Levothyroxine in Pregnancy? Still No Clear-cut Answers

Veronica Hackethal, MD

March 01, 2017

Treating subclinical hypothyroidism and hypothyroxinemia during pregnancy does not significantly improve cognitive outcomes in offspring compared with no treatment, according to a new study published online in the New England Journal of Medicine.

"On the basis of a comprehensive battery of tests through 5 years of age, we did not find significantly better neurodevelopmental outcomes in children whose mothers had received thyroxine treatment for subclinical hypothyroidism or hypothyroxinemia during pregnancy than in children whose mothers did not receive such treatment," write Brian Casey, MD, of the University of Texas Southwestern Medical Center, and colleagues.

The study also found that receiving levothyroxine did not significantly improve pregnancy or neonatal outcomes.

Whether to treat subclinical hypothyroidism during pregnancy is a matter of debate.

The American College of Obstetricians and Gynecologists (ACOG) says a recommendation for routine screening is premature due to lack of clinical trials demonstrating improved outcomes with levothyroxine treatment.

On the other hand, the American Thyroid Association (ATA), while acknowledging that no clear consensus yet exists, has said that providers may consider treating subclinical hypothyroidism during pregnancy.

Early Treatment May Be of Benefit, Unlikely to Be Harmful

The crux of the matter is that observational studies have linked subclinical hypothyroidism during pregnancy to adverse outcomes, including placental abruption and preterm birth, as well as admission to the neonatal intensive care unit and lower-than-normal IQ in offspring.

But past trials have produced conflicting evidence regarding treatment of subclinical hypothyroidism and whether this actually improves outcomes.

Results of a recent study, for example, showed that treating subclinical hypothyroidism significantly decreases the risk of pregnancy loss, but only in women with higher levels of thyroid-stimulating hormone (TSH) to start with. The results suggested that some women may be overtreated for subclinical hypothyroidism during pregnancy.

In an editorial accompanying this latest study by Dr Casey and colleagues, David Cooper, MD, Johns Hopkins University School of Medicine, Baltimore, Maryland, and Elizabeth Pearce, MD, Boston University School of Medicine, Massachusetts, compare their results with those of several past studies, including the Controlled Antenatal Thyroid Screening (CATS) trial. The latter also failed to show a benefit in obstetrical outcomes or cognitive function in offspring after treatment of subclinical hypothyroidism during pregnancy.

Drs Cooper and Pearce point out that the findings by Dr Casey et al indicate that screening and treating subclinical hypothyroidism, "if performed well into the second trimester," as was the case in this trial, is "unlikely to be beneficial."

However, most women in the United States — over 75% — have their first prenatal visit during the first trimester, making earlier treatment "feasible."'

"We continue to endorse the recent guidelines of the American Thyroid Association, since the early initiation of low-dose levothyroxine therapy for subclinical hypothyroidism may be of benefit, is inexpensive, and is unlikely to be harmful," they conclude.

No Difference in IQ Scores at 5 Years for Levothyroxine vs Placebo

In the new study, Dr Casey and colleagues screened pregnant women between 8 and 20 weeks' gestation for subclinical hypothyroidism (elevated thyrotropin and normal free-thyroxine [T4] levels). They also screened women for hypothyroxinemia (normal thyrotropin and low free-T4 levels). Next, they separated women into separate trials based on whether they had subclinical hypothyroidism (n = 677) or hypothyroxinemia (n = 526) and randomized women in each one to levothyroxine or placebo.

Women received monthly thyroid-function tests and had their doses of levothyroxine adjusted as necessary. Offspring received annual developmental behavioral testing for the first 5 years.

The trials took place at 15 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network.

At 5 years, the follow-up rate was 92%. Of women who received levothyroxine in the subclinical-hypothyroidism group, 93% met treatment goals, while 83% in the hypothyroxinemia group did. Women reached treatment goals at a median of 24 weeks' gestation.

In the subclinical-hypothyroidism study, children whose mothers received levothyroxine had a median IQ at 5 years of 97, compared with 94 in children whose mothers received placebo (P = .71).

In the hypothyroxinemia study, children whose mothers received levothyroxine had a median IQ of 94, compared with 91 in children whose mothers received placebo (P = .30).

No significant differences in pregnancy and neonatal outcomes existed between levothyroxine and placebo groups. Behavioral and attention assessments fell within normal limits for all groups. And treatment with levothyroxine did not affect any other pregnancy or neonatal outcomes, the authors conclude.

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Dr Casey reports no relevant financial relationships. Disclosures for the coauthors are listed on the journal website. Dr Pearce reports personal fees and nonfinancial support from Merck Serono and IBSA Institut Biochimique outside the submitted work. Dr Cooper has no relevant financial relationships.

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N Engl J Med. 2017;376:815-825, 876-877. Abstract, Editorial

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