Transient hyperthyroidism and hyperemesis gravidarum: Clinical aspects T. Murphy Goodwin, MD, Martin Montoro, MD, and Jorge H. Mestman, MD Los Angeles, California OBJECTIVES: Our objectives were to describe the presentation and course of hyperemesis gravidarum with respect to thyroid function and to test the hypothesis that patients with biochemical hyperthyroidism differ in clinical presentation from euthyroid hyperemesis patients. STUDY DESIGN: Sixty-seven patients seen at Los Angeles County Women's Hospital over a 10-month period with hyperemesis gravidarum were studied prospectively with respect to thyroid function. RESULTS: Forty-four patients (66%) had biochemical hyperthyroidism (increased free thyroxine index [n = 39) or suppressed thyroid-stimulating hormone [n = 40)) that was self-limited, resolving by 18 weeks' gestation. Hyperthyroid patients were more likely than euthyroid patients to have abnormal electrolyte levels (23/39 [59%) vs 6/28 [21%) and increased liver enzyme levels (23/59 [59%) vs 5/28 [18%), P < 0.01). The severity of hyperemesis was found to vary directly with the degree of hyperthyroidism. CONCLUSIONS: Hyperthyroidism is a common, self-limited finding in hyperemesis. The cause of the hyperthyroidism may be linked to the cause of hyperemesis itself. (AM J OBSTET GVNECOL 1992;167: 648-52.)
Key words: Hyperthyroidism, hyperemesis gravidarum, pregnancy, thyroid, vomiting
Over the past 10 years no more than 70 patients with transient hyperthyroidism and hyperemesis gravidarum have been described in several case reports l -3 and four series,,-7 (Two other groups, Lao et al. 8 and Chin and Lao,9 apparently described different aspects of the same group of patients reported on by Swaminathan et al. 7) In spite of the recognition of this association important questions regarding the presentation and management of hyperthyroidism and hyperemesis are unresolved. Incidence data differ widely (21 % to 70%). Overlap with subclinical intrinsic thyroid disease has not been systematically ruled out. Antithyroid medication has been advocated for a subset of hyperthyroxinemic hyperemesis patients, although with scant justification ..' 8, 9 Little is known about the status of ultrasensitive thyroid-stimulating hormone (TSH) in hyperemesis patients, although this test is now used routinely in the study of patients with thyroid disorders. Finally, although Mori et al. 10 have shown a relationship between the severity of vomiting and the degree of thyroid stimulation in simple "morning sickness," such a relationship has not been found among hyperemesis patients .. ' 5, 8, 9 This may be due to the difficulty in obFrom the Division of Maternal-Fetal Medicine, University of Southern California. Received for publication October 18, 1991; revised March 2, 1992; accepted March 13, 1992. Reprint requests: T. Murphy Goodwin, MD, Division of MaternalFetal Medicine, Women's Hospital, Room 5K-40, 1240 N. Mission Road, Los Angeles, CA 90033.
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jectively distinguishing grades of severity of vomiting. This association may be important in understanding the cause of hyperemesis. A prospective study was undertaken to describe the clinical and biochemical presentation and natural history of hyperemesis gravidarum with respect to thyroid function and to test the hypothesis that patients with evidence of biochemical hyperthyroidism differ in clinical presentation from those without this finding_ Material and methods Hyperemesis gravidarum was defined as persistent vomiting with large ketonuria on dipstick examination and >5% weight loss in women presenting at < 16 weeks' gestation. All patients had onset of vomiting in the first trimester and no other cause for the vomiting. All patients were well before the onset of vomiting. Patients with a history of thyroid disease, abnormal results of thyroid examination or presence of thyroid antibodies, fever, evidence of other condition responsible for vomiting, or multiple gestation were excluded from this study. Patients with a preliminary diagnosis of hyperemesis gravidarum admitted to the emergency room holding area for intravenous hydration were interviewed at random and examined by a single physician (T.M.G.) to determine eligibility for the study. No patient was taking proprietary antiemetic formulations at the time of initial evaluation. Pelvic ultrasonography was performed in each case to confirm gestational age and a
Hyperthyroidism and hyperemesis gravidarum
Volume 167 Number 3
normal-appearing singleton gestation. The fOllowing tests were performed at the time of admission: serum sodium, potassium, bicarbonate, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and serum amylase. Total thyroxine, total triiodothyronine, resin triiodothyronine uptake, and sensitive TSH (Tandem High Sensitivity, Hybritech, San Diego) were drawn after rehydration. Patients with abnormal electrolyte levels remained in hospital until those levels normalized. Patients with elevated free thyroxine index or suppressed TSH were tested for antimicrosomal antibodies, antithyroglobulin antibodies (Direct addition radioimmunoassay kit, Kronus, Dana Point, Calif.), and TSH receptor antibodies (competitive binding kit, Kronus). These patients were evaluated serially with thyroid function studies. Patients with elevated aminotransferase levels were studied for hepatitis B surface antigen, anti-hepatitis A immunoglobulin M, and hepatitis B core antibody immunoglobulin M. All patients with abnormal results of thyroid or liver studies were given follow-up appointments in the highrisk obstetrics clinic within 2 weeks. Comparisons between groups were analyzed with the Student t test or Mann-Whitney U test for nonnormal distributions. For analysis of the relation among groups according to the severity of vomiting and the degree of thyroid stimulation, one-way analysis of variance was used. The study was approved by the Institutional review board of the University of Southern California. Unless otherwise stated, all laboratory data refer to the date of initial presentation. Results
In the lO-month period during 1989 and 1990,92 patients were examined. Seventy-four were found to satisfy the study criteria, and 67 had data collection suitable for analysis. Of the original 92 patients, two were excluded for evidence of thyroid illness (Grave's disease, primary hypothyroidism), two had multiple gestation, and 15 had evidence of other acute illness. One patient was excluded because of the presence of anti microsomal antibodies. Three patients refused to have the required blood drawn, and specimens were misplaced in two cases. Table I shows the characteristics of the population. Hyperthyroid hyperemesis patients did not differ from others with respect to gestational age at presentation, parity, number of days of vomiting, or amount of weight loss. Table II shows the spectrum of biochemical abnormalities in patients with hyperemesis at initial presentation. Of the 39 patients with elevated free thyroxine index at initial presentation, two had elective abortions in the first trimester and five were lost to follow-up. Thirty-two patients underwent follow-up to
649
Table I. Population characteristics (n = 67) Age (yr) Mean ± SO Range Estimated gestational age (wk) Mean ± SO Range Height (in) Mean ± SO Range Weight (lb) Mean ± SD Range Prepregnancy weight by patient history (lb) Mean ± SO Range Race (No. and %) Hispanic Asian Black Parity (No. and %)
o 1
2 >2
24.0 ± 5.0 16-37 9.7 ± 2.2 6-15.9 61.6 ± 3.0 55-70 116.9 ± 22.0 82-192 127.7 ± 22.2 96-202 63 (94%) 1 (2%) 3 (4%) 39 (58%) 9 (13%) 8 (12%) 11(17%)
normalization of the free thyroxine index over a period of 1 to 10 weeks. No patient had physical findings specific for thyrotoxicosis (goiter, tremor, lid lag, proximal muscle weakness). None received antithyroid medication. All patients for whom follow-up was available had documentation of normal free thyroxine index by 18 weeks' gestation. In no case did evidence of hyperthyroidism persist after resolution of vomiting, although seven patients had continued vomiting for 2 to 14 weeks after normalization of thyroid studies. Of 28 patients with elevated aminotransferase levels, two had elective abortions and seven were lost to followup. Nineteen underwent follow-up to resolution over 2 to 9 weeks. None had serologic evidence of active viral hepatits. Six patients had a mildly elevated amylase level but no other signs or symptoms of pancreatitis. The amylase level returned to normal within one week in five of six cases, and the clinical course of these patients did not differ from other patients with hyperemesis gravidarum. Hyperthyroid patients with hyperemesis had a higher mean arterial pressure (89 ± 11 vs 81 ± 10 mm) and pulse (97 ± 15 vs 82 ± 9 beats/min, p < 0.01) but the difference resolved promptly with hydration in all but two patients. Those with biochemical evidence of hyperthyroidism were significantly more likely to exhibit biochemical abnormalities on admission, as shown in Table Ill. Conversely, patients with more severe hyperemesis exhibited a greater degree of biochemical hyperthyroidism. This is shown in Fig. 1, where patients are grouped according to the
650
Goodwin, Montoro, and Mestman
September 1992 Am J Obstet Gynecol
Table II. Biochemical abnormalities in hyperemesis gravida rum (n = 67) 'l< Thyroid Free thyroxine index >13.2 Free triiodothyronine index >225 . TSH (fLU / ml) Undetectable Suppressed Free thyroxine index> 13.2 or TSH 24 hours fo r persistent electrolyte abnormalities. }T41, Free th yroxine index; FT31 , free triiodothyronine index; asterisk. each of three groups differed from others with respect to free thyroxine index, free triiodothyronine index, and TSH (p < 0.05).
whether the course of hyperthyroid heperemesis might be ameliorated by antithyroid therapy. There are several problems with this proposition. Although patients with overt hyperthyroidism may be first seen for vomiting,14 it is distinctly uncommon. Most patients with vomiting in pregnancy have normal thyroid function , 10 and even in those with evidence of elevated thyroid function tests vomiting can persist after resolution of the biochemical hyperthyroidism. In addition, overtly hypothyroid patients who become pregnant may, in our experience, present with severe vomiting. Therefore
652
Goodwin, Montoro, and Mestman
treatment with antithyroid medication would not seem justified. The converse, that vomiting itself might induce the thyroid stimulation, would serve to explain the association between severity of vomiting and degree of biochemical hyperthyroidism, but evidence for such an effect of vomiting is lacking. In fact, we have found no evidence of biochemical hyperthyroidism among 10 first-trimester pregnant women with severe vomiting not caused by hyperemesis. Thus it seems likely that that the source of the hyperthyroidism is closely linked to the cause of the vomiting but is not causative in and of itself. It is possible that human chorionic gonadotropin, acting through distinct mechanisms, plays a role in the causation of both hyperthyroidism and hyperemesis. REFERENCES I. Valentine BH, jones C, Tyack A]. Hyperemesis gravidarum due to thyrotoxicosis. Postgrad Med 1980;56: 746-7. 2. Dozeman R, Kaiser FE, Cass 0, Pries]. Hyperthyroidism appearing as hyperemesis gravidarum. Arch Intern Med 1983; 143:2202-3. 3. jeffcoate WJ, Bain C. Recurrent pregnancy-induced thyrotoxicosis presenting as hyperemesis gravidarum. Br j Obstet Gynaecol 1985;92:413-5.
September 1992 Am J Obstet Gyneco1
4. Bouillon R, Naesens M, van Assche FA, et al. Thyroid function in patients with hyperemesi, gravidarum. AM j OBSTET GYNECOL 1982; 143:922-96. 5. Bober SA, McGill AC, Turnbridge WMG. Thyroid function in hyperemesis gravidarum. Acta Endocrinol 1986; III :404-10. 6. Montoro M, Spencer C, Jacobson S, Alexander D, Mestman .IH, Nicoloff ]. Evidence for a physiologic role of hCG as a thyroid stimulator in hyperemesis gravidarum. Clin Res 1984;32:20A. 7. Swaminathan R. Chin RK, Lao TTH, Mak YT, Panesar NS, Cockram CS. Thyroid function in hyperemesis gravidarum. Acta Endocrinol 1989;120:155-60. 8. Lao TT, Chin RKH, Chang AMZ. The outcome of hyperemetic pregnancies complicated by transient hyperthyroidism. Aust N ZJ Obstet GynaecoI1987;27:99-101. 9. Chin RKH, Lao TTH. Thyroxine concentration and outcome of hyperemetic pregnancies. Br .I Obstet Gynaecol 1988;95:507 -9. 10. Mori M, Amino M, Tamaki O. Morning sickness and thyroid function in normal pregnancy. Obstet Gynecol 1988;72:355-9. II. Chopra Ij, Hershman .1M, Pard ridge WM, et al. UCLA conference: thyroid function in non thyroidal illnesses. Ann Intern Med 1983;98:946-50. 12. Evans Aj, Li TC, Selby C,Jeffcoate W]. Morning sickness and thyroid function. Br j Obstet Gynaecol 1986;93: 520-2. 13. Adams RH, Gordon j, Combes B. Hyperemesis gravidarum. I. Evidence of hepatic dysfunction. Obstet Gynecol 1968;31 :659-64. 14. Rosenthal FD, Jones C, Lewis SI. Thyrotoxic vomiting. BMj 1976;2:209-11.
Key words: Hyperthyroidism, hyperemesis gravidarum, pregnancy, thyroid, vomiting
Over the past 10 years no more than 70 patients with transient hyperthyroidism and hyperemesis gravidarum have been described in several case reports l -3 and four series,,-7 (Two other groups, Lao et al. 8 and Chin and Lao,9 apparently described different aspects of the same group of patients reported on by Swaminathan et al. 7) In spite of the recognition of this association important questions regarding the presentation and management of hyperthyroidism and hyperemesis are unresolved. Incidence data differ widely (21 % to 70%). Overlap with subclinical intrinsic thyroid disease has not been systematically ruled out. Antithyroid medication has been advocated for a subset of hyperthyroxinemic hyperemesis patients, although with scant justification ..' 8, 9 Little is known about the status of ultrasensitive thyroid-stimulating hormone (TSH) in hyperemesis patients, although this test is now used routinely in the study of patients with thyroid disorders. Finally, although Mori et al. 10 have shown a relationship between the severity of vomiting and the degree of thyroid stimulation in simple "morning sickness," such a relationship has not been found among hyperemesis patients .. ' 5, 8, 9 This may be due to the difficulty in obFrom the Division of Maternal-Fetal Medicine, University of Southern California. Received for publication October 18, 1991; revised March 2, 1992; accepted March 13, 1992. Reprint requests: T. Murphy Goodwin, MD, Division of MaternalFetal Medicine, Women's Hospital, Room 5K-40, 1240 N. Mission Road, Los Angeles, CA 90033.
6/1/37861
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jectively distinguishing grades of severity of vomiting. This association may be important in understanding the cause of hyperemesis. A prospective study was undertaken to describe the clinical and biochemical presentation and natural history of hyperemesis gravidarum with respect to thyroid function and to test the hypothesis that patients with evidence of biochemical hyperthyroidism differ in clinical presentation from those without this finding_ Material and methods Hyperemesis gravidarum was defined as persistent vomiting with large ketonuria on dipstick examination and >5% weight loss in women presenting at < 16 weeks' gestation. All patients had onset of vomiting in the first trimester and no other cause for the vomiting. All patients were well before the onset of vomiting. Patients with a history of thyroid disease, abnormal results of thyroid examination or presence of thyroid antibodies, fever, evidence of other condition responsible for vomiting, or multiple gestation were excluded from this study. Patients with a preliminary diagnosis of hyperemesis gravidarum admitted to the emergency room holding area for intravenous hydration were interviewed at random and examined by a single physician (T.M.G.) to determine eligibility for the study. No patient was taking proprietary antiemetic formulations at the time of initial evaluation. Pelvic ultrasonography was performed in each case to confirm gestational age and a
Hyperthyroidism and hyperemesis gravidarum
Volume 167 Number 3
normal-appearing singleton gestation. The fOllowing tests were performed at the time of admission: serum sodium, potassium, bicarbonate, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and serum amylase. Total thyroxine, total triiodothyronine, resin triiodothyronine uptake, and sensitive TSH (Tandem High Sensitivity, Hybritech, San Diego) were drawn after rehydration. Patients with abnormal electrolyte levels remained in hospital until those levels normalized. Patients with elevated free thyroxine index or suppressed TSH were tested for antimicrosomal antibodies, antithyroglobulin antibodies (Direct addition radioimmunoassay kit, Kronus, Dana Point, Calif.), and TSH receptor antibodies (competitive binding kit, Kronus). These patients were evaluated serially with thyroid function studies. Patients with elevated aminotransferase levels were studied for hepatitis B surface antigen, anti-hepatitis A immunoglobulin M, and hepatitis B core antibody immunoglobulin M. All patients with abnormal results of thyroid or liver studies were given follow-up appointments in the highrisk obstetrics clinic within 2 weeks. Comparisons between groups were analyzed with the Student t test or Mann-Whitney U test for nonnormal distributions. For analysis of the relation among groups according to the severity of vomiting and the degree of thyroid stimulation, one-way analysis of variance was used. The study was approved by the Institutional review board of the University of Southern California. Unless otherwise stated, all laboratory data refer to the date of initial presentation. Results
In the lO-month period during 1989 and 1990,92 patients were examined. Seventy-four were found to satisfy the study criteria, and 67 had data collection suitable for analysis. Of the original 92 patients, two were excluded for evidence of thyroid illness (Grave's disease, primary hypothyroidism), two had multiple gestation, and 15 had evidence of other acute illness. One patient was excluded because of the presence of anti microsomal antibodies. Three patients refused to have the required blood drawn, and specimens were misplaced in two cases. Table I shows the characteristics of the population. Hyperthyroid hyperemesis patients did not differ from others with respect to gestational age at presentation, parity, number of days of vomiting, or amount of weight loss. Table II shows the spectrum of biochemical abnormalities in patients with hyperemesis at initial presentation. Of the 39 patients with elevated free thyroxine index at initial presentation, two had elective abortions in the first trimester and five were lost to follow-up. Thirty-two patients underwent follow-up to
649
Table I. Population characteristics (n = 67) Age (yr) Mean ± SO Range Estimated gestational age (wk) Mean ± SO Range Height (in) Mean ± SO Range Weight (lb) Mean ± SD Range Prepregnancy weight by patient history (lb) Mean ± SO Range Race (No. and %) Hispanic Asian Black Parity (No. and %)
o 1
2 >2
24.0 ± 5.0 16-37 9.7 ± 2.2 6-15.9 61.6 ± 3.0 55-70 116.9 ± 22.0 82-192 127.7 ± 22.2 96-202 63 (94%) 1 (2%) 3 (4%) 39 (58%) 9 (13%) 8 (12%) 11(17%)
normalization of the free thyroxine index over a period of 1 to 10 weeks. No patient had physical findings specific for thyrotoxicosis (goiter, tremor, lid lag, proximal muscle weakness). None received antithyroid medication. All patients for whom follow-up was available had documentation of normal free thyroxine index by 18 weeks' gestation. In no case did evidence of hyperthyroidism persist after resolution of vomiting, although seven patients had continued vomiting for 2 to 14 weeks after normalization of thyroid studies. Of 28 patients with elevated aminotransferase levels, two had elective abortions and seven were lost to followup. Nineteen underwent follow-up to resolution over 2 to 9 weeks. None had serologic evidence of active viral hepatits. Six patients had a mildly elevated amylase level but no other signs or symptoms of pancreatitis. The amylase level returned to normal within one week in five of six cases, and the clinical course of these patients did not differ from other patients with hyperemesis gravidarum. Hyperthyroid patients with hyperemesis had a higher mean arterial pressure (89 ± 11 vs 81 ± 10 mm) and pulse (97 ± 15 vs 82 ± 9 beats/min, p < 0.01) but the difference resolved promptly with hydration in all but two patients. Those with biochemical evidence of hyperthyroidism were significantly more likely to exhibit biochemical abnormalities on admission, as shown in Table Ill. Conversely, patients with more severe hyperemesis exhibited a greater degree of biochemical hyperthyroidism. This is shown in Fig. 1, where patients are grouped according to the
650
Goodwin, Montoro, and Mestman
September 1992 Am J Obstet Gynecol
Table II. Biochemical abnormalities in hyperemesis gravida rum (n = 67) 'l< Thyroid Free thyroxine index >13.2 Free triiodothyronine index >225 . TSH (fLU / ml) Undetectable Suppressed Free thyroxine index> 13.2 or TSH 24 hours fo r persistent electrolyte abnormalities. }T41, Free th yroxine index; FT31 , free triiodothyronine index; asterisk. each of three groups differed from others with respect to free thyroxine index, free triiodothyronine index, and TSH (p < 0.05).
whether the course of hyperthyroid heperemesis might be ameliorated by antithyroid therapy. There are several problems with this proposition. Although patients with overt hyperthyroidism may be first seen for vomiting,14 it is distinctly uncommon. Most patients with vomiting in pregnancy have normal thyroid function , 10 and even in those with evidence of elevated thyroid function tests vomiting can persist after resolution of the biochemical hyperthyroidism. In addition, overtly hypothyroid patients who become pregnant may, in our experience, present with severe vomiting. Therefore
652
Goodwin, Montoro, and Mestman
treatment with antithyroid medication would not seem justified. The converse, that vomiting itself might induce the thyroid stimulation, would serve to explain the association between severity of vomiting and degree of biochemical hyperthyroidism, but evidence for such an effect of vomiting is lacking. In fact, we have found no evidence of biochemical hyperthyroidism among 10 first-trimester pregnant women with severe vomiting not caused by hyperemesis. Thus it seems likely that that the source of the hyperthyroidism is closely linked to the cause of the vomiting but is not causative in and of itself. It is possible that human chorionic gonadotropin, acting through distinct mechanisms, plays a role in the causation of both hyperthyroidism and hyperemesis. REFERENCES I. Valentine BH, jones C, Tyack A]. Hyperemesis gravidarum due to thyrotoxicosis. Postgrad Med 1980;56: 746-7. 2. Dozeman R, Kaiser FE, Cass 0, Pries]. Hyperthyroidism appearing as hyperemesis gravidarum. Arch Intern Med 1983; 143:2202-3. 3. jeffcoate WJ, Bain C. Recurrent pregnancy-induced thyrotoxicosis presenting as hyperemesis gravidarum. Br j Obstet Gynaecol 1985;92:413-5.
September 1992 Am J Obstet Gyneco1
4. Bouillon R, Naesens M, van Assche FA, et al. Thyroid function in patients with hyperemesi, gravidarum. AM j OBSTET GYNECOL 1982; 143:922-96. 5. Bober SA, McGill AC, Turnbridge WMG. Thyroid function in hyperemesis gravidarum. Acta Endocrinol 1986; III :404-10. 6. Montoro M, Spencer C, Jacobson S, Alexander D, Mestman .IH, Nicoloff ]. Evidence for a physiologic role of hCG as a thyroid stimulator in hyperemesis gravidarum. Clin Res 1984;32:20A. 7. Swaminathan R. Chin RK, Lao TTH, Mak YT, Panesar NS, Cockram CS. Thyroid function in hyperemesis gravidarum. Acta Endocrinol 1989;120:155-60. 8. Lao TT, Chin RKH, Chang AMZ. The outcome of hyperemetic pregnancies complicated by transient hyperthyroidism. Aust N ZJ Obstet GynaecoI1987;27:99-101. 9. Chin RKH, Lao TTH. Thyroxine concentration and outcome of hyperemetic pregnancies. Br .I Obstet Gynaecol 1988;95:507 -9. 10. Mori M, Amino M, Tamaki O. Morning sickness and thyroid function in normal pregnancy. Obstet Gynecol 1988;72:355-9. II. Chopra Ij, Hershman .1M, Pard ridge WM, et al. UCLA conference: thyroid function in non thyroidal illnesses. Ann Intern Med 1983;98:946-50. 12. Evans Aj, Li TC, Selby C,Jeffcoate W]. Morning sickness and thyroid function. Br j Obstet Gynaecol 1986;93: 520-2. 13. Adams RH, Gordon j, Combes B. Hyperemesis gravidarum. I. Evidence of hepatic dysfunction. Obstet Gynecol 1968;31 :659-64. 14. Rosenthal FD, Jones C, Lewis SI. Thyrotoxic vomiting. BMj 1976;2:209-11.
