Children of women with gestational diabetes and obesity may be twice as likely to develop attention-deficit/hyperactivity disorder (ADHD) compared to those whose mothers were not obese, according to new research.
Gestational diabetes mellitus (GDM) has been linked to an increased risk of neuropsychiatric disorders in offspring. Hyperglycemia, or high blood sugar, can predispose fetuses to stress, chronic inflammation, hypoxia, and fetal hyperinsulinemia, which in turn can interfere with fetal brain development during critical prenatal windows, leading to neurobehavioral disorders such as ADHD later in life.
Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition that affects development and behavior, usually diagnosed in childhood. It is characterized by symptoms of inattention, hyperactivity, and impulsivity that can impair the ability to concentrate, learn, and control impulses.
The condition has multifactorial causes, involving genetic and environmental factors, and can continue into adulthood, impacting professional and personal life.
In addition to the deleterious effects of hyperglycemia, in recent decades maternal obesity has emerged as one of the main risk factors not only for neonatal complications, such as macrosomia, large-for-gestational-age (LGA) babies, prematurity, and perinatal mortality but also for long-term adverse consequences on the mental health of the offspring.
Several population studies have described an association between maternal obesity and ADHD diagnosis in offspring. This association has also been described in pregnancies complicated by GDM.
However, despite efforts to prevent maternal obesity, currently, approximately 30% of women of reproductive age are obese at their first prenatal visit, increasing to 47% in pregnancies complicated by GDM.
In this scenario, gestational weight gain (GWG) becomes a modifiable risk factor, since excessive GWG (EWG) has been associated with adverse pregnancy outcomes, such as LGA, cesarean delivery, and a low Apgar score in diabetic and non-diabetic populations.
Furthermore, in animal studies, maternal overnutrition during pregnancy triggers an inflammatory cascade, resulting in alterations in the fetal serotonergic system. Disturbances in the fetal serotonergic system by certain medications have been associated with neurodevelopmental disorders later in life.
Thus, it seems plausible that in human studies, EWG may also have long-term adverse consequences on offspring mental health.
However, in contrast to maternal obesity, the few current published studies have failed to demonstrate an independent relationship between EWG during pregnancy and ADHD in offspring, with no studies in a high-risk population such as GDM pregnancies.
With this background, a study published in The Journal of Clinical Endocrinology & Metabolism aimed to investigate whether offspring of women with GDM exposed to maternal overweight and obesity are more likely to develop ADHD later in life and the role of EWG in these associations.
In this cohort study of singleton births >22 weeks gestation of women with GDM between 1991 and 2008, gestational weight gain above the National Academy of Medicine (NAM) recommendations was classified as EWG. Maternal weight was recorded prospectively during pregnancy.
Anthropometric data were obtained as follows: patients were weighed with calibrated scales, wearing light clothing and without shoes, to the nearest 0.1 kg. Height was measured to the nearest 0.5 cm. BMI was calculated as weight in kilograms divided by height in meters squared (kg/m2).
Pre-pregnancy BMI was calculated based on maternal self-reported weight before pregnancy at the first prenatal visit and classified into 4 groups:
underweight (BMI < 18.5 kg/m2)
normal weight (18.5 kg/m2 ≤ BMI < 25 kg/m2)
overweight (25 kg/m2 ≤ BMI < 30 kg/m2)
obese (BMI ≥ 30 kg/m2)
GWG at the end of pregnancy was calculated as: the final weight measured at the last prenatal visit, prepregnancy weight. According to the 2009 Institute of Medicine (now NAM) guidelines, GWG was classified as insufficient, adequate, and excessive if it was below, within, or above the recommendations as follows:
12.5 to 18 kg (underweight)
11.5 to 16 kg (normal weight)
7 to 11.5 kg (overweight)
5 to 9 kg (obese)
ADHD was identified from medical records according to the International Classification of Diseases (ICD)-10 codes: F90 and F91 for ADHD. These codes include children with and without medical treatment.
Cox regression models estimated the effect of maternal prepregnancy weight and EWG on ADHD risk (identified from medical records), adjusted for pregnancy outcomes and GDM-related variables.
The results showed that 13% of the 1,036 children included in the study were diagnosed with ADHD. Among women who began pregnancy obese, the risk of their children developing ADHD was 66% higher.
However, excessive weight gain during pregnancy was only a relevant risk factor when combined with pre-pregnancy obesity.
The rates of ADHD according to maternal pre-pregnancy weight were 7.1% for underweight, 11.4% for normal weight, 14.2% for overweight, and 16.4% for obesity. Only maternal obesity was independently associated with ADHD, but not maternal overweight or EWG.
When assessing the joint contribution of maternal weight and EWG, maternal obesity with EWG was associated with the highest risk of ADHD. Pre-pregnancy obesity without EWG was not associated.
Crude cumulative incidence of attention-deficit/hyperactivity disorder by maternal prepregnancy BMI and EWG. Normal weight included n = 14 with weight < 18.5 kg/m2. Abbreviations: BMI, body mass index; EWG, excessive weight gain; w/, with; w/o, without.
Several strengths of this study should be highlighted. They reported the longest follow-up (almost 20 years) assessing the long-term effects of maternal prenatal weight. Furthermore, maternal weight was collected prospectively during pregnancy, thus avoiding recall bias.
Second, ICD-10 codes were selected for the diagnosis of ADHD due to the complexity of the diagnosis. The robustness of these codes is supported by recently published data from a sample of 6,834 students aged 5–17 in Spain reporting an overall prevalence of ADHD using the Diagnostic and Statistical Manual of Mental Disorders criteria, comparable to a previous study by the same group using ICD-10 codes.
In addition, only children who had regular consultations with a pediatrician/physician were included in the analyses to minimize ascertainment bias. Third, the same diagnostic criteria for GDM and treatment targets were applied throughout the data collection period.
Finally, although obstetric and neonatal treatment protocols changed over time, the year of birth was included in the adjusted models to overcome this plausible bias.
In conclusion, the results of this study suggest that the negative repercussions of EWG in children within the setting of a high-risk population (GDM with obesity) were not only observed during the prenatal period but also years later with the development of ADHD.
Although maternal obesity is strongly associated with ADHD, obese women who followed weight gain recommendations during pregnancy significantly reduced this risk. These findings reinforce the importance of close medical monitoring during pregnancy, especially in cases of diabetes and obesity.
Future studies with larger participants are needed to confirm these findings and better understand the relationship between gestational weight gain and ADHD.
READ MORE:
Role of Excessive Weight Gain During Gestation in the Risk of ADHD in Offspring of Women With Gestational DiabetesÂ
Verónica Perea, Andreu Simó-Servat, Carmen Quirós, Nuria Alonso-Carril, Maite Valverde, Xavier Urquizu, Antonio J Amor, Eva López, Maria-José Barahona
The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 10, October 2022, Pages e4203–e4211, https://doi.org/10.1210/clinem/dgac483
Abstract:
Context:
Although attention-deficit/hyperactivity disorder (ADHD) has been associated with gestational diabetes mellitus (GDM) and maternal obesity, excessive weight gain (EWG) during pregnancy has scarcely been evaluated.
Objective:
This study aimed to assess the joint effect of maternal weight and EWG on the risk of ADHD in offspring of GDM pregnancies.
Methods:
In this cohort study of singleton births >22 weeks of gestation of women with GDM between 1991 and 2008, gestational weight gain above the National Academy of Medicine (NAM) recommendations were classified into EWG. Cox regression models estimated the effect of maternal pregestational weight and EWG on the risk of ADHD (identified from medical records), adjusted for pregnancy outcomes and GDM-related variables.
Results:
Of 1036 children who were included, with a median follow-up of 17.7 years, 135 (13%) were diagnosed with ADHD. ADHD rates according to pregestational maternal weight were 1/14 (7.1%) for underweight, 62/546 (11.4%) for normal weight, 40/281 (14.2%) for overweight, and 32/195 (16.4%) for obesity. Only maternal obesity was independently associated with ADHD (HRadjusted 1.66 [95% CI, 1.07-2.60]), but not maternal overweight or EWG. On evaluating the joint contribution of maternal weight and EWG, maternal obesity with EWG was associated with the highest risk of ADHD (vs normal weight without EWG; HRadjusted 2.13 [95% CI, 1.14-4.01]). Pregestational obesity without EWG was no longer associated (HRadjusted 1.36 [95% CI, 0.78-2.36]).
Conclusion:
Among GDM pregnancies, pregestational obesity was associated with a higher risk of ADHD in offspring. Nonetheless, when gestational weight gain was taken into account, only the joint association of obesity and EWG remained significant.
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