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Update in Endocrinology

Janet A. Schlechte, MD*
[+] Article, Author, and Disclosure Information

From the University of Iowa, Iowa City, Iowa.

*Adapted for publication in Annals of Internal Medicine by Jennifer Fisher Wilson and Michael Berkwits, MD, MSCE.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Janet A. Schlechte, MD, Department of Internal Medicine, University of Iowa, 200 Hawkins Drive, 157 MRF, Iowa City, IA 52242; e-mail, janet-schlechte@uiowa.edu.

Ann Intern Med. 2007;147(8):563-572. doi:10.7326/0003-4819-147-8-200710160-00009
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This year's Update in Endocrinology includes various endocrine disorders that are frequently managed by practicing internists. The Table suggests some changes in clinical practice that may emerge from these studies.

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In Response
Posted on January 28, 2008
BNJ Walters
University of Western Australia
Conflict of Interest: None Declared

The "Update in Endocrinology" (Schlechte, October 2007) assigned unwarranted significance to the study of Negro et al. and draws conclusions that, if implemented, would carry enormous costs for healthcare and no proven benefit for women.

This was a study of 984 pregnant women. All were clinically and biochemically euthyroid, but 115 had varying levels of thyroid peroxidase antibody (TPOAb). These women were randomized to various doses of thyroxine (57 women) or no treatment (58 women), despite all having normal TSH levels. They were compared with the 869 who were TPOAb negative. The antibody positive women in the treatment group were divided into three groups based upon their TSH level and an increasing dosage of thyroxine administered, the lowest dose to women with TSH "less than 1 mIU/litre" and the highest to those with TSH from 2-4.2 mIU/litre.

The study concluded that euthyroid pregnant women positive for TPOAb develop impaired thyroid function associated with an increased risk of miscarriage and premature delivery. These conclusions require qualification that was not given by the authors. The authors noted 8 miscarriages in the 58 patients in the untreated TPOAb positive group. This in fact represents a low rate of miscarriage for normal women (see below). Of these miscarriages, 6 occurred at 8 weeks or less. It cannot be argued that these would have been prevented by thyroxine treatment, as the study conclusions infer. In the group of 57 women given thyroxine, the mean gestation at which treatment was commenced was 10-11 weeks. Only 40% had commenced treatment by 8 weeks, all of whom had taken only a few days of thyroxine. It is highly implausible that any treatment for such a short time could have prevented miscarriage, given that the processes leading to miscarriage evolve over a period of days to weeks.

Moreover, the 2 miscarriages in the treated group of 57 women (at 7 and 10 weeks) occurred after thyroxine was commenced. It appears that the miscarriage rate after treatment was commenced did not differ between the 2 groups. Nearly all of the miscarriages in the untreated group (6 of 8) occurred at gestations earlier than any treatment was commenced in the treatment group. For this reason, no conclusion may be drawn regarding the effect of treatment on miscarriages before 8 weeks, the period when most occur.

As mentioned above, the miscarriage rate in the untreated group was 13.5%, a rate that is in fact less than the normal rate. The largest study of miscarriage risk (Nybo Andersen et al) showed a rate of nearly 20% in women of age 30 years, and higher thereafter. The rate of 2.5 to 3.5% cited by Negro et al for the large control group and the thyroxine treated group in their study is unusually low and betrays either incomplete ascertainment of miscarriage, or late entry of women to the study after the gestation by which most miscarriages have occurred. With the unusually low miscarriage figures cited, women from around the world would flock to Lecce for a miraculous reduction in their miscarriage risk.

The finding that there was a higher rate of preterm delivery (less than 37 weeks) in those not given thyroxine refers to only 13 cases. There was no difference in morbidity, birth weight, birth "height", "cranial perimeter" or APGAR score between the babies in the treated and untreated groups. Thus it is likely that the 13 preterm babies were born no more than a few days before 37 weeks. The difference in preterm delivery was of borderline significance and remains most likely a chance finding.

For these reasons, one cannot support Dr Schlechte's "Clinical Bottom Line" that suggests measurement of thyroid antibodies in all pregnant women, particularly considering the cost of such an undertaking. Even if one accepts the findings of this study, the inference is that over 1000 women must be screened for TPOAb to prevent 6 miscarriages and 9 cases of slightly preterm delivery with no change in average birth weight or morbidity. Studies of medical problems in pregnant women should take particular cognizance of the unique variations in biology (such as background rates of miscarriage) that occur in pregnancy. This ground is full of traps for the unwary.

Negro R, Formoso G, Mangieri T etal. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006;91: 2587-91

Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ. 2000 ;320:1708-12

BNJ Walters FRACP, FRANZCOG Clinical Associate Professor in Obstetric Medicine School of Women's and Infants' Health University of Western Australia King Edward Memorial Hospital Bagot Rd, SUBIACO 6008 Australia

Conflict of Interest:

None declared

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