Treatment of autoimmune thyroid disease in pregnancy

Treatment with levothyroxine in women with autoimmune thyroid disease (AITD, Hashimoto's) might improve the complications of miscarriage and premature delivery.


Hypothesis: If underlying mild thyroid hypofunction plays a role to explain increased pregnancy loss, this would then constitute a reasonable argument to systematically screen women for the presence of thyroid autoantibodies and/or mild thyroid insufficiency and give them the potential benefit of levothyroxine treatment 


There are four studies which have investigated whether medical intervention would benefit women with thyroid autoimmunity 

Study 1- Vaquero et al: (fig1) 

27 women with thyroid antibodies (AITD) and two previous first-trimester miscarriages were subdivided into 11 women with AITD who received iv Igs during pregnancy and 16 women with AITD who received levothyroxine, started before conception and continued during pregnancy. The pregnancy success rate was 81% in the thyroxine-treated group, compared with 55% in the other group. Despite its inherent limitations (small number of cases and absence of randomization, etc.), the study was the first intervention trial showing a positive effect of thyroid hormone administration in women who were habitual aborters 



Study 2- Negro et al: 

Levothyroxine was administered to 36 euthyroid infertile women with AITD, all who underwent in vitro fertilization. Clinical pregnancies were diagnosed by ultrasonography performed 5 weeks after embryo transfer. The endpoints of assisted reproduction technologies were pregnancy rates, miscarriage rates and delivery rates. Miscarriage rates also included early pregnancy loss (biochemical pregnancies). The authors showed that the miscarriage rate was reduced to 33%, compared with 52% in 36 untreated controls. The study, however, failed to reach statistical significance, perhaps because of the small number of cases.



Study 3- Negro et al (fig 2) 

This was a study of pregnant women who were euthyroid in the early stages of pregnancy but who had positive thyroid autoantibodies (TPO-Abs). The goal was to see if any of these women would benefit from levothyroxine administration to reduce the rate of spontaneous miscarriage and premature delivery. Caucasian pregnant women (n = 984) was investigated between November 2002 and October 2004. Measurements of TPO-Abs and thyroid function tests were carried out at the first prenatal visit. Thyroid function tests were repeated at 20 and 30 weeks of gestation and finally 3 days after delivery. Among the cohort, 115 women (11.7%) had positive thyroid autoantibodies. The women with AITD were randomly assigned to two groups: group A (n = 57) received levothyroxine; group B (n = 58) received no treatment. women without AITD served as controls for thyroid function testing and pregnancy outcomes. Levothyroxine given as 0.5 µg/kg·d of levothyroxine (when serum TSH was < 1 µU/ml), 0.75 µg/kg·d (when TSH was 1–2 µU/ml), and 1 µg/kg·d (when TSH was > 2 µU/ml or presence of a high TPO-Ab titer: > 1500 kIU/liter). The trial design in this study was randomized and prospective but not placebo controlled or double blind. 

The study confirmed previously know findings:  1) Euthyroid women with thyroid autoantibodies tend to be older when they become pregnant; 2) Even though euthyroid in early gestational stages, these women tend to have a reduced thyroid functional reserve 3) They have an increased risk for obstetrical complications (miscarriage and premature delivery) 4) When given the benefit of treatment with thyroid hormone, they normalize thyroid function tests and behave as control women. 

New findings of the study:  Levothyroxine administration to women with autoimmune thyroid disease (Hashimoto's) allowed for a significant decrease in the rate of obstetrical complications, with the miscarriage rate reduced by 75% (from 13.8 to ± 3.5%) and the frequency of premature delivery by 69% (from 22.4 to ± 7%); Note: There is no reason to believe that levothyroxine administration played a role in altering underlying autoimmunity. Also, the age difference between women with AITD and control women was not large enough to explain the different rates of miscarriage and premature birth and obviously even less the changes observed in such rates after treatment with levothyroxine

Should all pregnant women be screened for thyroid antibodies?:

There is no firm consensus on this topic. The endocrinologists at Houston Thyroid and Endocrine do check thyroid antibodies.  If these antibodies are positive then the TSH goal in these women is 1.0 to 2.5  iU/L.  This is the Endocrine Society August 2007 Guideline  for autimmune thyroid disease and miscarriage: Although a positive association exists between the presence of thyroid antibodies and pregnancy loss, universal screening for antithyroid antibodies and possible treatment cannot be recommended at this time. As of this date, only one adequately designed intervention trial has demonstrated a decrease in the miscarriage rate in thyroid antibody-positive euthyroid women. USPSTF recommendation level is C; evidence is fair (grade 2 recommendation).  



References:

1. Vaquero E, Lazzarin N, De Carolis C, Valensise H, Moretti C, Romanini C 2000 Mild thyroid abnormalities and recurrent spontaneous abortion: diagnostic and therapeutic approach. Am J Reprod Immunol 43:204–208 
2. Negro R, Mangieri T, Coppola L, Presicce G, Casavola EC, Gismondi R, Locorotondo G, Caroli P, Pezzarossa A, Dazzi D, Hassan H 2005 Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod 20:1529–1533 
3. Roberto Negro, Gianni Formoso, Tiziana Mangieri, Antonio Pezzarossa, Davide Dazzi, and Haslinda Hassan. Levothyroxine Treatment in Euthyroid Pregnant Women with Autoimmune Thyroid Disease: Effects on Obstetrical Complications. The Journal of Clinical Endocrinology & Metabolism 91(7):2587–2591
4. Glinoer D. Miscarriage in women with positive anti-TPO antibodies: is thyroxine the answer? J Clin Endocrinol Metab. 2006 Jul;91(7):2500-2
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