Shake-Up Needed in Thyroid Evaluation Before, During Pregnancy?

Maternal thyroid dysfunction in pregnancy — at high as well as low levels — as early as 8 weeks of gestation but primarily before 14 weeks is associated with adverse neurodevelopmental outcomes in the child, suggesting an earlier window for potential intervention than previously recommended, new research shows.

"To the best of our knowledge, this study is the first to show that the association of maternal thyroid function with offspring neurodevelopment attenuates from early pregnancy onwards," say Toyah A. Jansen, MSc, and colleagues of the Erasmus University Medical Center, Rotterdam, the Netherlands. They report their findings in an article published online June 28 in The Lancet Diabetes & Endocrinology.

This suggests that early pregnancy "is the most vulnerable period of the fetus for low or high maternal thyroid function," they add.

The new findings therefore indicate that the traditional time window for diagnosing and treating thyroid dysfunction in pregnancy — between 13 and 18 weeks of gestation — may be wrong and that this evaluation should be probably be moved to earlier in gestation, the authors say.

This in turn could "offer an explanation for why some randomized controlled trials examining the effect of levothyroxine treatment of maternal subclinical hypothyroidism or hypothyroxinemia in pregnancy on offspring IQ showed no beneficial effect," they assert.

And in an accompanying editorial, Francesco Vermiglio, MD, and Mariacarla Moleti, PhD, of the Department of Clinical and Experimental Medicine, University of Messina, Italy, say the new study's association between offspring brain development and maternal hyperthyroid function, as well as hypothyroid function, is also noteworthy in light of research typically linking hyperfunction specifically only to pregnancy outcomes but not neurodevelopment.

Physicians should therefore exercise caution when treating hyperthyroidism in pregnancy, warn Vermiglio and Moleti.

TSH Might Be a More Specific Predictor for Grey Matter in Kids Than FT4

Jansen and colleagues identified 1981 mother–child pairs from the Generation R study, with births between December 2001 and June 2005.

Prospective data included maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurements in early or mid-pregnancy (up to 18 weeks), as well as brain MRI for the children at age 10 years.

Consistent with previous findings — and adjusted for factors including maternal age, ethnicity, smoking, child sex, and gestational age at blood sampling — the data showed an inverted U-shaped association between maternal levels of TSH at a median of 13.1 weeks of gestation and the child's neurodevelopmental outcomes at a median age of 9.9 years, with reductions in total grey matter (P = .007) and cortical grey matter volume (P = .02).

The associations between maternal TSH and child total grey matter volume (P interaction = .05) and cortical volume (P interaction = .08) differed according to the gestational age at blood sampling.

Further stratification showed the association with maternal TSH was most evident as early as 8 weeks' gestation, with the association diminishing after approximately 14 weeks' gestation.

Although this team's previous research has shown a similar inverted U-shaped association between maternal FT4 levels and total grey matter and cortex volume, those associations were not observed in this new study following adjustment for total intracranial volume, they note.

"Our results imply that TSH might be a more specific predictor for total grey matter or cortical grey matter development than FT4," the authors speculate.

Earlier Window for Intervention?

Maternal thyroid dysfunction is known to be linked to adverse neurodevelopmental outcomes in the child, including lower IQ and a higher risk of autism, schizophrenia, and attention-deficit hyperactivity disorder.

However, previous research, including a study published in 2017 (N Engl J Med. 2017;376:815-825), has looked but found no association between treatment of maternal thyroid dysfunction and neurological outcomes. The new findings do therefore raise the question: Were previous researchers simply targeting the wrong gestational time frame?

"The initiation of treatment in these trials, with thyroid hormone replacement therapy starting between 13 and 18 weeks of gestation, was later than our estimated optimal timing," explain Jansen and colleagues.

"The absence of association from the 14th week onwards [in the new study] is an important novel finding that should be considered during clinical risk assessment and when timing interventions during clinical practice, as well as in the design of future studies of the effects of levothyroxine treatment for mild thyroid disease in pregnancy," they state.

"Our results strongly indicate that future studies will benefit from inclusion of participants during early pregnancy, preferably during the first trimester," with any stratified analysis taking into account gestational age at blood sampling.

Overtreatment of Women in Pregnancy Could Damage Kids' Brains

In their editorial, Vermiglio and Moleti note the cognitive implications of effects seen in children's grey matter, in particular, but not in other brain morphology.

"Indeed, increasing numbers of studies report correlations between grey matter volumes and intelligence or cognitive function, with IQ in children being most strongly correlated with prefrontal grey matter volume," they write.

And they stress, "The risk of brain damage associated with low TSH concentrations [indicative of hyperthyroid function] raises concerns about the potential for suboptimal neurodevelopmental outcomes in the offspring of mothers on levothyroxine treatment before pregnancy, who are currently advised to independently increase their daily dose of levothyroxine by 20% to 30% upon confirmation of pregnancy."

"This strategy, although effective in minimizing the risk of maternal hypothyroidism during the crucial first trimester, results in a three-to-seven times increased risk of overtreatment in selected patients," they warn.

Need for Better Reference Range for Gestational Thyroid Hormone

Collectively, the findings underscore the need for clarification of key parameters — in terms of optimal thyroid hormone levels, as well as timing of treatment, the editorialists assert.

"Identification of gestational thyroid hormone reference ranges that are truly adequate for the developing fetal brain is crucial," they add.

Furthermore, "maternal thyroid dysfunction should ideally be diagnosed well before the vulnerability period, ie, when pregnancy is ascertained or ideally preconceptionally, because it takes 3 to 5 weeks for euthyroidism to be restored and few women receive obstetric care before 8 to 12 weeks of pregnancy."

Jansen and colleagues concur: "Our data could aid clinicians in optimizing risk assessment strategies related to a timely thyroid function assessment and potential replacement therapy."

The study and editorial authors have reported no relevant relationships.

Lancet Diabetes Endocrinol. Published June 28, 2019. Abstract, Editorial

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