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.