Transient hyperthyroidism of hyperemesis gravidarum

BJOG: an International Journal of Obstetrics and Gynaecology June 2002, Vol. 109, pp. 683 688 Transient hyperthyroidism of hyperemesis gravidarum Jackie Y.L. Tan a, *, Keh Chuan Loh b, George S.H. Yeo c, Yam Cheng Chee a Objective To characterise the clinical, biochemical and thyroid antibody profile in women with transient hyperthyroidism of hyperemesis gravidarum. Design Prospective observational study. Setting Hospital inpatient gynaecological ward. Population Women admitted with hyperemesis gravidarum and found to have hyperthyroidism. Methods Fifty-three women were admitted with hyperemesis gravidarum and were found to have hyperthyroidism. Each woman was examined for clinical signs of thyroid disease and underwent investigations including urea, creatinine, electrolytes, liver function test, thyroid antibody profile and serial thyroid function test until normalisation. Main outcome measures Gestation at which thyroid function normalised, clinical and thyroid antibody profile and pregnancy outcome (birthweight, gestation at delivery and Apgar score at 5 minutes). Results Full data were available for 44 women. Free T4 levels normalised by 15 weeks of gestation in the 39 women with transient hyperthyroidism while TSH remained suppressed until 19 weeks of gestation. None of these women were clinically hyperthyroid. Thyroid antibodies were not found in most of them. Median birthweight in the infants of mothers who experienced weight loss of > 5% of their pre-pregnancy weight was lower compared with those of women who did not ( P ¼ 0.093). Five women were diagnosed with Graves disease based on clinical features and thyroid antibody profile. Conclusions In transient hyperthyroidism of hyperemesis gravidarum, thyroid function normalises by the middle of the second trimester without anti-thyroid treatment. Clinically overt hyperthyroidism and thyroid antibodies are usually absent. Apart from a non-significant trend towards lower birthweights in the infants of mothers who experienced significant weight loss, pregnancy outcome was generally good. Routine assessment of thyroid function is unnecessary for women with hyperemesis gravidarum in the absence of any clinical features of hyperthyroidism. INTRODUCTION Transient hyperthyroidism occurs in up to two-thirds of women with hyperemesis gravidarum 1. Although the cause of transient hyperthyroidism is not completely understood, human chorionic gonadotropin (hcg) is likely to play a central role in its pathogenesis. Structural homology exists not only between hcg and thyroid stimulating hormone (TSH) but also between their receptors, forming the basis of the cross reactivity. The thyrotropic action of hcg has been demonstrated clearly in various studies 2 4. Further evidence comes from clinical studies which have reported higher hcg levels in women with hyperemesis gravidarum and other studies which have shown a positive correlation a Department of General Medicine, Tan Tock Seng Hospital, Singapore b Endocrine Unit, Tan Tock Seng Hospital, Singapore c Department of Maternal Fetal Medicine, KK Women s and Children s Hospital, Singapore * Correspondence: Dr J. Y. L. Tan, Department of General Medicine, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433. D RCOG 2002 BJOG: an International Journal of Obstetrics and Gynaecology PII: S 1 47 0-0 3 2 8(0 2)0 1 2 23-5 between hcg levels and the severity of vomiting and the degree of thyroid stimulation 5,6. The aim of our study was to characterise the clinical, biochemical and thyroid antibody profile in women with transient hyperthyroidism of hyperemesis gravidarum. METHODS Hyperemesis gravidarum is defined as persistent vomiting, with onset occurring before 13 weeks of gestation, of such severity that the woman is unable to retain solids and liquids and requires hospital admission for intravenous hydration. Assessment of thyroid function was performed in women who had a protracted course (defined as hospitalisation exceeding the average length of stay for hyperemesis gravidarum which was three days at our institution) or in those who required recurrent admissions (defined as two or more admissions). No other cause for vomiting was found after careful examination and relevant investigations. Each woman was also examined for signs of thyroid disease and clinical thyroid status by the same physician with particular attention to the following features: resting pulse rate after adequate hydration, weight, www.bjog-elsevier.com

684 J.Y.L. TAN ET AL. Table 1. Characterisitcs of 39 women with transient hyperthyroidism. Characteristics Racial distribution n (%) Chinese 14 (35.9) Malays 13 (33.3) Indians 11 (28.2) Others 1 (2.6) Mean age (years) F SD 29.6 F 5.6 (range 19 40) Parity n (%) 0 16 (41.0) 1 11 (28.2) 2 7 (18.0) 3 5 (12.8) Mean gestation (weeks) at presentation F SD 9.2 F 1.9 (range 6 13) Number of admissions n (%) 1 19 (48.7) 2 8 (20.5) 3 12 (30.8) goitre, Graves ophthalmopathy and dermopathy. Pelvic ultrasound was performed to confirm gestational age and to exclude molar pregnancy. The following tests were done: urea, creatinine, electrolytes, liver function test, TSH receptor antibody, thyroid peroxidase antibody and thyroglobulin antibody and serial free thyroxine (T4) and TSH until normalisation. Free T4 and TSH were performed using a commercial kit (Abbott Axsym based on MEIA; functional TSH sensitivity of 0.06 miu/l). Hyperthyroidism was defined as TSH level of <0.1 miu/l and free T4 level of >26 pmol/l. A diagnosis of Graves disease was made if additional features were present: significantly elevated TSH receptor antibody >10 U/L or thyroid peroxidase antibody, diffuse goitre, Graves ophthalmopathy or dermopathy. The pregnancy outcomes studied included birthweight, gestation at delivery and Apgar score at five minutes. Comparison of birthweights between women who experienced significant weight loss (defined as >5% of the pre-pregnancy weight) and those who did not was made using non-parametric Mann Whitney U test. RESULTS Over a period of 18 months, 87 women hospitalised for hyperemesis gravidarum underwent thyroid function testing of whom 53 (60.9%) were identified to have hyperthyroidism. Nine women had incomplete follow up and were excluded from the study. Among the remaining 44 women, 39 were diagnosed with transient hyperthyroidism of hyperemesis gravidarum and five with Graves disease. Demographic data of the women with transient hyperthyroidism of hyperemesis gravidarum and Graves disease are shown in Tables 1 and 2, respectively. The proportion of Malay and Indian women with hyperemesis gravidarum appears to be greater than that which would be expected based on the country s racial distribution of Chinese, Malays and Indians. However, this can be explained by the fact that these figures parallel and reflect the racial composition of the hospital s obstetric population. In the group of 39 women with transient hyperthyroidism of hyperemesis gravidarum, biochemical investigations at initial presentation revealed hyponatraemia in 66.7%, hypokalaemia in 59%, raised aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels in 56.4% and raised total bilirubin in 12.8%, reflecting the severity of hyperemesis gravidarum (Table 3). The pattern of abnormal liver function test was that of mild to moderate elevation in AST and ALT and mild hyperbilirubinaemia. Viral hepatitis screen was negative in the women with abnormal liver function test. Free T4 levels normalised by 15 weeks of gestation in all without any anti-thyroid treatment (Fig. 1). TSH levels, however, remained suppressed for a longer period up to 19 weeks of gestation (Fig. 2). None of the women had clinically overt hyperthyroidism although 56% demonstrated significant weight loss. Mildly elevated thyroglobulin antibody and thyroid peroxidase antibody levels were seen in one and two women, respectively, but none had TSH receptor antibody level of >10 U/L. There were 35 singleton pregnancies and four twin pregnancies in the group of women with transient hyperthyroidism of hyperemesis gravidarum. In the singleton pregnancy group, 19 women underwent vaginal delivery, nine caesarean section, two had elective termination in the first trimester for social reasons, four delivered abroad or in other hospitals and one had a miscarriage at 15 weeks Table 2. Characteristics of five women with Graves disease. Patient Parity Goitre Other signs TRAb* TPOAb* TgAb* MTLG (30 years/chinese) 1 Present 5.9 85.5 8.4 BBAB (28 years/malay) 1 Present 3.3 >100 42 KS (27 years/indian) 4 Present 15.8 2.8 16.1 LFK (30 years/chinese) 1 Present Proptosis 19.1 2.7 2.6 Tachycardia (120/minute) CWC (33 years/chinese) 2 Absent Tachycardia (122/minute) 34.6 1.0 0.4 * Normal cutoff values: TSH receptor antibody <10 U/L; thyroid peroxidase antibody 0.3 U/mL; thyroglobulin antibody 0.3 U/mL.

TRANSIENT HYPERTHYROIDISM OF HYPEREMESIS GRAVIDARUM 685 Table 3. Biochemical and thyroid antibody profile in 39 women with transient hyperthyroidism. Values are given as n (%) unless otherwise shown. Biochemical abnormalities/thyroid antibody profile No. of patients Range of abnormal values Hyponatraemia (Na <135 mmol/l) 26 (66.7) 128 134 mmol/l Hypokalaemia (K <3.5 mmol/l) 23 (59) 2.4 3.4 mmol/l AST and/or ALT (>40 U/L) 22 (56.4) AST 41 154 U/L ALT 43 405 U/L Total bilirubin (>24 umol/l) 5 (12.8) 25 90 umol/l TSH receptor antibody (>10 U/L) 0 (0) Thyroid peroxidase antibody (>0.3 U/mL) 2 (5.1) 2.4 3.6 U/mL Thyroglobulin antibody (>0.3 U/mL) 1 (2.6) 7.7 U/mL of gestation because of chorioamnionitis. There were no preterm (before 37 weeks of gestation) deliveries. Median gestation at delivery was 39 weeks and median birthweight was 2970 g (Table 4). When the women were subdivided into those who experienced significant weight loss and those who did not, median birthweights were 2915 and 3117.5 g, respectively ( P ¼ 0.093). There was a preponderance of female babies with a female-tomale ratio of 2.6:1. In the twin pregnancy group, median gestation at delivery was 37 weeks and median birthweight was 2212.5 g. Three women delivered by the vaginal route and one underwent caesarean section. The ratio of female to male babies was 3:1 (Table 4). None of the babies from both groups had an Apgar score of 7 at 5 minutes. Five women were diagnosed with Graves disease based on clinical features already described. Four women had diffuse goitre, two had persistent tachycardia of 120/ minute (even after hydration) and one had proptosis (Table 2). Two women had hyponatraemia and one had abnormal liver function test. There was a positive family history of thyroid disease in one of the women. Propylthiouracil was started in two women who were overtly hyperthyroid. Treatment was not started in the remaining three women because they were not overtly hyperthyroid and also because there was spontaneous improvement in their thyroid function. Postnatally, one of these women developed postpartum thyroiditis and later suffered a relapse of Graves disease. DISCUSSION There exists a spectrum of abnormal thyroid function test caused by pregnancy. In the first and early second trimesters of pregnancy, hcg with its thyrotropic activity, albeit a weak one, plays an important role. In most normal pregnant women, the thyroid stimulatory effect of hcg is minor and short lived. In a study that looked at TSH blunting in a large group of pregnant women during the three trimesters, 18% of women in the first trimester had transiently subnormal TSH levels (as well as higher mean hcg levels) with almost half being undetectable (<0.05 mu/l). Eleven percent of the women with undetectable TSH levels also had elevated free T4 levels 7. Isolated TSH suppression therefore forms one end of this spectrum followed by the additional finding of elevated free T4 levels and finally, transient hyperthyroidism of hyperemesis gravidarum. Goodwin et al. 1 reported that 66% of women with hyperemesis gravidarum had biochemical hyperthyroidism or suppressed TSH and that the severity of hyperemesis varied directly with the degree of hyperthyroidism. In this study, we looked at the Table 4. Pregnancy outcome in 39 women with transient hyperthyroidism. Pregnancy outcome Singleton pregnancy (n ¼ 35) Twin pregnancy (n ¼ 4) Median gestation (weeks) at delivery 39 (range 37 40) 37 (range 35 38) Mode of delivery: n (%) Vaginal delivery 19 (54.3) 3 (75) Caesarean section 9 (25.7) 1 (25) Termination 2 (5.7) 0 (0) Others 1 (2.9) 0 (0) Delivered abroad/in other hospitals 4 (11.4) 0 (0) Birthweight (g) Mean 2998.4 2202.6 Median 2970 (range 2250 3655) 2212.5 (range 1750 2680) Female:male ratio 2.6:1 3:1

686 J.Y.L. TAN ET AL. Fig. 1. Mean free T4 levels by gestation. *Mean free T4 levels established in the normal population. **Mean free T4 levels in women with hyperemesis gravidarum. clinical, biochemical and thyroid antibody profile of a group of women at the extreme end of this spectrum, i.e., with both hyperemesis gravidarum and hyperthyroidism, and attempted to establish the clinical characteristics which could help distinguish between transient hyperthyroidism of hyperemesis gravidarum and Graves disease. Most of the women in the study had transient hyperthyroidism of hyperemesis gravidarum and only 11% were diagnosed with Graves disease. This is not unexpected as the initial presentation of Graves disease in pregnancy is unusual. However, it can still occur for the first time because it is well known that exacerbation of Graves disease may develop in the first and early second trimesters of pregnancy due to the thyroid stimulatory effect of hcg. In the transient hyperthyroidism of hyperemesis gravidarum group, all of the women were clinically euthyroid. Previous studies have similarly reported that women with transient hyperthyroidism of hyperemesis gravidarum lack clinical features of hyperthyroidism 1. A plausible explanation may be that the duration of increased thyroid function is relatively brief and transient such that there is insufficient time for the development of clinically overt hyperthyroidism. Indeed, these dynamic changes in thyroid Fig. 2. Percentage of TSH <0.1 miu/l by gestation.

TRANSIENT HYPERTHYROIDISM OF HYPEREMESIS GRAVIDARUM 687 function, particularly in free T4 levels, were observed in our study when we performed serial measurements. Others have suggested that peripheral conversion to triiodothyronine (T3) is spared based on the finding of less frequently elevated free T3 index as compared with free T4 index 1. In a study on serum levels of reverse T3 in hyperemesis gravidarum, results were consistent with a shift from T3 to rt3 production. As rt3 is physiologically inactive, this mechanism may account for the lack of clinical hyperthyroidism 8. Two useful clinical features which helped to distinguish between transient hyperthyroidism of hyperemesis gravidarum and Graves disease were the presence of goitre (in an iodine replete population) and severe tachycardia of 120/ minute. Goitre was found in four and severe tachycardia in two of the five women with Graves disease, whereas both features were not observed in any of the women with transient hyperthyroidism of hyperemesis gravidarum. Weight loss was a poor discriminator with 56% and 26% of women with transient hyperthyroidism of hyperemesis gravidarum and Graves disease respectively demonstrating significant loss. In our study, free T4 levels normalised by 15 weeks of gestation in women with transient hyperthyroidism of hyperemesis gravidarum. TSH remained suppressed for a longer period up to 19 weeks of gestation. None of the women required treatment with anti-thyroid medication. This is consistent with other studies which have reported that resolution of hyperthyroidism occurs within a time frame of 1 10 weeks 1. Glinoer et al. 7 showed that hcg remained abnormally elevated for several weeks during the second trimester and that normalisation of free T4 levels paralleled the decline in hcg, supporting its role in the pathogenesis of transient hyperthyroidism of hyperemesis gravidarum. Unfortunately, our study did not look at hcg levels. Lower birthweights have been observed in infants born to mothers with hyperemesis gravidarum, particularly in the group of women who experience significant weight loss where there appears to be a greater risk of intrauterine growth restriction 9,10. The mean birthweight in singleton pregnancies (2998.4 g) was lower than the population mean of 3100 g, but whether this is directly related to hyperemesis gravidarum alone or of any clinical significance remains unknown. Birthweight is affected by multiple factors and it was not the primary purpose of our study to address these factors. The trend towards lower birthweights, particularly in the infants of women who experienced significant weight loss, may however highlight the need for closer monitoring of fetal growth in this group. Due to the benign nature of transient hyperthyroidism of hyperemesis gravidarum with respect to maternal and fetal outcomes, our data support that routine thyroid function testing is not necessary for all women with hyperemesis gravidarum. The transient biochemical abnormality normalises spontaneously by mid-gestation and does not alter management of these women. Graves disease, which is the most common cause of hyperthyroidism in our population, can generally be diagnosed based on clinical features as was demonstrated in our study. Thyroid antibody testing provides further confirmation. There was a preponderance of female babies born to mothers with a ratio of 2.6 3:1. This has also been observed in other studies on hyperemesis gravidarum 11 13. The common factor appears to be high hcg levels which, in addition to its thyrotropic effect, has been hypothesised to support female conceptions. In normal pregnancies, a female fetus is associated with higher concentrations of hcg at birth than a male fetus although the concentrations in early pregnancy are not known 14. Further evidence comes from studies that show a significant excess of female infants born after hormonal induction of ovulation with hcg 15. CONCLUSION In conclusion, hyperthyroidism associated with hyperemesis gravidarum is of a transient nature where free T4 levels normalise by 15 weeks of gestation without antithyroid treatment. TSH levels remained suppressed for a longer period. Clinically overt hyperthyroidism and thyroid antibodies are usually absent in these women. The presence of certain clinical signs, significantly elevated thyroid antibodies and persistence of thyroid function abnormalities beyond the gestation that is observed for transient hyperthyroidism of hyperemesis gravidarum helps to distinguish the woman with Graves disease. Apart from a non-significant trend towards lower birthweights in the infants of mothers who experienced weight loss, pregnancy outcome was generally good. Due to the benign nature of transient hyperthyroidism of hyperemesis gravidarum, we suggest that routine assessment of thyroid function is unnecessary for women with hyperemesis gravidarum and should be confined only to those who demonstrate clinical features of hyperthyroidism. References 1. Goodwin TM, Montro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992;167:648 652. 2. Hershman JM, Lee H-Y, Sugawara M, et al. 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