Update on Prepregnancy Maternal Obesity: Birth Defects and Childhood Outcomes

Abstract

Obesity is a growing global health epidemic. It is estimated that more than 20% of pregnancies are complicated by obesity. Prepregnancy obesity has been associated with birth defects such as neural tube defects, macrosomia, fetal death, and long-term effects such as asthma on the offspring. We provide a summary of the most recent studies and meta-analyses on obesity and birth outcome. Possible mechanisms of actions are explored and recommendations for further research are highlighted.

Introduction

Obesity is a growing global health epidemic affecting adults and children in both developed and developing countries.^{1 2 3 4} One in five women in the United Kingdom and approximately 36% of adults in the United States are classified as obese.⁵ Prevalence of obesity in pregnancy has been rising since 1993, and it was estimated that 50% of childbearing women in the United Kingdom were overweight or obese in 2006.⁶

It is well known that obesity is a major risk factor in adults for noncommunicable diseases such as diabetes, cardiovascular diseases, musculoskeletal disorders, and some cancers, resulting in premature death and disability. At least 2.8 million people die every year as a result of being overweight or obese.⁷ Obesity also affects pregnancy and more than 20% of pregnancies are complicated by obesity.^{5 6 7 8} Maternal obesity has been associated with increased rates of preeclampsia, gestational diabetes and need for operative delivery,^{9 10 11} and increased risks of adverse reproductive outcomes affecting fetal development, the neonatal period, and overall childhood development.^{12 13}

Obesity is a multifactorial condition in which environmental, biological and genetic factors play an essential role. It represents a state of altered hormonal and inflammatory activity associated with fatty tissue.¹⁴ A woman may be obese prior to pregnancy or become obese during pregnancy due to excessive gestational weight gain. These are both independent factors, and we focus on prepregnancy obesity in this review. The World Health Organization defines obesity as abnormal or excessive fat accumulation that may impair health. Body mass index (BMI) is a measure calculated by dividing a person's weight (kg) by the square of the height (m²).⁷ A BMI greater than or equal to 30 is considered obese, whereas a BMI greater than or equal to 25 is overweight. Maternal obesity is defined as a BMI of 30 kg/m² or greater, and being overweight during pregnancy (maternal overweight) is defined as a BMI between 25 and 29.9 kg/m². Maternal obesity can be further divided into class I (BMI = 30–34.9), class II (BMI = 35–39.9), and class III (BMI ≥40).¹⁵

Earlier publications have reviewed the association between maternal obesity and comorbid conditions, such as hypertensive disease or diabetes, with adverse pregnancy outcomes and fetal malformations.^{16 17 18} More recent studies have added to existing knowledge, and associations between other outcomes in offspring such as neurodevelopmental disorders and asthma are emerging. In this paper, we review the metabolic differences in obese and nonobese women, and provide an update of evidence on fetal development and neurodevelopmental outcomes in offspring of maternal obese women.

Metabolic Changes and Obesity in Pregnancy

Intrauterine Environment and “Fetal Programming”

The intrauterine environment in pregnancy is thought to play a major role in physiologic alterations in the offspring. It is hypothesized that the intrauterine environment can “program” later development of obesity, hypertension metabolic syndrome, and neurodevelopmental outcomes in the offspring. This is known as the fetal programming hypothesis.^{19 20} The intrauterine environment is affected by altered nutritional experiences and chemical changes during pregnancy.

Obese women tend to have increased levels of insulin, cytokines, protein hormones, and leptin, regardless of the presence of comorbidities such as diabetes.^{10 21} In addition, obese women have higher insulin resistance and are at increased risk of metabolic syndrome-like disorders during pregnancy, such as hypertension, hyperlipidemia, glucose intolerance, and coagulation disorders.²²

High levels of proinflammatory cytokines such as tumor necrosis factor-α, interleukin, monocyte chemotactic protein-1, and procoagulant proteins are found in obese nonpregnant individuals.^{23 24} It is thought that obesity increases baseline proinflammatory mediators, which increases the risk of maternal diseases (preeclampsia) and neonatal complications.^{25 26 27 28 29 30 31 32 33 34}

Fetal Development

The hormonal and chemical changes that occur in pregnancy can affect various stages in fetal development and maternal health. Insulin and leptin function as growth factors and can elevate progesterone concentrations. This can alter transcriptional activity during oocyte growth and impair mechanisms of RNA translation and degradation during oocyte maturation. This leads to reduced oocyte quality and poor embryogenesis.³⁵ Hence, the environmental messages are translated to the structure and function of the developing fetus leaving a permanent mark. Changes in gene-environment interactions start in the periconception period and continue into later life producing a phenotype, which continues to evolve.³⁶

Insulin and leptin are involved in the development of the central nervous system in early stages of pregnancy. Alterations in levels of these hormones have been shown to induce changes in brain development in animal models.^{37 38} It is thought that in humans, alteration in the developmental program of specific brain cell networks could lead to conditions such as metabolic syndrome and neurologic disorders in the offspring at later ages.³⁹

Obesity and Other Maternal Metabolic Phenotypes

The maternal phenotype may have a direct impact on the infant's phenotype, in particular when combined with hormonal tensions caused by over or under placental nutrition.⁴⁰ Maternal metabolic phenotypes include obesity, pregestational diabetes (types 1 and 2), gestational diabetes, and hypertension.

Metabolic abnormalities are not uniform in all obese persons, and an individual can be metabolically healthy but obese; or have metabolically disturbances but have a normal body weight. The standard measure of obesity is the BMI, which is calculated using overall body weight rather than fat percentage. In the average individual, excess weight is primarily due to increased adipose tissue. Adipose tissue is composed of subcutaneous and visceral depots. Subcutaneous tissue forms a continuous layer beneath the skin and is not confined to specific areas. Visceral adipose tissue is confined to the intra-abdominal area, and can be measured with indicators such as waist circumference (applicable to women only during early pregnancy or at preconception), or directly by imaging techniques such as computed tomography.^{41 42} Obese individuals can have high or low visceral adiposity phenotypes. Viscerally obese patients represent a subgroup of obese individuals who are at greater risk of metabolic abnormalities.^{43 44} This includes insulin resistance leading to overproduction of free fatty acids, and increased secretion of triglyceride rich lipoproteins.⁴² Viscerally obese individuals have also been shown to have impaired fibrinolysis, increased susceptibility to thrombosis, and to be in a chronic inflammatory state.⁴² Hence, mothers with visceral obesity expose their fetuses to an altered metabolic intrauterine environment, which increases the risk of obesity and other metabolic disorders later in the life of the offspring (Table 1). This effect has the potential to play a role in future generations, as seen with type 2 diabetes in Pima Indians over the last three decades.⁴⁰ The incidence of type 2 diabetes has increased two- to fourfold in this population after a transmission cycle of metabolic phenotype, due to a secular increase in maternal type 2 diabetes and subsequent childhood obesity.⁴⁰ Further research is needed to assess the long-term effects of overnutrition on the offspring—specifically focusing on the effect of an extra increment of maternal adiposity. In addition, further understanding of the intrauterine mechanisms related to the transmission of obesity through generations is needed by conducting long-term follow-up studies.

Table 1. Maternal metabolic phenotypes and potential risks to offspring.

Metabolic phenotypes	Association with obesity	Exposure window	Metabolic changes and intrauterine environment	Potential risks to offspring	Possible mechanism
Maternal undernutrition	This can occur in obesity due to poor dietary habits	First and second trimesters	Lack of essential nutrients, imbalance of vitamin B12 and folate levels, reduced folate levels	Overeating, obesity, and diabetes in offspring, restricted fetal growth, risk of structural defects, development of neural tube defects	Hypothalamic appetite “programmed” to adapt, influences cellular growth and synthesis of amino acids, underdevelopment of neural tube
Gestational diabetes			Overnutrition, increase in transfer of nutrients, hyperglycemia, stimulates fetal islets hyperinsulinemia	Macrosomia at birth, fetal adiposity, increased risk of childhood obesity and diabetes	Growth promoted in Insulin sensitive organs, alters structure and function of the pancreas, increases fat deposition
Pregestational diabetes in mother	Associated with obesity as a risk factor.	First trimester	Extratransfer of glucose	Increased risk of obesity in offspring and increased risk of diabetes	Hampers fetal β-cell formation, alters structure and function of the pancreas, stimulates fetal islets, and causes hyperinsulinemia
Visceral adiposity	Associated with obesity	First trimester	Increase in insulin glucose levels and leptin; insulin resistance and procoagulant proteins cause impaired fibrinolysis and increased susceptibility to thrombosis, proinflammatory cytokines (tumor necrosis factor-α, interleukin-6), monocyte chemoattractant protein-1	Risk of; macrosomic baby, neurodevelopmental disorders, type 2 diabetes, fetal death, birth defects, childhood asthma	Elevate progesterone concentrations (induce changes in brain development), fetal programming, increase risk of maternal diseases (e.g., preeclampsia), chronic inflammatory state

If maternal undernutrition occurs early in intrauterine life (first and second trimesters), the offspring are also more likely to be obese in adult life.⁴⁵ It has been suggested that undernutrition during this time can lead to underdevelopment of the hypothalamic appetite centers leading to overeating and obesity in postnatal life.⁴⁶

All three types of maternal diabetes (type 1, type 2, and gestational) are associated with an increased fetal and infant growth rate (Table 1). Gestational diabetes usually occurs in the later stages of pregnancy. Gestational diabetes is thought to induce hyperglycemia in the fetus (in later stages of pregnancy) and causes dysfunction of the pancreas, chronic hyperinsulinemia, and macrosomia.⁴⁷ Type 2 diabetes is associated with an increase in obesity and type 2 diabetes in the offspring. This effect is thought to occur in early pregnancy due to alterations in the intrauterine environment.⁴⁸

Interventions to prevent effects of obesity and diabetes on the offspring should be targeted to females throughout their life span, particularly in the preconception time period, as pregnancy itself may be too late to intervene.

Major Congenital Malformations

Complications such as fetal neural tube defects and other fetal anomalies have been investigated in relation to maternal obesity. An update of the latest evidence is discussed and presented in Table 2.

Table 2. Potential outcomes related to maternal obesity, postulated mechanisms, and gap in knowledge.

Outcome	Reference	Association	Postulated mechanism	Issues and gaps in knowledge
Major congenital malformations
Cardiac malformations	Cai et al 201457	Meta-analysis; 24 studies: Overweight BMI ≥25 <30 OR = 1.08a (95%CI; 1.02, 1.15, n = 798,054, 11 studies); BMI ≥30 <35 Moderate (severe) OR = 1.15a (95%CI; 1.11, 1.20, n = 735,281, five studies); BMI ≥35 (severe) OR = 1.39a (95%CI; 1.31, 1.47 n = 665,528, five studies)	Maternal hypoglycemia could interfere with glycolysis during embryogenesis, influencing the migration of neural crest cells essential for the development the heart	Cases in most studies generally have low validity and ascertainment. There is a lack of consistency in studies.
	Stothard et al 200917	Meta-analysis of 18 studies:
Spina bifida		OR = 2.24a (95% CI; 1.86, 2.69, n = 863; five studies)
Anencephaly		OR = 1.39a (95% CI; 1.03, 1.87, n = 373; four studies)
Other birth defects:	Stothard et al 200917	Meta-analysis of 18 studies:	Obesity is a risk factor for diabetes; hence undiagnosed diabetes and hyperglycemia	Many studies used crude estimates and did not control for potential confounders. Some studies use small sample sizes. Further studies on dose response (i.e., varying BMI levels) are needed. Large, high-quality population-based studies are needed to confirm findings. Birth defects in elective terminations are not included in many studies. In Waller et al,18 controls are not matched to cases; there are demographic differences between cases and controls (e.g., maternal education). Definition of obesity due to BMI is not uniform across studies. Many studies use self-reported height and weight to calculate BMI can be over- or underestimated. There is a need for direct measurements.
Cleft lip and palate		OR = 1.20a (95%CI; 1.03, 1.40; n = 1,188; three studies)
Cleft palate		OR = 1.23a (95%CI; 1.03, 1.47 n = 865; three studies)
Hydrocephaly		OR = 1.68a (95%CI; 1.19, 2.36; n = 188; three studies)
Anorectal atresia	Waller et al 200718	(Excluded gestational diabetes n = 14,314) OR = 1.41 (95% CI; 1.01, 1.97)
Hypospadias		OR = 1.21 (95% CI; 0.93, 1.58)
Limb reduction defects		OR = 1.21 (95% CI; 0.89, 1.63)
Diaphragmatic hernia		OR = 1.16 (95% CI; 0.83, 1.96)
Omphalocele		OR = 1.27 (95% CI; 0.83, 1.96)
Other adverse pregnancy outcomes
Fetal death	Aune et al 201462	Meta-analysis of seven studies; n = 690,622 RR: 1.21 (95% CI; 1.09, 1.35; n = 7 studies	Increased risk of preeclampsia, gestational diabetes, type 2 diabetes, gestational hypertension and congenital anomalies Increased inflammatory responses, vascular, endothelial dysfunction, altered lipid metabolism in obese women Increased risk of congenital malformations Hyperlipidemia can cause increased thromboxane production, which increases risk of placental thrombosis and decreases placental perfusion leading to infarction and abruption of placenta	Further studies are needed: to investigate mechanisms. Fetal deaths in low- and medium-income countries for generalizability. On gestational weight gain and fetal death are needed.
Fetal growth abnormalities: Macrosomia	Alberico et al 201469	OR = 1.7 (95% CI; 1.4, 2.2; cohort; n = 14,109)	Insulin resistance and glucose intolerance increase fetal glucose, insulin, steroids, and growth hormones, resulting in fetal fat deposition and accelerated birth weights	Further studies are needed to investigate the postulated mechanism, over successive generations.
Metabolic syndrome in offspring	Boney et al 200571	HR: 1.81 (95% CI; 1.03, 3.19; n = 175; 6–11-year-old)	Fetal programming due to overnutrition, and imbalance of glucose, insulin, and inflammatory markers in the intrauterine environment	Require more studies to understand the fetal programming and transmission through successive generations.
Neurodevelopmental outcomes
Child cognition	Basatemur et al 201382	Increase in maternal BMI negatively affects child cognition at 5 and 7 years of offspring	Inflammatory intrauterine environment Increase in the permeability of the fetal blood-brain barrier Inflammation of the fetal brain Increase in leptin levels, which is involved in brain development Possibility of a common genetic pathway underlying obesity and poor mental health Underlying predisposing factor, e.g., stress related to caloric intake, increasing cortisol secretions, which affect fetal brain development	Many unmeasured confounders related to neurodevelopment are not adjusted for in studies. Further studies are needed to establish this relationship. Some studies are small in size. Some studies used symptoms as an outcome and not the actual diagnosis of conditions such as ADHD.
Child cognition	Tanda et al 201384	Offspring to obese mothers had reduced cognitive test scores
Child intelligence quotient	Neggers et al 200386	Lower intelligence quotient in children of prepregnant obese mothers
Autism in offspring	Reynolds et al 201489	Positive screen for autism OR: 9.875 (95% CI; 0.88, 3.70) n = 62
Delayed mental development of off spring	Hinkle et al 201290	Increase risk of delayed mental development (RR 1.38 (95% CI; 1.03, 1.84; cohort; n = 6,850)
ADHD in offspring	Chen et al 2014103	Increased risk of ADHD in offspring HR (obesity) = 1.64, (95% CI; 1.57, 1.73; cohort n = 673,632)
Teacher-rated high inattention	Rodriquez et al 2010102	OR: 2.09 (95% CI; 1.19, 4.82; cohort n = 1,714)
High ADHD symptom score	Rodriquez et al 200891	OR:1.89 (95% CI; 1.13, 3.15; cohort n = 14,519)
Asthma
Asthma or wheeze	Forno et al 2014108	Meta-analysis of 14 studies n = 108,321 or (OR = 1.31; 95% CI: 1.16, 1.49)	Proinflammatory state in intrauterine environment can affect immune or pulmonary development	Other factors associated with obesity can also increase risk of asthma. Prospective randomized trials of maternal weight management are needed.

Abbreviations: ADHD, attention deficit/hyperactivity disorder; BMI, body mass index; CI, confidence intervals; HR, hazards ratio; OR, odds ratio; RR, risk ratio.

^aUnadjusted for potential confounders.

Neural Tube Defects

A meta-analysis of 12 studies (cohort and case-control) reported the odds of an infant being born with a neural tubal defect (NTD) in overweight and obese mothers were odds ratio (OR)_(unadjusted): 1.22 (95% confidence interval [CI]; 0.99, 1.49, 12 studies), (overweight); OR_(unadjusted): 1.70 (95% CI; 1.34, 2.15, 11 studies) (obese); and OR_(unadjusted): 3.11 (95% CI; 1.75, 5.46, 5 studies) (severely obese) compared with mothers with normal prepregnancy BMI.¹³ The main limitation of these studies is the possibility of confounding by comorbidities such as diabetes, which although controlled for, may be undetected. A subsequent meta-analysis also demonstrated a statistically significant association between obese mothers and spina bifida, OR: 2.24 (95% CI; 1.86, 2.69; n = 863, five studies) and anencephaly OR: 1.39 (95% CI; 1.03, 1.87; n = 373, four studies).¹⁷ The reasons for the NTD association are not known. Obesity may be associated with factors that reduce folate levels and possible reasons for the increased risk of NTD in infants with obese mothers include: altered glucose metabolism earlier in pregnancy,⁴⁹ differences in nutritional requirements, and poor diet habits.^{50 51} In addition, recent genetic studies indicate that maternal metabolic genes associated with hyperglycemia and insulin resistance may interact to increase the risk of NTDs.⁵² Increased risk of NTDs has been attributed to lower levels of folate in obese women.⁵³ However, an epidemiological study has shown no difference in the risk of the NTD spina bifida in the offspring of obese women who have taken a standard 400-μg dose of folic acid supplementation.⁵⁴ Another hospital-based study found that the reduced risk of NTDs after supplementation with folic acid was weaker in obese mothers or mothers with an increased BMI (BMI ≥27).⁵⁵ The Centre for Maternal and Child Enquiries and The Royal College of Obstetrics and Gynecology guidelines advise that obese women should take 5 mg of folic acid supplements daily, periconceptionally and throughout the first trimester.⁵⁶ An audit of the implementation of the Centre for Maternal and Child Enquiries and the Royal College of Obstetrics and Gynecology recommendations for 5 mg folic acid supplementation has shown that these guidelines are not adhered to, and these groups have recommended that awareness be increased regarding the risk of NTDs in the obese women.⁵⁶

Congenital Heart Defects

A systematic review and meta-analysis of 24 studies has estimated the risk of congenital heart defects in offspring with nondiabetic but moderate and severely obese mothers to be: OR: 1.15 (95% CI; 1.11, 1.20, n = 1,176,564, 11 studies) and OR: 1.39 (95% CI; 1.31–1.47, n = 1,176,564, 5 studies), respectively.⁵⁷ This risk was further increased when analyzed in women with gestational diabetes. Gestational diabetes is usually manifested in the second and third trimesters, after the fetal heart has already formed. However, fetal hyperinsulinemia and an altered intrauterine environment may have developed due to mild undetected hyperglycemia earlier in pregnancy. The types of congenital defects that prepregnancy and gestational maternal obesity have been associated with include left ventricular outflow tract defects (hypoplastic left heart syndrome and aortic valve stenosis), anomalous pulmonary venous return; conotruncal defects (tetralogy of Fallot), septal defects (secundum atrial), and right ventricular outflow tract defects (pulmonary valve stenosis).^{58 59} However, these findings are not consistent in all studies and further high-quality epidemiologic studies are needed to clarify these associations.¹⁷

Other Birth Defects

A systematic review and meta-analysis that examined 13 types of birth defects in addition to spina bifida and cardiac septal anomalies found a statistically significant increased risk of: cleft lip and palate (OR: 1.20; 95% CI; 1.03, 1.40, n = 1188, three studies), cleft palate alone (OR: 1.23; 95%CI; 1.03–1.47, n = 865, three studies), and hydrocephaly (OR: 1.68; 95% CI; 1.19–2.36, n = 188, three studies) in infants born to obese mothers.¹⁷ This was not mirrored in infants of mothers who were overweight and no dose response relationship was evident between maternal BMI and risk of birth defects. Subsequent studies in Australia (n = 111), the United States (n = 14,319), and Saudi Arabia (n = 37,168) reported an association of prepregnancy obesity with orofacial clefts, limb reduction defects (over twofold), and urinary tract defects.^{18 60 61} In addition, the US study¹⁸ reported increased risks of anorectal atresia, hypospadias, limb reduction defects, diaphragmatic hernia, and omphalocele. The Australian study was limited by small sample size⁶¹ and the study conducted in Saudi Arabia did not adjust for prepregnancy diabetes.⁶⁰

Risk of Other Adverse Pregnancy Outcomes

Fetal Mortality

A meta-analysis of 38 cohort studies showed a moderate to strong increase in relative risk of fetal death, stillbirth, neonatal, perinatal, and infant death with an increase in maternal BMI.⁶² The relative risk of fetal death was 1.21 (95% CI; 1.09, 1.35; n = 690,622, seven studies); similar relative risks were found for stillbirth, perinatal, and neonatal deaths. The greatest risk was in severely obese women with a BMI of 40 or greater, which was estimated to be a two- to threefold higher risk than for those with a BMI of 20 or greater. Other meta-analyses report similar findings.⁶³ Diabetes is often a comorbidity of obesity, and many of the studies investigating fetal death and obesity control for this factor; however, the rates of diabetes diagnosis reported in these studies were lower than those in the general literature, indicating that many cases of diabetes in these studies were likely not diagnosed. Despite this, a few studies that controlled for diabetes do show diabetes rates consistent with the general population, indicating that obesity is an independent risk factor for fetal death (Table 2).^{16 64 65}

Fetal Growth Abnormalities

Maternal obesity OR: 1.7 (95% CI; 1.4, 2.2, n = 14,109) and extensive gestational weight gain OR: 1.9 (95% CI; 1.6, 2.2, n = 14,109) are independently associated with an increased risk of macrosomia and large for gestational age birth weight.^{64 66 67 68 69} Insulin resistance and glucose intolerance increase fetal glucose, insulin, steroids, and growth hormones, resulting in fetal fat deposition and increased birth weights. Macrosomia and large for gestational age weight put the infant at risk of hyaline membrane disease OR: 2.14 (95% CI; 1.73, 2.66, n = 116,976), extended assisted ventilation OR: 1.71 (95% CI; 1.44, 2.04, n = 116,976), birth injury OR: 1.58 (95% CI; 1.37, 1.84, n = 116,976), and meconium aspiration OR: 1.42 (95% CI; 1.09, 1.89, n = 116,976) (Table 2).⁷⁰

Obesity and Metabolic Syndrome in the Offspring

Children of obese mothers have increased risk of metabolic syndrome (hazard ratio [HR] = 1.81; 95% CI; 1.03–3.19)⁷¹ and are more likely to be obese.^{71 72 73 74} The molecular mechanisms by which maternal obesity might result in an increased risk of childhood obesity and metabolic syndrome are unknown. The rise in childhood obesity and metabolic syndrome coincides with an increased interest in the impact of the intrauterine environment on fetal gene expression and development.⁷⁵ It is thought that overnutrition of the fetus and the in utero environment are major contributors to obesity and metabolic disturbances in the offspring.^{76 77} Nutritional imbalances during critical periods of fetal development are thought to program the fetus for metabolic syndrome later in life (Table 2).^{78 79 80}

Neurodevelopmental Outcomes

There is evidence that maternal obesity may increase the risk of poor neurodevelopmental outcomes in full-term infants.^{81 82} In animal models, maternal obesity has been associated with abnormal brain development, including impaired hippocampal growth, impaired hippocampus progenitor cell division, and neuronal production.⁸³ A possible explanation for this is the inflammatory process associated with maternal obesity causing inflammation of the fetal brain.

Epidemiologic studies suggest an association with lower general cognitive capabilities,^{84 85 86} and an increased incidence of autism spectrum disorders,^{87 88 89} developmental delay,⁹⁰ and attention deficit/hyperactivity disorder (ADHD)⁹¹; however, more evidence is required to substantiate these associations. A meta-analysis of 12 studies investigating the association of maternal obesity and neurodevelopmental outcomes in the offspring was not conclusive; however, authors suggested that there might be an increased risk of certain cognitive and psychiatric conditions across the lifespan.⁸¹ It was noted that many of the studies possessed methodological limitations; for example, in one study the potential association between prepregnancy maternal obesity and reduced offspring intelligence quotient differed in different time periods, suggesting an unrecognized confounder may be affecting the result.⁸⁵

A recent prospective cohort study (n = 62) investigating the risk of autism and maternal obesity found that maternal obesity was associated with an increased risk of developmental delay, poor language skills (in mothers with a BMI ≥30; β =  − 9.36; 95% CI; −15.11, −3.61; p = 0.002), and a positive screen for autism at the age of 2 years (OR = 9.88, 95% CI; 0.88, 3.70, p = 0.002).⁸⁹ However, this study had a small sample size, and was subject to misdiagnosis of autism due to ambiguity in diagnostic tests. The association between metabolic conditions during pregnancy and autism spectrum disorder and developmental disorders appears in another study, which examined obesity in combination with other metabolic conditions.^{87 88} Further investigations using large population sizes and maternal obesity as the independent factor are required to explore this association further.

A prospective cohort study using data from Sweden, Denmark, and Finland investigated the association between maternal obesity and ADHD.⁹¹ This study measured teacher-rated ADHD symptoms in 12,556 school-aged children. Maternal overweight or obesity was associated with a higher risk of having a child with ADHD symptoms compared with children of women of normal weight.⁹¹ Although there is no clear mechanism known for this, the authors suggest several possibilities. Subjects with ADHD may share a common genetic trait that make individuals more prone to obesity.⁹² Observations show an increased prevalence of obesity amongst those with mental disorders, and genetic studies link ADHD and obesity to the same dysfunction in dopaminergic and serotonergic systems.^{93 94 95 96 97} Other causal theories include increased stress and cortisol levels, which can increase BMI and increase the risk of ADHD in the offspring^{98 99}; organic pollutants in the food chain, which are stored in adipose tissue¹⁰⁰; and increased synthesis of leptin.¹⁰¹

This study was then replicated with 1,714 Swedish preschool children within the same cohort and showed a higher risk of teacher-rated inattentive symptoms of ADHD among offspring overweight/obese mothers compared with normal-weight mothers.¹⁰² A more recent population-based cohort study (n = 673,632) using linkage of Swedish national and regional registers reported an increased risk of offspring ADHD HR_(overweight) = 1.23, 95% CI; 1.18–1.27, p = 0.01; HR_(obesity) = 1.64, 95% CI; 1.57–1.73, p = 0.01) in association with obese mothers after adjustment for measured covariates. However, after making comparisons between siblings, this association was no longer present. The authors concluded that the association could be due to unmeasured familial confounding. Further studies are required to clarify this.¹⁰³

Prepregnancy obesity could be linked to neurodevelopmental pathways through a variety of indirect noncausal pathways. Outcomes such as cognitive, emotional, and behavioral development could be linked to the postnatal period, familial risk, and child health problems, rather than the prenatal period. In addition, genetic and environmental confounders such as maternal cognitive problems, maternal psychiatric conditions, and poor socioeconomic status may contribute to neurodevelopmental outcomes.⁸¹ Such factors can act individually to increase risk and also interact with each other making interpretations of studies in this area challenging. Neurodevelopmental outcomes are usually detected later in childhood. The older the child becomes the longer the exposure time to postnatal environmental and other external risk factors, making it more difficult to determine the association between the effects of the fetal intrauterine environment and neurodevelopmental outcomes. To minimize these challenges due to genetic and environmental risks factors, future studies may benefit from examining subsequent pregnancies in the same mother-partner pair. Although studies suggest a link between prepregnancy obesity and neurodevelopmental outcomes, because of the limitations in study designs, findings should be interpreted with caution. More data are needed to confirm these associations.

Asthma in Offspring

There is growing evidence that maternal obesity in pregnancy and gestational weight gain is associated with increased risk of asthma in offspring and may slow down improvement in airway hyper-reactivity that usually occurs in children with asthma as they grow older.^{104 105 106 107} It is thought that different dietary patterns or proinflammatory states associated with obesity may affect fetal immune or pulmonary development, thus leading to asthma.¹⁰⁷ A meta-analysis of 14 studies, n = 108,321, reported that children whose mothers were obese during pregnancy were at higher risk of asthma or wheeze (Table 2). The results showed higher odds of asthma or wheeze ever (OR: 1.31; 95% CI; 1.16–1.49) or current (OR: 2.21; 95% CI; 1.07–1.37). Each 1 kg/m² increase in maternal BMI was associated with a 2 to 3% increase in odds of childhood asthma.¹⁰⁸ A major limitation of these studies is that although maternal obesity is a risk factor for childhood obesity, other factors such as childhood obesity can also increase the risk of asthma. More prospective studies investigating the association of maternal obesity and asthma in the offspring are needed.

Recommendations and Conclusion

Interventions

Interventions targeting maternal obesity have the potential to improve outcomes in the offspring and subsequent future generations. Although some countries have produced guidelines and recommendations for lifestyle interventions during pregnancy, there is no international consensus and no standardized management strategy specifically for obese pregnant women.^{109 110}

The best window of opportunity to prevent fetal programming is in the periconceptional period. This is the period when gametogenesis, fertilization, implantation, embryogenesis, and placentation occur.¹¹¹ It is ideal that the metabolic environment is stabilized at this time; hence, interventions such as preconception assessment and counselling should be implemented prior to pregnancy. Once women are pregnant, interventions should aim to minimize gestational weight gain and correct metabolic imbalances.

There is lack of evidence to recommend the ideal weight gain for obese women during pregnancy.^{15 112} Evidence for effectiveness of lifestyle and dietary interventions is not clear. Example of dietary interventions that have been shown to be successful in controlling weight gain during pregnancy in randomized trials of obese nondiabetic pregnant women include a series of 10 consultations of 1 hour each¹¹³; dietary education with daily food records reviewed at prenatal visits,¹¹⁴ a series of four dietary counseling sessions combined with a free 6-month membership to fitness centers that include weekly training sessions with a physiotherapist.¹¹⁵

Guidance from the American Congress of Obstetricians and Gynecologists recommend all pregnant women, including those with increased BMI, are encouraged to participate in regular moderate-intensive physical activity for 30 minutes daily.⁴⁸ There is evidence to suggest that physical activity in healthy pregnant women is associated with improved maternal glucose control and reduced risk of macrosomia and adiposity in the offspring.^{47 116} In addition, physical activity is effective in reducing the incidence of type 2 diabetes in high-risk populations¹¹⁷ and improves insulin sensitivity independent of weight loss.¹¹⁸ The risk of developing gestational diabetes during pregnancy is decreased with physical activity, particularly if practiced regularly prior to pregnancy.¹¹⁹ Although there are studies that demonstrate the benefits of physical activity in pregnancy, an effective intervention needs to be implemented. Current studies investigating the impact of such interventions are small in subject size, with poor adherence to physical activity.^{120 121} A pilot randomized controlled trial of 183 subjects, investigated the impact of combined physical activity and dietary intervention on pregnancy and infant outcomes (e.g., glucose homeostasis, macrosomic babies). The intervention failed to impact on the level of physical activity, and there were no differences in physical activity between the control and intervention group. There is a need for a better understanding of the barriers of obese women engaging in physical activity during pregnancy to develop the interventions.

Current intervention studies do not focus on obese women who are at high risk, for example, women with a higher percentage of visceral adiposity, or a history of hypertension, cardiovascular disease, and diabetes. More intensive interventions should be targeted for these high-risk populations. Other measures such as waist circumference (before conception and/or very early in pregnancy) in addition to BMI should be used to screen for women with visceral adiposity. Interventions to correct metabolic imbalances such as blood glucose control should be placed at preconception.

Future Studies

Most studies investigating maternal obesity rely on self-reports of weight and height to calculate BMI, which can be over- or underestimated affecting the risk estimates. Furthermore, BMI does not measure adiposity. Hence future studies will benefit, using direct measures and by including measures of adiposity such as waist circumference. There is a need for more high-quality studies designed to adjust for confounders, including genetic and environmental risk factors. A better understanding of the mechanisms of the intrauterine environment and other mechanisms underlying the association with neurodevelopmental and asthma outcomes are needed. To prevent adverse outcomes of maternal obesity, more interventional studies are needed to help women reach and maintain health weights.

In summary, recent studies strengthen the evidence of an association between maternal obesity and neural tube defects, fetal mortality, congenital heart defects, and fetal growth abnormalities. Evidence of an association of maternal obesity to neurodevelopmental adverse events and asthma is emerging. Further exploration of these outcomes is required.