Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta‐analysis

Abstract

SummaryBackgroundIn the last 2 decades, several studies have examined the association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children and shown conflicting results.AimThis systematic review aimed to assess the evidence for an association between maternal thyroid hormone insufficiency during pregnancy and neurodevelopmental disorders in children. We also sought to assess whether levothyroxine treatment for maternal thyroid hormone insufficiency improves child neurodevelopment outcomes.MethodsWe performed systematic literature searches in MEDLINE, EMBASE, PSYCinfo, CINAHL, AMED, BNI, Cochrane, Scopus, Web of Science, GreyLit, Grey Source and Open Grey (latest search: March 2017). We also conducted targeted web searching and performed forwards and backwards citation chasing. Meta‐analyses of eligible studies were carried out using the random‐effects model.ResultsWe identified 39 eligible articles (37 observational studies and 2 randomized controlled trials [RCT]). Meta‐analysis showed that maternal subclinical hypothyroidism and hypothyroxinaemia are associated with indicators of intellectual disability in offspring (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.20 to 3.83, P = .01, and OR 1.63, 95% CI 1.03 to 2.56, P = .04, respectively). Maternal subclinical hypothyroidism and hypothyroxinaemia were not associated with attention deficit hyperactivity disorder, and their effect on the risk of autism in offspring was unclear. Meta‐analysis of RCTs showed no evidence that levothyroxine treatment for maternal hypothyroxinaemia or subclinical hypothyroidism reduces the incidence of low intelligence quotient in offspring.LimitationsAlthough studies were generally of good quality, there was evidence of heterogeneity between the included observational studies (I 2 72%‐79%).ConclusionMaternal hypothyroxinaemia and subclinical hypothyroidism may be associated with intellectual disability in offspring. Currently, there is no evidence that levothyroxine treatment, when initiated 8‐ to 20‐week gestation (mostly between 12 and 17 weeks), for mild maternal thyroid hormone insufficiency during pregnancy reduces intellectual disability in offspring.

Maternal lithium chloride exposure alters the neuroendocrine‐cytokine axis in neonatal albino rats

“…Alternatively, lithium can exert this disturbance by initiating cellular hypothyroidism (Bolaris, Margarity, & Valcana, ), reducing the birth weight (Harari et al, ), decreasing the energy balance (Brietzke, Stabellini, Grassi‐Oliveira, & Lafer, ), increasing cytokine imbalances (Grignon & Bruguerolle, ) and activating DNA fragmentation in cerebrum of rats (Shao, Young, & Wang, ). In addition, hypothyroidism impairs development of the monoaminergic system (Ahmed, Abdel‐Latif, Mahdi, et al, ; Ibrahim, Tousson, El‐Masry, Arafa, & Akela, ; Tousson, Ibrahim, Arafa, & Akela, ), causing a pathophysiological status (Van Herck et al, ) and neurodevelopmental disorders (Andersen et al, ; Gilbert, Goodman, Gomez, Johnstone, & Ramos, ; O'Shaughnessy et al, ; Salazar, Cisternas, Martinez, & Inestrosa, ; Thompson et al, ). Thus, the potent variations in the monoamine levels might be an adaptive mechanism to achieve homeostasis in the body following the hypothyroid state induced by LiCl.…”

“…Furthermore, lithium can initiate brain disorders, coma, seizures, neural toxicity (Ahmad, Elnakady, Farooq, & Wadaan, ; Aral & Vecchio‐Sadus, ; Bartha, Marksteiner, Bauer, & Benke, ) and epilepsy (Xiao et al, ) via disrupting the levels of Serotonin (5‐HT) (Ayano, ; Stahl, ; Yadav et al, ), Dopamine (DA) (Malhi, ; McFarlane et al, ; O’Donnell & Gould, ) and Norepinephrine (NE) (De Bartolomeis, Tomasetti, Cicale, Yuan, & Manji, ; Sastre, Nicolay, Bruguerolle, & Portugal, ; Schildkraut, Logue, & Dodge, ). Interestingly, thyroid disorders can perturb the production of cytokines (Ahmed, Abdel‐Latif, & Ahmed, ; De Vito et al, ; Silva, Ocarino, & Serakides, ), causing brain disorders during growth/development (Andersen, Andersen, Vestergaard, & Olsen, ; O'Shaughnessy et al, , ; Thompson et al, ). However, studies of possible toxicological effects of LiCl on the neonatal neuroendocrine‐cytokine axis are scarce.…”

Maternal, cord, and three‐year‐old child serum thyroid hormone concentrations in the Health Outcomes and Measures of the Environment study

“…Disruption of the thyroid axis during key developmental periods adversely affects pregnancy outcomes, child neurodevelopment and growth . The importance of maternal thyroid function during this period is highlighted by the adverse neurodevelopmental effects observed among offspring born to mothers with suboptimal maternal thyroid function during this critical period . Even mild variation in maternal thyroid function within the clinically normal range can adversely affect foetal growth and neurodevelopment with lasting effects into childhood .…”

Neonatal Thyroid Stimulating Hormone and Subsequent Diagnosis of Autism Spectrum Disorders and Intellectual Disability

“…Maternal and congenital hypothyroidism, generally manifested as low levels of T4/T3 or high levels of TSH (hormones in a negative feedback loop), are widely recognized causes of intellectual disability (ID) [Rose et al, 2006]. Maternal thyroid conditions before, during, and after pregnancy have been linked to ASD risk [Andersen, Laurberg, Wu, & Olsen, 2014;Fetene, Betts, & Alati, 2017;Getahun et al, 2018;Roman et al, 2013;Thompson et al, 2018;Yau et al, 2015]. However, the relationship of ASD with the fetus's own thyroid axis, which directs substantial growth and differentiation in brain regions critical to cognitive, social, and sensory functioning in late gestation and post-birth [Vasudevan, Morgan, Pfaff, & Ogawa, 2013], remains unclear [Bernal, 2007;Morreale de Escobar, Obregon, & Escobar del Rey, 2004].…”