Kesha Baptiste-Roberts1
(1)
School of Nursing and College of Medicine, Department of Public Health Sciences, The Pennsylvania State University, Heshey, PA, USA
Kesha Baptiste-Roberts
Email: kab50@psu.edu
Abstract
The current epidemic of obesity among women of childbearing age has serious implications for both the woman and her potential offspring. The adverse pregnancy outcomes associated with maternal obesity, as well as the long-term implications for the mothers’ health, are well established. However, there is increasing evidence indicating that offspring of obese mothers have an increased risk of obesity, cardiometabolic risk, adverse neurodevelopmental outcomes, and respiratory challenges, which follow them all the way to adulthood. This chapter provides clinicians and researchers with an overview of the long-term health implications for offspring exposed to maternal obesity.
Keywords
Maternal obesityDevelopmental programmingOffspring healthCardiometabolic riskNeurodevelopmental outcomesAsthma
Key Points
· There is substantial evidence linking maternal obesity and excessive gestational weight gain to an increased risk for obesity in the offspring.
· Although only a small body of evidence exists, there is a link between maternal obesity and adverse neurodevelopmental outcomes and asthma.
· The evidence available on the long-term health impact of exposure to maternal obesity during pregnancy warrants the development of intervention strategies targeting reduction of obesity in women of reproductive age prior to initiating pregnancy.
· Future research should focus on the conduct of human studies to elucidate the mechanisms underlying the associations between maternal obesity and long-term offspring health.
Introduction
Given the epidemic increase in overweight/obesity in the United States, it is not surprising that national data show that a substantial number of women begin pregnancy either overweight (12.1 %) or obese (22 %) [1]. In a recent study including 75,403 women from 26 states and New York City, the authors report that one in five women who delivered a live birth were obese [2]. Of this group of women, non-Hispanic blacks had approximately a 70 % higher prevalence of obesity when compared to non-Hispanic whites and Hispanics (black: 28.9 %; white: 17.4 %; Hispanic: 17.4 %) [2].
Maternal obesity is of great significance not only because of adverse effects on maternal health and pregnancy outcomes, but also because of the growing evidence of persistent deleterious effects on the offspring. As detailed in Chap. 9, maternal obesity is associated with short-term risk in the offspring, but there is increasing evidence that maternal obesity may have longer-term influences on offspring health, which may be in part attributed to shared genetic and environmental factors in addition to developmental programming. As such, the potential social and economic costs in terms of health of future generations present a significant burden.
Developmental Programming
There is a growing body of evidence suggesting that events in utero have long-term influences on disease risk later in life [3]. In 1977, epidemiologic studies of Anders Forsdahl in Norway demonstrated a causative link between early-life environmental factors and subsequent disease [4]. More recently, David Barker and colleagues in the United Kingdom have expanded this area of research, giving birth to the fetal origins hypothesis which proposes that changes in fetal nutrition and endocrine status result in developmental adaptations that can cause permanent structural, physiological, and metabolic changes in a fetus, which predisposes him/her to cardiovascular, metabolic, and endocrine disease in adult life [3]. Recently this idea of developmental programming has been described as the developmental origins of health and disease [DOHaD] which proposes that the conditions presented during a critical window of development can lead to permanent programmed alterations in physiology [5]. Over the last decade, population-based studies conducted in the United Kingdom, Sweden, Finland, Japan, India, and the United States consistently support the idea of developmental programming of adult disease [6]. These studies have primarily focused on the effect of undernutrition and low offspring birth weight on increased risk of cardiovascular disease, type 2 diabetes, and hypertension, all of which share obesity as a common risk factor. Moreover, these studies provided the basis for the thrifty phenotype hypothesis, where the developing fetus adapts to an adverse intrauterine environment and has a survival advantage if the post birth environment is also poor, but these adaptations may be not well suited to an abundant postnatal environment [7].
Maternal obesity and intrauterine overnutrition are not commonly studied programming factors. However, given the rise in maternal obesity, recent studies have focused on the detrimental effects of intrauterine overnutrition. The pregnant obese mother has increased levels of circulating inflammatory cytokines, increased insulin resistance, glucose levels and lipids, and an elevated supply of nutrients to the developing fetus. A developmental overnutrition hypothesis has been developed which proposes that increased fuel supply to the developing fetus leads to permanent changes in offspring metabolism, behavior, appetite regulation with increased risk of obesity, metabolic, and behavioral problems in adult life [5, 8, 9]. Most of the studies designed to test the overnutrition hypothesis have been primarily conducted using animal models which allows for in depth investigation of the complex pathways involved. These pathways are quite complex and multifactorial. There is the complex maternal-fetal relationship during pregnancy and the potential influence of the postnatal environment. As such, it is difficult to disentangle these effects in human studies. In this developing area, most of the research thus far report phenotypic outcomes, but the underlying mechanisms are yet to be understood.
Consequences of Maternal Obesity on Offspring Outcomes
We have only recently begun to investigate the influence of maternal obesity on long-term offspring outcomes. This is due in part to the lack of suitable data sets with good records on maternal obesity prior to and during pregnancy and offspring of a suitable age to manifest outcomes of interest. However, there is accumulating evidence of the influence of maternal obesity on childhood and adolescent obesity, as well as metabolic outcomes including insulin resistance, hypertension dyslipidemia, adverse neurodevelopmental outcomes, and asthma.
Obesity
Offspring obesity risk is the most studied long-term effect of maternal obesity. There is consistent evidence, which suggests that maternal obesity has long-term detrimental effects on offspring obesity risk [8]. Several studies have demonstrated a relationship between increased pre-pregnancy body mass index [BMI] and maternal BMI during pregnancy with increased BMI in the offspring [8, 10–15]. One large cohort study with 8,400 children, reported that children born to obese mothers (using BMI in the first trimester) were twice as likely to be obese by 2 years of age [10]. This risk of obesity persisted with increasing age, such that for women with BMI ≥30, the prevalence of childhood obesity in their offspring at ages 2, 3, and 4 years was 15.1, 20.6, and 24.2 %, respectively. Offspring of obese mothers had between 2.4 and 2.7 times the obesity prevalence of offspring of mothers with normal BMI (18.5–24.9 kg/m2) at the different ages assessed. In addition, there is also evidence of alterations in body composition of offspring of obese mothers, specifically fat mass [16–18]. In several studies, the influence of maternal obesity on offspring obesity persists into adulthood even after adjustment for current lifestyle factors up until the age of 31 [8].
Gestational Weight Gain
In humans, there are no studies addressing overnutrition specifically during pregnancy; however, gestational weight gain may closely reflect this exposure in utero for the developing fetus. A number of studies have demonstrated an association between maternal gestational weight gain and later obesity in childhood [19–21], adolescence [12, 22, 23], and early adulthood [15, 24, 25], while some have not shown this association [26, 27]. The effects in these studies are less than that observed with maternal obesity, but given the high prevalence of excessive gestational weight gain, these associations are important. Nevertheless, there is some evidence that the effect of excessive gestational weight gain is stronger among underweight/normal weight women [24]. In contrast, there is evidence showing modest association between excessive gestational weight gain among normal weight women and a stronger association among mothers with higher pre-pregnancy BMI [15]. Interestingly, Stuebe et al. [15] also reported an increased risk of offspring obesity for obese mothers who gained less than 15 lb, thus suggesting the importance of adequate nutrition during fetal development.
Interpregnancy weight gain is another important contributor to offspring obesity. Maternal weight gain and increased BMI between pregnancies has also been found to be associated with increased risk of overweight in offspring compared with their siblings [28]. In addition, interventional strategies to reduce the weight of obese women via bariatric surgery also reduce the risk of obesity in subsequent offspring compared to those born before the weight loss intervention [29, 30]. These data show a disproportionate risk in offspring from the same mother under different in utero conditions. One 21 year prospective study [24] reported that the offspring of mothers who became overweight or remained overweight or obese over 21 years were more likely to be overweight at age 21. These results persisted even after adjustment for age, education, tobacco consumption during pregnancy, offspring birth weight, breastfeeding, TV watching, sports participation, and family meals. These findings suggest that if mothers maintain a healthy weight over a long postpartum period, their offspring may have a reduced risk of obesity.
Although there is consistent evidence of an association between maternal obesity and offspring obesity risk, the mechanisms underpinning this association are not well understood. However, the use of animal models has highlighted the possible role of altered leptin production and regulation, changes in hypothalamic regulation of key genes involving appetite control and energy balance, alterations in skeletal muscle metabolism, and altered placental structure and function [8].
Metabolic Outcomes
Human studies assessing the relationship between maternal obesity and offspring cardiometabolic risk are limited. A small number of studies have explored other cardiometabolic outcomes such as insulin sensitivity, glucose levels, lipids, and even type 2 diabetes. These studies are summarized in Table 11.1.
Table 11.1
Obesity during pregnancy and offspring cardiometabolic disease risk
|
Series (year) [reference] |
Design |
Sample/setting |
Maternal obesity measure |
Cardiometabolic outcome |
Age at follow-up |
Key findings |
|
Blood pressure |
||||||
|
Filler et al. (2008) [31] |
Cohort |
Children’s Hospital, London Health Science Centre, UK N = 1,915 children |
Pre-pregnancy BMI reported retrospectively by mother at 24–28 weeks GA |
Systolic blood pressure [SBP] and diastolic blood pressure [DBP] |
Mean age = 8.3 ± 5.2 years |
BMI z-score correlated significantly with SBP (Spearman r = 0.214, p < 0.0001), and DBP z-scores (Spearman r = 0.143, p < 0.0001) |
|
Lawlor et al. (2004) [32] |
Cohort |
Mater-University study of pregnancy and its outcomes (MUSP) N = 3,864 |
Maternal pre-pregnancy BMI |
Systolic blood pressure [SBP] |
5 |
For every standard deviation unit increase in maternal pre-pregnancy BMI, there was a 0.38 increase in SBP, respectively (p < 0.05), after adjustment for potential confounders |
|
Wen et al. (2011) [33] |
Cohort |
Collaborative Perinatal Project N = 30, 461 |
Maternal pre-pregnancy BMI |
Systolic blood pressure [SBP] |
7 |
Compared to normal weight, pre-pregnancy overweight obesity was associated with a higher offspring SBP (0.89 mmHg 95 % CI: 0.52, 1.26) |
|
Laor et al. (1997) [34] |
Cohort |
Jerusalem N = 10,883 |
Maternal pre-pregnancy BMI |
Systolic blood pressure [SBP] and diastolic blood pressure [DBP] from military draft records |
17 |
Women: Pearson correlation 0.053 and 0.049 for SBP and DBP, respectively Men: Pearson correlation 0.053 and 0.060 for SBP and DBP, respectively |
|
Hochner et al. (2012) [35] |
Cohort |
Jerusalem Perinatal Study [JPS] N = 1,400 |
Maternal pre-pregnancy BMI |
Systolic blood pressure [SBP] and diastolic blood pressure [DBP] |
32 |
For every unit increase in maternal pre-pregnancy BMI, there was a 0.441 and a 0.287 increase in SBP and DBP, respectively (p < 0.05) |
|
Fraser et al. (2010) [36] |
Cohort |
Avon Longitudinal Study of Parents and Children [ALSPAC] N = 3,457 |
Maternal pre-pregnancy weight |
Systolic blood pressure [SBP] and diastolic blood pressure [DBP] |
9 |
For every unit increase in maternal pre-pregnancy weight, there was a 0.108 increase in SBP (95 % CI: 0.087, 0.130) For every unit increase in maternal pre-pregnancy weight, there was a 0.028 increase in SBP (95 % CI: 0.013, 0.043) |
|
Metabolic markers |
||||||
|
Mingrone et al. (2008) [37] |
Case control |
N = 67 Cases = 52 Offspring of mothers with BMI ≥30 kg/m2 Control = 15 Offspring of mothers with normal weight, BMI <25 kg/m2 |
Maternal pre-pregnancy BMI |
Insulin sensitivity calculated from OGTT |
23.8 ± 4.5 years |
Cases were more insulin resistant than controls Women: (398.58 ± 79.32 vs. 513.81 ± 70.70 ml−1 · min−1, p < 0.0001; Men: 416.42 _ 76.17 vs. 484.242 ±45.76 ml−1 · min−1, p < 0.05) Insulin secretion after OGTT was higher in cases than control Men: (63.94 ± 21.20 vs. 35.71 ± 10.02 nmol · m−2, p < 0.01) but did not differ significantly in women |
|
Hochner et al. (2012) [35] |
Cohort |
Jerusalem Perinatal Study [JPS] N = 1,400 |
Maternal pre-pregnancy BMI |
Insulin Glucose LDL HDL Triglycerides |
32 |
For every unit increase in maternal pre-pregnancy BMI, there was a 0.008 increase in insulin (p = 0.007) For every unit increase in maternal pre-pregnancy BMI there was a 0.001 decrease in glucose (p = 0.875) For every unit increase in maternal pre-pregnancy BMI, there was a 0.010 decrease in HDL (p = 0.033) For every unit increase in maternal pre-pregnancy BMI, there was a 0.012 (p = 0.240) and a 0.007 (p = 0.020) increase in LDL and triglycerides, respectively |
|
Fraser et al. (2010) [36] |
Cohort |
Avon Longitudinal Study of Parents and Children [ALSPAC] N = 3,457 |
Maternal pre-pregnancy weight |
Lipids: HDL, triglycerides |
9 |
For every unit increase in maternal pre-pregnancy weight, there was a 0.002 decrease in HDL (95 % CI: −0.003, −0.001) For every unit increase in maternal pre-pregnancy weight, there was a 1.002 increase in triglycerides (95 % CI: 1.000, 1.003) |
OGTT: 75 g oral glucose tolerance test
There have only been a few studies to examine the relationship between maternal obesity and blood pressure [31–35]. Most of these have examined blood pressure during childhood only [31–33], and just one study has examined offspring blood pressure during adolescence [34] and in adulthood, respectively [35]. These studies consistently report a significantly positive association between maternal obesity and blood pressure as shown in Table 11.1. To our knowledge, to date, only two studies have examined the association between maternal obesity and metabolic markers such as insulin and glucose in offspring beyond 1 year. Mingrone et al. [37] compared insulin sensitivity, insulin secretion, and body composition in offspring of obese mothers with those born to mothers with normal weight. They found that offspring of obese mothers were significantly more insulin resistant (410 ± 91 vs. 500 ± 60 ml−1 · min−1) and had higher prevalence of hyperinsulinemia than offspring of normal weight mothers, but found no difference in β-cell glucose sensitivity impairment. Similarly, in the Jewish Perinatal Family Follow-Up Study birth cohort, Hochner and colleagues investigated the association between maternal obesity and cardiometabolic risk factors in offspring at age 32 [35]. In this study, maternal obesity was independently associated with insulin, triglycerides levels, and lower HDL as shown in Table 11.1. These findings concur with the findings of Catalano et al. who reported that at birth, offspring of obese mothers had higher insulin resistance, leptin, and IL-6, suggesting that maternal obesity results in a high cardiometabolic risk phenotype, with increased cardiometabolic risk beginning at birth [38]. One study [11] examined the association between maternal obesity and metabolic syndrome in offspring. Boney et al. [11] reported an independent effect of maternal obesity on risk of metabolic syndrome in a study of 179 children at ages 6–11 years.
Asthma
Previous studies have found that obesity and asthma occur concurrently in both children and adults. However, the causal direction and mechanisms are not understood [39]. Overweight is associated with increased levels of proinflammatory cytokines. As such, offspring of obese mothers are exposed to increased levels of proinflammatory cytokines during fetal development which may affect the immunological and pulmonary development and result in asthma symptoms after birth. There is a very small body of literature on the association between maternal obesity and asthma and asthma-related symptoms [40–46]. All of these studies consistently show an increased risk of asthma [41, 43–46] or wheezing [40, 42] as shown in Table 11.2 among children between 6 months and 16 years for offspring of mothers who are obese compared to offspring of nonobese mothers. One study even demonstrated a dose response relationship between the degree of maternal overweight status during pregnancy and increased risk of asthma in the offspring [43].
Table 11.2
Obesity during pregnancy and asthma in the offspring
|
Series (year) [reference] |
Design |
Sample/setting |
Maternal obesity measure |
Asthma measure |
Age at follow-up |
Findings |
|
Reichman et al. (2008) [45] |
Birth cohort study |
Fragile Families and Child Wellbeing study, an ongoing longitudinal birth cohort study 1998–2000 75 hospitals in 20 US cities N = 1,971 |
Pre-pregnancy weight and height abstracted from medical record |
Maternal interview self-report |
3 years |
Obese mothers had 52 % higher odds than nonobese mothers of having a child diagnosed with asthma (OR = 1.52; 95 % CI: 1.18, 1.93) in the univariate and a 34 % higher odds (OR = 1.34; 95 % CI: 1.03, 1.76) after adjustment for covariates (sociodemographic, medical obstetric, and behavioral factors) |
|
Harpsoe et al. (2013) [41] |
Danish birth cohort study |
N = 38,874 mother-child pairs from the Danish National Birth Cohort [DNBC] (enrollment 1996–2002) |
Self-reported weight and height measures from baseline interview and self-reported gestational weight gain |
Self-reported doctor-diagnosed asthma |
7 years |
Compared with children of normal weight mothers, children of mothers with high BMI had significantly increased odds of doctor-diagnosed asthma ever (p < 0.0001), children of obese mothers (adjusted OR, 1.54; 95 % CI: 1.34, 1.76) or very obese (adjusted OR, 1.52; 95 % CI: 1.21, 1.91) The odds of doctor-diagnosed asthma ever increased significantly with increasing GWG (p = 0.01) with the highest odds among mothers gaining ≥25 kg during pregnancy compared with mothers gaining 10–15 kg (adjusted OR, 1.17; 95 % CI: 1.02, 1.33) |
|
Patel et al. (2012) [44] |
Prospective cohort study |
Northern Finland birth cohort July 1985–June 1986 N = 6,945 |
Pre-pregnancy and height were abstracted from medical record and BMI calculated |
Self-reported asthma symptoms |
15–16 years |
High maternal pre-pregnancy weight was significantly associated with ever asthma in adolescents (OR = 1.28, 95 % CI: 1.06, 1.54 and for current asthma; OR = 1.30, 95 % CI: 1.01, 1.67 for current asthma) Higher maternal pre-pregnancy weight in the top tertile was significantly associated with an increase in the risk of ever wheeze and current wheeze (OR = 1.22, 95 % CI: 1.01, 1.47 and OR = 1.52, 95 % CI: 1.19, 1.95), respectively |
|
Lowe et al. (2011) [43] |
Retrospective cohort study |
Sweden. All children born in Stockholm County, Sweden between 1998 and 2009 N = 129,329 |
BMI calculated from initial antenatal visit (8–10 weeks of gestation) BMI ≥ 30 |
Asthma in offspring |
Higher maternal BMI was consistently associated with an increased risk of asthma in the child both in terms of medicine use and hospitalization Association was linear at all ages. At age 6–8 years, the effect of maternal BMI was somewhat stronger in girls (OR = 1.04, 95 % CI: 1.02, 1.05) per unit increase in BMI) than in boys (OR = 1.01, 95 % CI: 1.00, 1.03); p for interaction = 0.01) and was also weaker in fourth and subsequent children (p for interaction = .03) |
|
|
Haberg et al. (2009) [40] |
Cohort study |
Norwegian mother and child cohort study (MoBa) N = 33, 192 |
Maternal BMI calculated from self-reported pre-pregnancy weight and height obtained via questionnaire |
Lower respiratory tract infections [LRTIs], hospitalization for LRTIs and wheeze reported at 6 and 18 months after birth obtained via self-report |
6, 18 months |
The risk of wheeze increased linearly with maternal BMI in pregnancy and was 3.3 % higher (95 % CI: 1.2, 5.3) for children with mothers who were obese during pregnancy than for children of mothers with normal BMI |
|
Kumar et al. (2010) [42] |
Cohort |
N = 1,191 Boston Birth Cohort (1998-present) followed to a mean age of 3.0 ± 2.4 years |
Self-reported pre-pregnancy weight and height |
Recurrent wheezing (4 or more episodes of medically attended wheezing illness in the subject’s life time using electronic medical record abstraction) |
~3 years |
Children of obese mothers (BMI ≥ 30) had an increased risk of recurrent wheezing OR = 3.51, 95 % CI: 1.68, 7.32 |
|
Scholtens et al. (2010) [46] |
Cohort |
N = 3,963 participants in the prevention and incidence of asthma and mite allergy study |
Self-reported pre-pregnancy weight and height |
Self-reported wheeze, dyspnea, and use of prescription inhaled corticosteroids |
8 years |
Among children predisposed to asthma (n = 1,058, i.e., having at least one parent with asthma), pre-pregnancy overweight was associated with increased risk of asthma at 8 years (OR = 1.52, 95 % CI: 1.05, 2.18) |
OR odds ratio
Neurodevelopmental Outcomes
The cardiovascular and endocrine systems may not be the only systems altered by maternal obesity during pregnancy. In fact, a systematic review suggests that infants born to obese mothers are at increased risk of central nervous system (CNS) developmental problems [47]. There is substantial evidence from animal models which suggests that maternal obesity increases the risk of the development of neurological and psychological dysfunction. Results from extant human studies provide additional support that maternal obesity may be linked to mental health disorders in children as summarized in Table 11.3. In a recent systematic review [58] of 12 studies reviewed, five provided clear support for an association between maternal obesity and neurodevelopmental problems including childhood IQ [53], attention-deficit/hyperactivity disorder [ADHD] [55], schizophrenia [49, 51], and eating disorders [59].
Table 11.3
Obesity during pregnancy and long-term neurodevelopment outcomes in offspring
|
Series (year) [reference] |
Design |
Sample/setting |
Maternal obesity measure |
Neurodevelopmental outcome |
Age at follow-up |
Key findings |
|
Jones et al. (1998) [48] |
Cohort study |
Finland (N = 10,578) |
Pre-pregnancy BMI reported retrospectively by mother at 24–28 weeks GA |
Schizophrenia (psychiatrist diagnosed using DSM III R) |
28 years |
Odds ratio [OR] = 2.1, 95 % Confidence Interval [CI]: 0.9, 4.6 for children of mothers with BMI > 29 kg/m2 compared with children of mothers with BMI 19.1–29.0 kg/m2 |
|
Schaefer et al. (2000) [49] |
Cohort study |
Child Health Development Study [CHDS], USA Births between 1959 and 1967 63 cases of schizophrenia and 6,570 unaffected offspring |
BMI measured at study enrolment by healthcare personnel |
Schizophrenia and spectrum disorders diagnosed using the DIGS |
30–38 years |
Relative Risk [RR] = 2.9, 95 % CI: 1.3, 6.6 for children of mothers with BMI > 30 kg/m2 compared with BMI 20.0–26.9 kg/m2 |
|
Wahlbeck et al. (2001) [50] |
Cohort study |
Prospective birth cohort, Finland Births between 1924 and 1933 N = 7,086 |
Late pregnancy BMI from birth records |
Schizophrenia diagnosis obtained from Hospital Discharge Register |
Offspring had a small increased odds of schizophrenia for each unit decrease in maternal late pregnancy BMI (OR = 1.09, 95 % CI 1.02–1.17) Compared to offspring of mothers with a late pregnancy BMI >30, those with mothers with late pregnancy BMI <30 had around a threefold increased odds of schizophrenia |
|
|
Kawai et al. (2004) [51] |
Case–control study |
Japan cases: N = 52, controls: N = 6,570 born on or after 1966 |
BMI measured at first and last antenatal care visits by clinic personnel |
Schizophrenia (psychiatrist diagnosed using DSM IV) |
19 |
For every 1 unit increase in early pregnancy BMI, odds of schizophrenia increased 24 % (OR = 1.24, 95 % CI 1.02–1.50) For every one unit increase in late pregnancy BMI, odds of schizophrenia increased 19 % (OR = 1.19, 95 % CI 1.00, 1.41) |
|
Krakowiak et al. (2012) [52] |
Case–control study |
California, USA. Data of children enrolled in the CHARGE (Childhood Autism Risks from Genetics and the Environment) study N = 1,004; ASD(517), DD(172), Control(315) |
BMI ≥ 30, with onset before pregnancy |
Autism spectrum disorder [ASD], developmental delays [DD] |
The risk of having a child with ASD or DD, relative to typical development [TD] was significantly increased among obese women (ASD, OR: 1.67 [95 % CI: 1.10–2.56]; DD, OR: 2.08 [95 % CI: 1.20–3.61]); >20 % of case mothers were obese compared with 14.3 % of controls. The prevalence of any MC was higher in the ASD (28.6 %) and DD (34.9 %) groups compared with controls (19.4 %), with respective adjusted ORs of 1.61 (95 % CI: 1.10–2.37) and 2.35 (95 % CI: 1.43–3.88). |
|
|
Neggers et al. (2003) [53] |
Prospective cohort study |
Sample from a prospective cohort (USA). Mother–children pairs (average age <5 years) (N = 355), born in 1985–1989 |
Pre-pregnancy BMI self-reported by mother at ∼23 weeks after LMP. |
Diminished intellectual ability, but not motor skills. |
Maternal pre-pregnancy BMI was a significant negative predictor of IQ (β = −0.25, P = 0.001) and nonverbal ability (β = −0.29, P = 0.02) Each increase of 1 unit in maternal BMI associated with significantly reduced IQ and nonverbal IQ Overall IQ scores of offspring of obese women were 4.7 points lower and nonverbal scores 5.6 points lower than those whose mothers had normal BMI |
|
|
Heikura et al. (2008) [54] |
Cohort |
Two Finnish birth cohorts (1966, N = 12,058 and 1986, N = 9,032) at <11.5 years old |
Pre-pregnancy BMI self-reported retrospectively at 25 weeks after LMP |
Intellectual disability (ID – IQ < 70) |
1966 obese: OR = 1.3, 95 % CI: 0.5, 3.1 1986 obese: OR = 3.6, 95 % CI: 2.0, 6.6 Maternal obesity is a new disadvantageous factor associated with ID, while low socioeconomic status has remained as the major factor associated with ID |
|
|
Rodriguez et al. (2008) [55] |
Prospective birth cohort |
3 Prospective birth cohorts (Scandinavia) 7- to 12-year olds (N = 12,556). Born 1978–1987 |
BMI from medical records at < 10 weeks after LMP |
ADHD |
Positive association between high BMI and/or weight gain in moms and core symptoms of ADHD in school-age offspring. For women with high BMI, weight gain further increased odds (OR = 1.24, 95 % CI: 1.07, 1.44). Each unit increase in BMI: OR = 1.04, 95 % CI: 1.02, 1.07. Overweight (BMI > 26): OR = 1.43, 95 % CI: 1.12, 1.83 |
|
|
Rodriguez (2010) [56] |
Prospective birth cohort |
Prospective birth cohort (Sweden) 5-year olds (N = 1,714). Born 1999–2000 |
Pre-pregnancy BMI from the Swedish Medical Birth Register |
ADHD symptom scores (mother and teacher rated) |
Parent report: no increased odds for any outcome Teacher report: Overweight: Inattention: OR = 2.00, 95 % CI: 1.20, 3.35 Hyperactivity: insignificant Negative emotionality: OR = 1.81, 95 % CI: 1.22, 2.69 Obese: Inattention: OR = 2.09, 95 % CI: 1.19, 4.82 Hyperactivity: insignificant Negative emotionality: insignificant |
|
|
Fernandes et al. (2012) [57] |
Animal case–control study |
Lab offspring of obese mice (OO, N = 9); offspring of control (OC, N = 8) |
Hyperactivity/ADHD |
OO were more active and also had enhanced cardiovascular reactivity Results support a direct biological link between in utero exposure to maternal obesity and hyperactivity in the adult offspring |
SSD includes schizophrenia, schizoaffective disorder, other non-affective psychosis, and schizotypal personality disorder; DSM III R, DIGS, Diagnostic Interview for Genetic Studies
Schizophrenia
Schizophrenia is fairly common. A review using data from several studies reported the median values per 1,000 persons for the distributions for point and lifetime prevalence as 4.5 and 4.0, respectively [60, 61]. Estimates of the lifetime risk of developing schizophrenia range from 0.3 to 2 % with an average of approximately 0.7 % [60]. As with other neurodevelopmental conditions, schizophrenia risk has genetic and environmental determinants [61, 62]. Accumulating evidence suggests that schizophrenia may have origins in early life like other neurodevelopmental and metabolic conditions. Cohort studies have reported an association between risk of schizophrenia and birth weight, suggesting that adult schizophrenia may be related to alterations in fetal development [63–69]. Several studies have also linked various maternal and obstetric factors with an increased risk of schizophrenia [65, 70–72]. These include gestational diabetes, preeclampsia, emergency cesarean section, and maternal obesity.
There is a paucity of evidence on maternal obesity and schizophrenia risk [48–51, 72]. A recent review included four studies [48–51] with 305 schizophrenia cases and 24,442 controls [72]. All but one study reported an increased risk of schizophrenia among offspring of mothers with high maternal BMI during pregnancy. Two of these studies [48, 49] reported slightly more than a twofold risk of schizophrenia in offspring of mothers with a pre-pregnancy BMI in the highest category (>29 and >30 kg/m2) compared to offspring of mothers with pre-pregnancy BMI in the lowest category (19.1–29 and 20.0–26.9 kg/m2). Kawai et al. [51] examined the association between early pregnancy maternal BMI and schizophrenia and found a 24 % increased odds of schizophrenia in the offspring with one unit increase in maternal BMI during early pregnancy. In addition, Kawai et al. [51] also reported a 19 % increase in the odds of schizophrenia with a one unit increase in late pregnancy maternal BMI, while in contrast, Wahlbeck and colleagues reported that offspring of mothers with a late pregnancy BMI <24 kg/m2 had 3.75 higher odds of schizophrenia compared to offspring of mothers with BMI >30 kg/m2 [50].
Although there was one discrepant finding, there is evidence of increased risk of schizophrenia in adult offspring of mothers who were obese during pregnancy. Several factors could explain these findings. High pre-pregnancy BMI can increase the risk of obstetric complications, some of which are established risk factors for schizophrenia. As such, the increase in schizophrenia risk observed in offspring of obese mothers may be explained by the increased complication rates in obese mothers. Another possible explanation is the development of gestational diabetes. Maternal obesity is associated with increased risk of gestational diabetes and poor glucose control during pregnancy is also associated with increased risk of neurodevelopmental abnormalities, and there is some evidence of an association with increased risk of schizophrenia [65]. However, Kawai et al. [51] refute this explanation reporting that none of the mothers in their study were diagnosed with diabetes. Khandaker et al. propose maternal infection as a potential mediating factor since there is a strong association between infection and risk of schizophrenia [71] and obese women are more susceptible to infection [72]. In addition, maternal obesity may also contribute to the risk of neurodevelopmental disorders though activation of the innate immune system and/or increasing levels of inflammatory cytokines [72].
There is a great need for further research. Future studies should focus on the untangling of obstetric complications, diabetes, maternal infection, and immune responses that may mediate the association between maternal obesity and schizophrenia.
Attention-Deficit/Hyperactivity Disorder [ADHD]
There is a paucity of literature specifically on the relationship between maternal obesity and attention-deficit/hyperactivity disorder [ADHD]. In the studies reviewed, pre-pregnancy obesity was associated with an increased risk of ADHD [55–57]. One study reported a twofold increase in the risk of emotional intensity regulation [56]. Obesity prior to pregnancy also doubles the risk of the offspring developing ADHD compared to offspring of mothers with a healthy weight status [55]. Although there may be some genetic influences on the development of ADHD, even after adjustment for parental ADHD, the association between maternal obesity and increased risk for ADHD in the offspring persisted [56]. One proposed mechanism is dysfunction in dopaminergic and serotonergic systems that lead to ADHD symptoms [55].
Autism
Recent evidence indicates that fetal exposure to maternal obesity may be associated with an increased risk of developing autism spectrum disorder [ASD] [52]. Leptin, a hormone produced by adipose tissue, when produced in excess is thought to be associated with placental dysfunction that disrupts neurological development in utero [73]. When a group of children with ASD was compared with a group of children without ASD, the group with ASD had higher levels of leptin. However, this possible mechanism is still in the early stages of investigation [74]. Placental dysfunction observed with hyperleptinemia has also been documented with high levels of inflammatory cytokines. Numerous studies have demonstrated that increased exposure of the developing fetus to inflammatory cytokines increases the risk of behavioral abnormalities consistent with ASD [75].
This field is at the budding stages of identifying and understanding the complex mechanisms by which maternal obesity influences the development of neural circuitry that regulates behavior. Despite the fact that few studies have examined the associations between maternal obesity and neurodevelopmental outcomes in the offspring, there is some evidence suggesting an increased risk of cognitive and psychiatric problems across the life span, although there are some inconsistencies. Nevertheless, additional work in this area needs to be done. Certainly there needs to be more evidence before maternal obesity prevention and treatment can be touted as beneficial to offspring neurodevelopment.
Conclusion
This current body of evidence indicates that the current epidemic of maternal obesity will put future generations at greater risk of adverse cardiometabolic, behavioral, and mental health outcomes. There is an opportunity to break the cycle of obesity during pre-pregnancy. The long-term goal must be to reduce the incidence of obesity in pregnancy and increase awareness as to the importance of establishment and maintenance of a healthy weight prior to initiating pregnancy. Patients need to be extensively educated during preconception counseling about the long-term implications of obesity during pregnancy, not only for their own health but that of their offspring which tracks into adulthood. Although this strategy is ideal, the prevalence of unintended pregnancy is fairly high. In the United States almost half (49 %) of pregnancies were unintended in 2006 [76].
Although animal models have been useful in elucidating underlying mechanisms, there is still a lot that remains unknown. Teasing out the relative contributions of the fetal and postnatal periods will be important in the design of effective interventional strategies to ensure optimal long-term health of the offspring. Animal studies have been providing some promising directions in interventional strategies. Some of these strategies include:
· Dietary restriction prior to pregnancy. Results from animal models demonstrated a reduction in the effects of maternal obesity on offspring programming [77, 78].
· Weight loss in obese women prior to pregnancy. There is some evidence of improved offspring metabolic phenotype following weight loss among obese women prior to initiating pregnancy [29, 30].
· Mild dietary restriction during pregnancy. During pregnancy, mild dietary restriction seems to be effective in reversing programming effects [79, 80].
· Weight loss strategies and simple dietary changes may improve the metabolic milieu of the mothers and may positively impact the offspring. It is important to increase awareness of healthy dietary behaviors before and during pregnancy in order to reduce maternal obesity with the long-term goal being to reduce health risks for future generations. The current evidence favors actions directed at controlling pre-pregnancy weight and preventing obesity in women of reproductive age. Failure to address maternal obesity may ultimately accelerate the obesity epidemic through successive generations independent of genetic and environmental factors.
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