Hyperthyroidism in Pregnancy–Cause And Treatment?

My wife is a 37 year old female with no significant past medical history. She is presently in the 15th week of a twin gestation which has been otherwise uneventful.The pregnancy is a natural conception. She is gravida 3 para 2 with a 9 week miscarraige during her first pregnancy. During routine screening for hypothroidism, a TSH of 0 was detected. Further labwork perfomed at approximatley 10-11 weeks (1/7/03) disclosed TSH of 0, Free T4 - 2.5 (0.78-2.19), T3 - 656 (230-420). The labs were repeated on 1/9/03 and revevealed TSH -0, Free T3 - 568 (230-420), TPO - undetectable, TSI -WNL. She has had intermittent vomiting which would not be described as hyperemesis. Note, during her first two uneventful pregnancies no vomiting was experienced. The patient is asymptomatic and physical examination was unremarkable except for presence of a barely palpable thyroid gland and a pulse of 105. No tremor was demonstrated. There was no exophthalmos or pretibial myxedema.

At that time she was referred to an endocrinlogist who suggested instituting PTU tx. He did not feel that this was necessarily purely Hcg mediated, and even if it was, treatment would still be appropiate to help decrease risk of miscarraige and other potential complications of hyperthyroidism. Her high risk obstetrician felt PTU should not be instituted. Give this difference of opinion a second endocrinologic opinion was sought who suggested close observation but no treatment at this time. He was, however, somewhat "on the fence." Fourteen week OB ultrasound was normal and demonstrated appropriate growth.The most recent labwork (2/3) revealed a TSH of 0, a free t3 of 527 (230-420), t4 - 1.9 (0.8-1.8) and a total t3 EIA of 411 (60-181).

At this point there is still uncertainty as to whether treatment with PTU is appropriate. Again, her only abnormality on physical exam is a pulse which now occasionally will go as high as 112 but typically at rest is 94-102. My main questions are (1) to treat or not to treat with PTU? (2) Beta blocker before tx with PTU if pulse increases? (3) Is there a risk of miscarriage without tx and when does this or any other comlication associated with hyperthyroidism occur in the second or third trimester? (4) If even in Graves disease hyperthyroidism improves in the second trimester, is it worth waiting as even patients with preexisiting hyperthyrodism may be treated to maintain a borderline hyperthyroid state in pregnancy? (5) Is there any other advice with respect to monitoring the pregnancy? Your input would be greatly appreciated. Thank you,

Philip Lakritz, MD, University Radiology Group, East Brunswick, NJ 08816

First Response

The patient is a 37-yr old woman presently pregnant with a twin pregnancy.

She has no personal nor familial history of Graves' disease nor apparently any related autoimmune thyroid disorder. Her lab tests clearly demonstrate thyrotoxicosis, albeit with mild symptoms & signs (increased vomiting; tachycardia; barely palpable thyroid gland). It would have been useful to learn more about her weight changes since conception, because it is our experience that the major symptom in pregnant mildly hyperthyroid women (due to hCG, which this case almost certainly is) is the absence of weight gain (or weight loss) in the first 10 weeks of gestation. No information was provided concerning her hCG levels.

Second Response

This woman presents almost typically the pattern of GTT (gestational transient thyrotoxicosis) due to hCG. As originally reported in the Journal of Clinical Endocrinology andMetabolism in 1990 (vol: 71; pp 276-287) and the Journal of Endocrinological Investigation in 1993 (vol:16; pp 881-888) by Glinoer et al., approximately 1/5 of normal pregnant women have a transient blunting of serum TSH around the time of peak hCG values, associated with higher peak hCG values (compared with those women without a TSH blunting). In 1/10 of the latter cases (thus, in 2 % of unselected pregnancies), thyroidal stimulation due to high hCG lasts more than the "classical short time pattern" of about one week, and hence leads to supranormal free T4 (and often free T3), thereby fulfilling the definition of GTT (non autoimmune gestational transient thyrotoxicosis). The syndrome starts around 10 weeks of gestation, is transient, and may last for up to 2 months. Thyrotoxic symptoms usually remain mild; excess vomiting is frequently associated and may become the main clinical concern (with hyperemesis gravidarum). In our experience, the administration of PTU was only required in 5-10 % of these cases, mainly when hyperemesis was severe and/or weight loss important. In the other cases, we either did nothing (except to reassure the patient and the family about the transient nature of the disorder) or we administered inderal for 1-2 months. For reasons that remain somewhat unclear, but are presumably related to the etiology of hyperemesis in this setting, beta-blocking agents rapidly improve the symptoms and signs. When PTU must be given, thyroid function should be checked quite often (every two weeks), in order to avoid hypothyroxinemia. If hCG measurements can be obtained (either total hCG or the free beta subunit), this can help predict the outcome since serum free T4 decreases in parallel with hCG (see Figure 6 in Thyroid Today; vol: 18; N° 2; page 7; 1995; by Glinoer).

As reported by us in Clinical Endocrinology in 1997 (vol: 46; pp 719-725), the occurrence of GTT is significantly enhanced in twin pregnancy, because of the higher hCG levels. It is therefore both the amplitude and the duration of peak hCG values that drive the prevalence and clinical severity of GTT.

Also, it should be remembered that abnormal variants of hCG, with a higher thyrotropic activity, have been reported and, in one family with two cases (mother and daughter), GTT without hCG elevation that was related to a TSH-receptor mutation yielding a gain of function to the TSH receptor for the stimulatory effect of normal circulating levels of hCG.

Finally, we believe that TSH receptor antibodies should always be measured in such cases because of the possible (although exceedingly rare) double occurrence of Graves' disease and GTT. Similarly, the fortuitous double occurrence of a solitary hot ("pretoxic") thyroid nodule and GTT does exist but is extremely rare in our experience, and has been seen only once in all the cases with GTT that we have witnessed over the last 15 years.

In summary, and to answer the practical questions asked :

  1. this woman most probably has thyrotoxicosis due to hCG and directly related to her twin pregnancy.
  2. I would not have given PTU (unless clinically necessary, which does not seem to be the case from the description given).
  3. I would have given inderal 40-60 mg/day (if no contra-indication) for a few weeks (until free T4 reverts to the normal range).
  4. There is, to my knowledge, no increased risk of a miscarriage.
  5. TSH-receptor antibodies should perhaps be checked again near the end of the second trimester, if one wants to be absolutely certain that one is not dealing with an atypical form of Graves' disease (which I do not believe, but one can never be totally sure).

Prof Daniel Glinoer