Rates of obesity are increasing globally, both in developing and developed countries, now considered a global pandemic [1]. An estimated 20% of pregnant women in the United Kingdom and 30% of those in the United States are obese (body mass index [BMI] of over 30 Kg/m${}^2$) [2, 3]. Moreover, it is projected that by 2030, nearly 1 in 2 adults in the United States will suffer from obesity, with nearly a fourth of the adult population suffering severe obesity (BMI $>$ 40) [4]. This dramatic increase in rates of overweight and obese women of childbearing age is of great concern in terms of public health. Evidence accrued from decades of observation and research show that maternal gestational weight gain as well as pre-pregnancy BMI have important effects on maternal and neonatal morbidity and mortality as well as long-term effects on the health of both mother and offspring [5, 6, 7, 8, 9, 10, 11]. This includes hypertensive and thromboembolic disorders, gestational diabetes, increased cesarean section rates, and wound infection [12, 13, 14, 15, 16]. Fetuses of obese mothers are at increased risk of macrosomia, complicated deliveries, and perinatal death [17, 18, 19, 20]. In addition, offspring are at increased risk of developing obesity, hypertension, diabetes, and cardiovascular morbidity in the future [21]. A possible association between maternal obesity and neurodevelopmental disorders, including autism spectrum disorders, and asthma has also been suggested [22].

Finally, some congenital malformations, including congenital heart anomalies and neural tube defects, were shown to be linked with maternal obesity, with a possible “dose-response” correlation [23]. Congenital anomalies are known to be a major cause of stillbirth and infant mortality, accounting for 20% of infant deaths in the United States [24], and are important contributors to preterm delivery and childhood morbidity. North American registries suggest that 3% of all live births in the country are affected by a structural anomaly [25]. Of those, 0.07% births are affected by a neural tube defect and 0.2% by a major heart anomaly. Investigators calculated, in a systematic review and meta-analysis, that the incidence of fetal neural tube defects and serious heart anomalies among the obese population might grow to 0.1% and nearly 0.3%, respectively [26].

In the following chapter we will review the data on various anomalies linked to maternal obesity, and explore potential underlying mechanisms.

One of the better-known anomalies shown to be correlated with maternal obesity are neural tube defects [27, 28, 29, 30, 31, 32], particularly anencephaly and spina-bifida.

A meta-analysis [26] combining data from eighteen studies originating from North America and Europe, which analyzed data from more than 26,000 cases of diverse anomalies diagnosed in neonates, sought to determine the added risk of maternal obesity to the development of these anomalies. When compared with mothers of normal BMI, the authors found that the OR of developing a neural tube defect in a pregnant obese mother is 1.87 (95% CI, 1.62–2.15; P = 0.001). The increased risk was significant also among mothers with BMI greater than 24 but less than 30 (i.e., overweight mothers) by an OR of 1.20 (95% CI, 1.04–1.38; P = 0.01).

A potential explanation for this significantly increased risk for NTDs may be related to folate deficiency. Humans cannot produce folate, and the requirement of this vitamin is partly supplied by dietary intake of folate and partly by the use of synthetic folate. Folate is required for cell division and cell maintenance and plays a major role in the re-methylation of plasma homocysteine, which accumulates when meat, fish or plant proteins are digested, to methionine. Homocysteine is neutralized quickly in the human body, as it is a toxic metabolite. When folate levels are reduced, increases in the plasma homocysteine level may cause a delay in the closure of the embryonic neural tube, causing defects in the neural tube [33].

It has previously been established that pregnant women suffering from obesity, also exhibit nutritional deficiencies, specifically reduced folate levels [34, 35]. A study examining the prevalence of micronutrient deficiency in patients with morbid obesity prior to bariatric surgery showed a high prevalence of micronutrient deficiencies, despite energy excess, with common deficiencies being vitamins B12 and D, folate, and iron [36]. Contrary to the belief that obese people consume higher amounts of food and should therefore have sufficient levels of micronutrients, the data demonstrate the reverse. It is postulated that food consumed in the obese population may be of low nutritional value, or, that periods of severe food restriction, undertaken to achieve rapid weight loss, might cause the deficiencies described above. In addition, since obesity is more prevalent among disadvantaged socio-demographic groups, these deficiencies can also be explained by lower health literacy [37].

Importantly, studies conducted at the genetic level have explored the correlation between genes responsible for maternal obesity or maternal hyperglycemia (which are often related) and the development of NTD in the fetus. An American group studying the relationship between the target genes found that when genes responsible for the transport of glucose across the fetal cells (e.g., SLC2A2) interact with the altered maternal LEP and ENPP1 genes (which regulate eating behavior and metabolic rate) they might modify their activity, increasing the risk of NTD in the fetus [38].

Obese mothers are at increased risk of having a fetus affected by a cardiovascular anomaly, compared with mothers of recommended BMI [27, 28, 29, 39, 40, 41]. According to the meta-analysis cited above [26] the odds ratio (OR) of a cardiovascular anomaly in a newborn delivered to an obese mother is 1.30 (95% CI, 1.12–1.51; P = 0.001). The cardiac septa defects seem to be the most affected (OR, 1.20; 95% CI, 1.09–1.31; P = 0.001), though a trend could also be seen in the incidence of transposition of the great arteries (OR, 1.41; 95% CI, 0.97–2.06; P = 0.07).

Additionally, when stratifying the risk of fetal anomalies according to maternal weight class, a “dose-dependent” effect can be observed, with gradually increasing rates of malformations of the nervous system, heart, digestive system, genital organs, and limbs. The relative risk (RR) for congenital heart defects was 1.05 (95% CI, 1.01–1.08) for overweight mothers (BMI 25 to 30) as compared to normal weight mothers (BMI 18.5 to 25), 1.15 (95% CI, 1.09–1.20) for women with class I obesity (BMI 30 to 35), 1.26 (95% CI, 1.16–1.37) among women with class II obesity (BMI 35 to 40), and 1.44 (95% CI, 1.27–1.63) for women with class III obesity (BMI $>$ 40) [42].

Several potential explanations have been suggested for this observed link between maternal obesity and congenital anomalies of the cardiovascular system. One of these involves the correlation between obesity and insulin resistance. When a nondiabetic person consumes an excessive amount of calories and gains weight, the body becomes markedly resistant to the action of insulin. Investigators have shown, using a euglycemic insulin-clamp technique, that tissue sensitivity to insulin declines by up to 40% when an individual becomes 40% over his or her ideal body weight [43]. Insulin resistance will eventually lead to a hyperglycemic environment for the developing embryo, and it is well established that maternal hyperglycemia can potentially cause anomalies in the fetus, most commonly cardiovascular anomalies [44]. The mechanism whereby hyperglycaemia may induce dysmorphogenesis has not been completely elucidated, though several studies have shown that a hyperglycemic environment may cause elevated levels of cell death and apoptosis among the neural crest cells in the developing fetus, leading to the development of a defective fetal heart [45]. Oxidative stress induced by diabetes has been shown to interfere with the process of cardiac neural crest migration at the early stages of organogenesis by inhibiting Pax3 expression, causing cell apoptosis and outflow tract defects [46]. In addition, several authors suggest liberation of free oxygen radicals, deficiency states of myo-inositol or arachidonic acid, and damage to the developing yolk sac, as possible explanations for this association [47]. Therefore, in obese pregnant women, undiagnosed hyperglycemia or diabetes is one potential explanation for the increased risk of congenital cardiac anomalies.

Another possible explanation for the association between obesity and cardiovascular defects could be improper nutrition, as mentioned above. A correlation between maternal vitamin consumption, especially folate, and embryonic cardiac defects have been demonstrated in a number of studies [48, 49]. The same phenomena have been shown to occur in animal studies. In particular, rats with folic acid deficiency were reported to produce cardiac malformed offspring, mostly with defects of the outflow tract, the great vessels and ventricular septal defects [50]. In addition, folic acid deficiency or abnormalities of the metabolism of folic acid and vitamin B12 result in increased levels of homocysteine, shown to induce neural tube and cardiac defects in chick embryos [51].

Obese mothers seem to be at an increased risk of having a fetus affected by either a cleft palate or a cleft lip and palate, compared with mothers of recommended BMI [28, 29, 41, 52]. The meta-analysis mentioned earlier [26] found that the OR for the development of a cleft palate was 1.23 (95% CI, 1.03–1.47; P = 0.02), whereas the OR for both a cleft lip and palate was 1.20 (95% CI, 1.03–1.40; P = 0.02). There was no significant increase in risk for the development of a cleft lip alone. However, there have also been a number of studies that did not show an increased risk of orofacial cleft in the fetuses of mothers with obesity [53, 54].

The potential underlying cause leading to the development of these anomalies in the offspring of obese mothers might be the higher prevalence of undetected diabetes or hyperglycemic state, in addition to improper nutrition as previously discussed. Although the risk of orofacial clefts in pregnancies complicated by diabetes has been shown to be elevated, the exact mechanism is unknown [55]. In rats, maternal hyperglycemia has been shown to cause defects in fetal expression of developmental genes) such as the sonic hedgehog gene and bone morphogenetic protein 4 (leading to offspring with different malformations including micrognathia and agnathia, as well as oral clefts [56]. On the other hand, there are conflicting data regarding the role of folic acid deficiency in the development of orofacial deformities [57, 58]. It has been shown that diabetic mothers taking folic acid at the start of their pregnancies had a significant reduction in the risk of orofacial clefts in their offspring when compared to diabetic mothers who did not take folic acid [59]. This might be the result of an altered gene methylation process causing epigenetic changes, thus damaging palatal development [60].

The offspring of mothers with obesity are at a greater risk of developing other congenital anomalies including: anorectal atresia [29, 61], hydrocephaly [28, 29, 61, 62] and limb reduction [29] when compared to mothers with recommended BMI. The OR of these anomalies occurring in the fetuses of obese mothers are 1.48 (95% CI, 1.12–1.97; P = 0.006), 1.68 (95% CI, 1.19–2.36; P = 0.003), and 1.34 (95% CI, 1.03–1.73; P = 0.03), respectively [26]. In addition, a large study done using the Swedish registry showed that maternal obesity is associated with other malformations such as hypospadias (OR, 1.31, 95% CI, 1.17–1.46), cystic kidney (OR, 1.40, 95% CI, 1.03–1.90), pes equinovarus (OR, 1.50, 95% CI, 1.29–1.75), and diaphragmatic hernia (OR, 1.81 95% CI, 1.29–2.55) [61], however these findings were not repeated by others [26]. Finally, several studies have suggested an increased risk of omphalocele [28, 29, 61] as well as a significant protective effect against the development of gastroschisis [29, 61, 63] (OR, 0.17; 95% CI, 0.10–0.30; P = 0.001).

As mentioned above, some of the anomalies described here can be explained by the oxidative stress occurring in pregnant obese women with an altered glucose metabolism. Increased glucose metabolism in fetal cells increases oxidative stress, which in turn inhibits the expression of Pax3 in neuroepithelial cells, preventing the accumulation of p53 protein- a tumor-suppressor protein. Low levels of p53 activate genes causing apoptotic cell death. Neuroepithelium suffering an excess of cell death fails to proliferate and migrate, leading to an open neural tube or a cardiac malformation, among other potential anomalies [46].

In addition to the potential etiologies described above, another possible explanation for the increased at-birth prevalence of some of these anomalies is the technical difficulty in preforming ultrasound scanning in obese women. It has been shown that adipose tissue may attenuate ultrasonic signals [64] in addition to increasing the distance between the transducer and the fetus being investigated, thus affecting image quality. Previous studies have found that obese women may be at twice the risk of suboptimal sonographic visualization during detailed fetal anatomy scanning, than women of normal body habitus [65]. This technical difficulty may potentially result in fewer terminations of pregnancy for fetal anomalies and increased prevalence at birth.

The offspring of pregnant women suffering from obesity are at increased risk of a wide range of congenital anomalies (Table 1). These anomalies may include neural tube defects, cardiovascular anomalies, oral clefts, and limb reduction anomalies. The exact etiology of this increased risk is not clear, but evidence suggests that two potential explanations: nutritional deficiencies (especially folic acid deficiency) and an undiagnosed hyperglycemic maternal environment. In addition, it is possible that the technical difficulty of detailed fetal anomaly scanning in obese gravitate, results in less frequent pregnancy terminations and therefore more fetal anomalies at birth (Fig. 1). The possible dose response pattern observed between the severity of obesity and teratogenic potential necessitates further investigation, which may also shed light on the underlying pathophysiology.

Fig. 1.

Pathways linking maternal obesity and congenital anomalies in offspring.

The increasing prevalence of obesity in general and particularly in the pregnant population may thus have serious health implications, not only to the parental generation but also to generations to come. Education regarding the many risks associated with obesity, for mothers and their babies, coupled with pre-pregnancy weight loss programs, may reduce the magnitude of this worrisome phenomenon.

OR and AW conceived of the study, performed the literature search and have written and edited the manuscript.

Not applicable.

We would like to acknowledge and thank Gideon Koren for his continuing support and mentorship.

This research received no external funding.

The authors declare no competing interests.