ANALYSIS AND COMMENTARY • • • • • •

In the past two decades, several population studies reported an association between euthyroid autoimmune disease, mild thyroid dysfunction (including isolated maternal hypothyroxinemia), and abnormal pregnancy outcome (mainly, but not limited to miscarriages, prematurity, and impaired neurodevelopment in the offspring). Not all the studies are consistent, with the same type and frequency of complications. Several major factors may have contributed to this, among them, iodine status in a given population, lack of thyroid-test trimester-specific reference intervals for each population, and exclusion of complications intrinsic to pregnancy, such as gestational diabetes and pregnancy-induced hypertension. Therefore, it may be hypothesized that screening for thyroid disease before pregnancy, or very early in pregnancy, and proper maternal treatment might prevent such abnormal outcomes. Unfortunately, this is a controversial topic among clinicians caring for these patients, with no definite answers in spite of recent guidelines published by The Endocrine Society and the American Thyroid Association (1,2). The provocative findings of the current study may result in more discussion and confusion about interpretation and significance of high “normal” FT₄ values in the first trimester of pregnancy. The current publication is part of the Generation R Study, a population-based cohort from early fetal life onward in Rotterdam, the Netherlands (3). For the study, serum TSH, FT₄, and TPOAb were obtained in the first trimester of pregnancy in 4464 women who delivered between April 2002 and January 2006, after exclusion of women with known comorbidities. Based on the 2.5th and 97.5th percentiles, maternal reference ranges were 0.03 to 4.04 mU/L for TSH and 10.4 to 22.0 pmol/L for FT₄. Fetal growth was estimated by ultrasound measurements in midpregnancy (gestational age, 20 weeks) and late pregnancy (gestational age, 30 weeks). Cord serum TSH and FT₄ levels were available in 2724 of their newborns. Outcome information on birth weight was obtained from medical records completed by community midwives and obstetricians. Accepted definitions for small-for-gestational-age (SGA), premature, and low-birth-weight (LBW) infants were used.

Serum FT₄ concentrations in the upper quintile of normal (between 17.01 and 22.00 pmol/L) were associated with reduced growth (SGA) in the fetus (116 g lower birth weight) and a 2.8-fold increased odds for infants weighing less than 2500 g (LBW) as compared with FT₄ concentrations in the lowest quintile (between 10.38 and 12.80 pmol/L). An interesting finding based on fetal ultrasonography was the lower birth weight detected only in late pregnancy, pointing, perhaps, to a specific complication of pregnancy such as pregnancy-induced hypertension as the reason for this finding.

One potential factor that was not discussed by the authors is the relation between initial TSH and FT₄ values, although they stated, “Trends toward lower maternal TSH levels and lower birth weight and estimated fetal weights were observed but did not reach statistical significance.” One unexplained finding was the absence of complications in the mothers with euthyroid chronic thyroiditis, 5.5% of their population. As discussed by Mannisto in the accompanying editorial (4), we are not yet ready to redefine normal levels for FT₄ in pregnancy or to measure FT₄ levels in all pregnant women. “Although an association between both early and late pregnancy high-normal free T₄ and lower birth size has been demonstrated, we are far from showing causality or a strength of association that merits action.”

References

1. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543-65.
2. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-25. Epub July 25, 2011.
3. Jaddoe VW, van Dulin CM, van der Heijden AJ, Mackenbach JP, Moll HA, Steegers EA, Tiemeier H, Uitterlinden AG, Verhulst FC, Hofman A. The Generation R Study: design and cohort update. Eur J Epidemiol 2010;25:823-41. Epub October 22, 2010.
4. Mannisto T. Is There enough evidence of poor fetal growth to merit narrowing free T4 reference ranges during pregnancy? J Clin Endocrinol Metab 2013;98:43-4.