CI 3.9–5.8) compared to offspring of non-diabetic mothers. CVD was associated with FGR rather than macrosomia (OR 1.29; 95% CI 1.24–1.35) (173). Accordingly, undernutrion during pregnancy was linked to decreased glucose tolerance up to age 58 (62) (Table 2).

Cesarean delivery and later childhood obesity are associated independently of the fact that Cesarean rates are per se higher in obese women and differences in the infant intestinal microbiome has been postulated as a potential explanation (174). Subfertility such as premature ovarian insufficiency or PCO is another factor that increases risk for CVD and metabolic disease (42, 76).

Children conceived through artificial reproduction techniques have higher glucose levels compared to controls (64). At the age of 5–6 years, glucose levels were increased by 0.4 mmol/l (95% CI 0.2–0.6) and 0.2 mmol/l (95% CI 0.0–0.5), respectively. Similarly, systolic and diastolic BP was elevated by 0.8 mmHg (95% CI −0.2 to 1.8) and 1.4 mmHg (95% CI 0.6–2.3). Since the duration of infertility correlates with BP in the offspring and with PE in the pregnant women, epigenetic and genetic factors have been implied (64).