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Journals A-Z Clinical Obstetrics & Gynecology 40(1) March 1997 ≫ Management of Hypothyroidism During Pregnancy.
Clinical Obstetrics and Gynecology
Issue: Volume 40(1), March 1997, pp 65-80
Copyright: © Lippincott-Raven Publishers
Publication Type: [Articles]
ISSN: 0009-9201
Accession: 00003081-199703000-00008
Management of Hypothyroidism During Pregnancy

MONTORO, MARTÍN N. MD

Author Information
Women's and Children's Hospital, Los Angeles, California
Correspondence: University of Southern California Women's and Children's Hospital, Room 5K40, 1240 N. Mission Road, Los Angeles, CA 90033.
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Abstract
 

This article will address the management of hypothyroidism in iodine plentiful areas.

 


 

Until recently, hypothyroidism during pregnancy has been considered rare because of reduced fertility, presumably due to frequent anovulatory cycles in hypothyroid women.1 In addition, if pregnancy occurred, a wide array of complications were reported. These complications included spontaneous abortions (more than twice the rate in normal women), more than 20% perinatal mortality (stillbirths and neonatal deaths), 10-20% congenital anomalies, as well as poor somatic and intellectual development in 50-60% of the surviving offspring if the pregnancy was completed.2,3 However, other reports describing isolated cases or small series also have been published, which shows successful pregnancy outcomes even in women who were profoundly hypothyroid.4,5 These variable outcomes have been the cause of considerable debate about the role that maternal thyroid status may play in fetal development and maturation and about the extent to which thyroid hormones cross the placental barrier in humans. In recent years, several studies in both animals and humans have contributed to a better understanding of the maternal-fetal relationship and have provided a more rational approach to treatment.

 
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Prevalence
 

Older publications give a fairly high incidence of hypothyroidism diagnosed before or during pregnancy: 9/1,000 white women and 3/1,000 black women. These numbers were obtained by clinical diagnosis and/or butanol extractable iodine (BEI) levels.6 The author's 4 report in 1981 described 11 cases of well-documented, overt hypothyroidism during the 5-year period from 1975-1980 during which 51,245 infants were delivered. There was an incidence of approximately 1/5,000 pregnancies. From 1981-1990,7 101 more patients were identified: 23 had overt hypothyroidism (low free thyroxine-T4-, elevated thyroid stimulating hormone (TSH)); 45 patients had subclinical hypothyroidism (normal free T4, elevated TSH); and 33 hypothyroid women who were euthyroid on thyroxine replacement therapy when they became pregnant. During those years 164, 611 deliveries took place, which gave an incidence of 1/1,629 deliveries. Other series (Davies et al.,8 Buckshee et al.,9 and Wasserstrum et al.10) do not provide enough information to ascertain the incidence in their respective institutions. An editorial comment in Buckshee et al.9 stated that at the Mercy Hospital for Women in Melbourne, Australia, there were 51,407 deliveries during the decade 1980-1989 and there were 55 pregnancies in 26 hypothyroid women, which resulted in an incidence of approximately 1/1,000 deliveries (but 1/2,000 pregnant women).

 

Three population studies have been published more recently, and all three give a fairly high incidence of previously undiagnosed subclinical hypothyroidism during pregnancy. Lejeune et al.11 from Brussels, Belgium found 41 cases in 1,900 (2.2%) women tested at their first visit; however, the screening was performed in an area of marginally low iodine intake, and the results may not be applicable to the United States (US) population. Klein et al.12 in the east coast of the US found that 49 (2.5%) of 2,000 women screened in the first trimester (15-18 wks) had TSH levels above 6 mU/l, and 6 of them (0.3%) had decreased both total and free-thyroxine concentrations as well. Unfortunately, there was no information obtained in any of these patients regarding clinical aspects of their thyroid disease (i.e., whether or not they were on any kind of therapy or the outcome of pregnancy). The thyroid function tests were performed in serum samples originally obtained for alpha-fetoprotein screening. Kamijo et al.13 in Japan screened 9,453 women, who were also in the first trimester, but they found a lower incidence (18 cases [0.19%]). In 12 of these women the TSH level returned to normal by approximately 18 weeks of gestation. However, Long et al.14 examined 309 consecutive pregnant teenagers but none were found to be hypothyroid, and all had normal T4 and TSH levels. They did find that 18 (6%) had a goiter of which 3 (1%) were caused by Hashimoto's thyroiditis and 9 (3%) were nontoxic goiters. The remainder had either Graves hyperthyroidism (2 cases) or subacute thyroiditis (4 cases). The incidence was similar to the findings in 600 nonpregnant adolescents who were examined during the same period of time.

 

Most of the data reported comes from university referral centers; therefore, the incidence is probably higher than in general obstetric practices or community hospitals.

 
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Causes of Hypothyroidism
 

The most common cause of hypothyroidism during pregnancy is autoimmune thyroid disease (Table 1). Thyroid autoantibodies have been detected in the majority of the cases first diagnosed during pregnancy.4,5,7-14 The goitrous form of chronic (Hashimoto's) thyroiditis seems to be the most common variety of spontaneous primary thyroid failure in women of childbearing age and, consequently, during pregnancy as well. The enlargement of the thyroid is caused by lymphocytic infiltration. Some women may have atrophic, nonpalpable thyroid glands, but this form also is thought to be caused by an autoimmune process that leads to destruction of the thyroid. A rare cause of hypothyroidism in chronic thyroiditis may be blocking antibodies to the TSH receptor, instead of the most common variety of TSH receptor antibodies, which are stimulating and the cause of Graves' disease.15

Graphic Table 1

Most of the cases not caused by chronic thyroiditis are secondary to previous treatment for Graves' hyperthyroidism with radio-iodine ablation or thyroidectomy. A rare case of thyroid ablation by high-dose external radiation (e.g., for Hodgkin's lymphoma) may be encountered during pregnancy. In some instances, thyroidectomy may have been performed for thyroid carcinoma, suspicious nodules, or toxic nodular goiter.4,5,7-10 Congenital hypothyroidism, a variety of inherited metabolic disorders of the thyroid, as well as thyroidhormone resistance syndromes, are not found very often during pregnancy.16,17 There are other rare causes of hypothyroidism that have not yet been reported during pregnancy such as infiltrative disorders of the thyroid (e.g., sarcoidosis, amyloidosis, hemochromatosis, cystinosis, invasisve fibrous thyroiditis or "Riedel's struma"). Transient hypothyroidism may occur in silent (painless) and subacute thyroiditis. A variety of medications (Table 2) may cause hypothyroidism by interfering with thyroidhormone synthesis, release, and/or pheripheral action, which includes iodide, antithyroid drugs (if the dosage is not properly adjusted), lithium and, particularly, amiodarone. Amiodarone is an effective drug for the treatment of supraventricular and ventricular cardiac arrhythmias. If there are no other alternatives, more pregnant women will be treated with this medication in the future. In the mother, it may cause hypothyroidism by decreasing the conversion from T4 to T3 and additionally, by the possible inhibition of T3 action. In the fetus, it has been reported to cause both hypothyroidism and hyperthyroidism, neurologic abnormalities, intrauterine growth retardation, and fetal bradycardia.18 Other drugs may increase thyroxine clearance such as carbamazepine, rifampin and, probably, phenytoin,19 whereas other drugs may interfere with intestinal absorption (e.g., cholestyramine, sucralfate, aluminum hydroxyde, and of special importance in pregnancy, ferrous sulfate).20,21 Secondary (central) hypothyroidism may be seen in pituitary or hypothalamic diseases.

Graphic Table 2
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Diagnosis
 
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CLINICAL
 

Hypothyroidism is frequently unsuspected unless the symptoms are very obvious and include fatigue, hair loss, dry skin, weight gain despite poor appetite, or cold intolerance (which is quite unusual in normal pregnancy) (Table 3). A goiter may or may not be palpable. Muscle aching, stiffness, and symptoms of carpal tunnel syndrome also may be present. The pulse rate may be slower than expected for pregnancy; in very advanced cases, there may be a prolonged relaxation phase of the deep tendon reflexes. Anemia also may be seen in hypothyroidism (see section on laboratory diagnosis). Autoimmune thyroid disease occurs more often as an isolated illness, but it also may be seen as part of a more generalized autoimmune process, which involves different endocrine glands or other structures ("Polyglandular Autoimmune Syndromes") and include adrenal insufficiency, type I diabetes mellitus, pernicious anemia, vitiligo, hypoparathyroidism, mucocutaneous candidiasis, alopecia, chronic active hepatitis, intestinal malabsorption syndromes, and myasthenia gravis. Gonadal failure may be part of these entities but those patients, obviously, will not be able to conceive except with the help of sophisticated infertility treatment. A history of menstrual irregularities before pregnancy may be elicited, particularly, menorrhagia, which is reported to occur frequently even in patients with mild hypothyroidism.22

Graphic Table 3

In the author's series of women with severe hypothyroidism 4,7 and in the series of Davis et al.8 classic symptoms were present in one third of the patients, another third had moderate symptomatology, and the remainder (30% of our patients and 20% of Davis') had few or no symptoms despite the very abnormal thyroid function tests. Subclinical hypothyroidism (normal T4, but elevated TSH levels) is even more difficult to uncover. The diagnosis is rarely, if ever, made solely on clinical grounds. A high index of suspicion is needed to make the diagnosis at an early stage; and therefore, to initiates treatment before the condition becomes severe or before complications occur.

 

In view of the difficulty in making the diagnosis of hypothyroidism on clinical grounds alone, a case could be made for universal screening of hypothyroidism in pregnancy. Outside of pregnancy, a recent study has shown that it is cost-effective to screen for hypothyroidism in patients who are 35 years old or older, and the cost compares favorably with other generally accepted preventive medical practices.23 No such cost benefit studies exist in pregnancy, and routine screening for hypothyroidism during gestation is not uniformly recommended. However, we highly recommend routinely screening certain high-risk groups (Table 4), which include previous therapy for hyperthyroidism or high-dose neck irradiation, previous postpartum thyroiditis (which is evidence of thyroid autoimmunity), the presence of a goiter (diffuse or nodular), family history of thyroid disease, treatment with amiodarone, suspected hypopituitarism, and type I diabetes mellitus. Jovanovic and Peterson 24 reported that 8/51 type 1 diabetic pregnant women with subclinical hypothyroidism and proteinuria, developed clinical hypothyroidism and increasing proteinuria (from 1.2 gm daily to 4 gm daily) as pregnancy advanced. The insulin requirements were at lower levels when the patients were more hypothyroid, but they returned to previous levels after thyroxine treatment. The titer of thyroid antibodies did not change as pregnancy advanced.24

Graphic Table 4

At a more moderate risk than patients with the conditions mentioned above, but still deserving screening, are patients who have any other endocrinopathy, autoimmune disorders, treatment with certain medications (see Table 2), or exposure to some industrial and environmental chemicals, (several chemicals have been found to be goitrogenic in animals, but the effects on humans are less well known), and hyperlipidemias.

 
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Laboratory
 

The interpretation of thyroid function tests during pregnancy is discussed elsewhere in this issue. The best laboratory test to diagnose hypothyroidism is the serum TSH. It makes it possible to diagnose primary hypothyroidism very early, before the clinical symptoms and signs are present. It also allows us to monitor therapy much more accurately. TSH determinations are widely available and the cost, in general, is not very high. Thus, it is a particularly cost-effective test. When an elevated TSH is found, a serum free T4 index and thyroid peroxidase antibodies (TPO-Ab) should be determined. In patients with secondary hypothyroidism (pituitary or hypothalamic disease), the free T4 index will be low and the serum TSH will be inappropriately within the normal range. Anemia may be commonly seen in hypothyroidism (in up to 30-40% of patients); it is more commonly normocytic because of decreased erythropoiesis. However, at times it may be macrocytic from vitamin B12 or folic acid deficiency. When a microcytic anemia is found, it is most commonly due to concomitant iron deficiency. Leukocyte counts are not affected; platelet counts are usually normal as well; but platelet function abnormalities may be present and occasionally, they pre-dispose the patient to bleeding. Other laboratory abnormalities that may be seen in the commonly performed chemistry panels include elevation of the serum lipids (cholesterol, LDL, triglycerides), creatine phosphokinase (CPK) and mild, reversible abnormalities of liver function tests.

 
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Implications of Hypothyroidism During Pregnancy
 

Several publications within the last few years have provided considerable evidence that women with thyroid antibodies (antiperoxidase or antimicrosomal, and antithyroglobulin), regardless of their thyroid function status, are at an increased risk of miscarriage 25-30; the risk is approximately twice the normal rate. It is not known if it is a direct toxic effect of the thyroid antibodies themselves, or if they are just markers of abnormal autoimmunity in patients who also have other antibodies better known to cause recurrent abortions (e.g., antiphospholipids, etc). The women in these reports were euthyroid,25,27-30 although it has been suggested that some of them may have been mildly hypothyroid at the time of the miscarriage.26 It is not known at present if the increased risk of miscarriage in these patients can be prevented or the form of treatment that might be effective. The presence of circulating maternal thyroid antibodies may have an impact in the fetus and newborn as well. Pop et al.31 reported that 19 children of a cohort of 230 born to euthyroid women with elevated TPO-Ab titers had significantly lower IQs (10.5 points) than the children of antibody-negative women (after correction for potential confounding variables). The possible mechanisms remained speculative in the paper; whether the antibodies were directly responsible or whether they might have caused thyroid insufficiency at some critical point of fetal development could only be theorized. Additional information about fetal thyroid disorders can be found in this issue in the article by Dr. Fisher.

 

Whether hypothyroidism alone (in the absence of thyroid antibodies) leads to an increased occurrence of spontaneous abortions as stated by most of the older publications 2,3 remains a matter of debate. The thyroid status of the patients in those reports is difficult to ascertain 4,5 because the diagnosis was made only on clinical grounds and/or because the butanol extractable iodine did not increase during pregnancy. It is possible that the increased rate of abortion in some of those reports might have occurred in women with autoimmune thyroid disease and circulating antibodies, which may also explain the lack of a clear correlation between the abortion rate and their thyroid function status.

 

The papers about the outcome of pregnancy in hypothyroid women published in the last 15 years 4,5,7-10 have consistently reported a much better outcome than earlier studies, although for years there were some reports of successful outcomes even in untreated, severely hypothyroid women.4,5 Currently, hypothyroidism is usually diagnosed and treated earlier in pregnancy; this early diagnosis is, very likely a major contributing factor to the improved outcome. A general improvement in perinatal care has occurred in the last 15-20 years and has probably benefited these patients as well by means of more effective fetal monitoring, earlier diagnosis of fetal distress, timely delivery when indicated, and more effective neonatal care.

 

In 1981 the authors reported the outcome of 11 pregnancies 4 in overtly hypothyroid women (mean total T4 = 2.3 ug/dL, TSH 105 mU/mL). In only four of the 11, the diagnosis was made before 24 weeks. Eight women received treatment and had no additional complications, although one infant was born with trisomy 21. (However, the mother was 41 years old.) Of the three untreated women, one developed severe pre-eclampsia resulting in intrauterine death at 29 weeks of gestation. The other two delivered normal infants at term. All other infants were normal at birth and were still normal at the age of 3 years. Another study, also from the authors' institution,7 reported the outcome of pregnancy in 23 overtly hypothyroid women (free T4 index 2.1 ± 1.5, TSH 89.7 ± 86.2 mU/mL), and 45 women who had subclinical hypothyroidism (free T4 index 8.7 ± 3.6, TSH 28.4 ± 47.1 mU/mL) at their initial antepartum visit. Very important facts in this study were (1) the relatively large number of patients and (2) women with other concurrent illnesses (such as chronic hypertension, anemia, or diabetes) were excluded; thus, the opportunity to better ascertain the relationship between the hypothyroidism and the outcome of pregnancy was allowed. In the overtly hypothyroid group (23 patients) there were 5 (22%), still hypothyroid at delivery, who developed severe hypertension and required early delivery. There was one intrauterine death, and all five (22%) of these newborns were small (<2,000 g) because of prematurity, but they were not small for their gestational age. The single intrauterine death occurred at 28 weeks in an 18-year-old severely hypothyroid primigravida who never took her thyroxine replacement; she presented with eclampsia and had a 800-g stillborn. The only malformation was one case of club feet. One woman also experienced postpartum hemorrhage. Of the 45 women with subclinical hypothyroidism, 7 (15%) developed hypertension and 4 (9%) had to be delivered prematurely. There were no deaths or congenital anomalies; however, one woman developed anemia (Hct < 26%). The main complication observed in these group of patients was pregnancy-induced hypertension and the need for premature delivery. The severity of the hypertension and the perinatal complications were greater in patients who were more severely hypothyroid at entry and still hypothyroid at the time of delivery. The patients who became euthyroid with treatment had a much lower rate of complications. If preeclampsia developed, it occurred later in gestation and posed much less risk to the mother and infant.

 

Davis et al.8 in 1988, reported the outcome of 28 pregnancies in 25 hypothyroid women in Dallas, Texas. Sixteen pregnancies occurred in overtly hypothyroid women (total T4 2.8 ± 0.5 ug/dL, TSH 87.9 ± 31 mIU/mL) and 7 (44%) developed pre-eclampsia; however, 5 of these 16 women were chronic hypertensives and 4 of them developed pre-eclampsia. There were two perinatal losses (stillbirths) that were related to pre-eclampsia and placental abruption. Altogether, there were three instances of placental abruption. There were five (31%) premature infants with birthweights <2,000 gm. Five women were also anemic (hct < 26%) and three had postpartum hemorrhage. Of the three women still hypothyroid at delivery, one was a chronic hypertensive who developed pre-eclampsia and delivered a 915-g infant at 27 weeks; the other two patients delivered at term but one had anemia (Hct < 26%), chronic hypertension, pre-eclampsia and postpartum hemorrhage. The other patient was a chronic hypertensive and also had postpartum hemorrhage. There were no congenital anomalies. In this group of women there were only five who did not experience any complications. In the 12 pregnancies in the women with subclinical hypothyroidism (total T4 9 ± 0.8 ug/dL, TSH 37 ± 3 mIU/mL), two (16%), developed pre-eclampsia, but one was a chronic hypertensive with class F diabetes mellitus. The infant was premature; there were 2 cases of postpartum hemorrhage, but there was no abruptio placentae or anemia. One stillbirth was attributed to congenital syphilis. The outcome was better in the women who were less hypothyroid. Many of the women in this report, however, also suffered from other severe chronic illnesses such as chronic hypertension, anemia, and diabetes with nephropathy. Therefore, it is difficult to ascertain the role of the hypothyroid state alone in the development of complications, but obviously hypothyroid women with other medical illnesses seem to be at a higher risk than with either disease alone.

 

Buckshee et al.9 reported, in 1992, the outcome of pregnancy in 26 hypothyroid women from New Delhi, India. The diagnosis of hypothyroidism was made during pregnancy in only two patients (at 14 and 16 weeks respectively) who were given thyroxine replacement; the rest were known to be hypothyroid before pregnancy and were already on replacement when pregnancy occurred. Five of the women needed an increase in the replacement dose and in two women it needed to be decreased as the pregnancy advanced. Thus, it appears that there were two overtly hypothyroid and five subclinically hypothyroid women. However, no thyroid function tests are given in this report, neither at entry nor at the time of delivery. Many of these women had other associated medical illnesses including diabetes mellitus (four), epilepsy (four), bronchial asthma (two), segmental glomerulonephritis (one) and pulmonary tuberculosis (one). The maternal complications observed include anemia in six (26%) patients, pre-eclampsia in seven (26.9%), post-partum hemorrhage in two (7.7%), postdates in eight (30.8%) and deficient lactation in five (19.2%). There were five cases of prematurity, two spontaneous and three iatrogenic, four cases of intrauterine growth retardation, one neonatal death in an infant born with hyperthyroidism, and a large goiter. The mother of the neonate had a thyroidectomy 4 years earlier for Graves' disease with subsequent hypothyroidism, and she was administered thyroxine replacement, 0.3 mg daily. There were no cases of placental abruption or stillbirth, and two (7.7%) minor congenital anomalies (scoliosis and tongue tie), which both occurred in euthyroid mothers on replacement throughout pregnancy. Pregnancy-induced hypertension was the most notable complication of pregnancy in this report.

 

In 1995, Wasserstrum and Anania 10 reported the outcome of pregnancy after reviewing the records of 42 women during 43 pregnancies from Houston, Texas. The patients with other medical illnesses, specifically diabetes and chronic hypertension, were excluded from the analysis. Nine pregnancies were in severely hypothyroid women (free T4 0.8 ± 0.8, TSH 47 ± 20 mU/L when they presented at 17 ± 3.6 weeks), and their outcome was compared with the remainder 34 women with milder hypothyroidism (free T4 2.1 ± 0.8, TSH 11 ± 13 mU/L at 19 ± 8.3 weeks). Five of the nine (56%) women who were more severely hypothyroid at entry underwent Caesarean section for fetal distress during labor, whereas there was only one (3%) case among the 34 women in the less hypothyroid group. There was a single intrauterine fetal demise at 28 week's gestation; the mother had presented euthyroid on thyroxine replacement and apparently remained euthyroid. There were no cases of pre-eclampsia/eclampsia, placental abruption, postpartum hemorrhage or congenital anomalies. The occurrence of fetal distress in labor correlated with the thyroid function tests at entry but not near term. A relation between the TSH level near term and fetal distress in labor was suggested, but it did not reach statistical significance. The authors speculate that severe hypothyroidism in early pregnancy somehow may exert irreversible effects in the fetoplacental vascular unit that are not corrected by subsequent thyroxine replacement and that become manifest only during the stress of labor without affecting fetal or postnatal growth. It is not mentioned whether the kind of fetal distress experienced during labor might have been amenable to detection by antepartum fetal surveillance. Despite the lack of statistical correlation, the patients who developed fetal distress had a greater degree of hypothyroidism at term than those who did not have fetal distress (free T4 1.5 ± 0.3, TSH 21.2 ± 9.9 mU/l versus free T4 1.9 ± 0.8, TSH 7.3 ± 6.1 mU/l), which indicated inadequate replacement and perhaps, less than optimal compliance. Nevertheless, and as reiterated by the authors, the correlation between thyroid function at entry and fetal distress in labor was very strong, whereas the correlation with the thyroid function near term showed a trend, but it did not quite reach statistical significance. A difference with all the other previous reports is the absence of pre-eclampsia. The authors state that they are sure there were no cases of severe pre-eclampsia, but they could not estimate the occurrence of mild pre-eclampsia due to the nature of their retrospective review.

 

From the previously mentioned studies, it can be summarized that the risk of miscarriage seems to be related to the presence of circulating thyroid antibodies and less clearly to the thyroid function status. None of the more recent reports give an increased frequency of congenital anomalies in these patients. The main complication found almost universally (except in Wasserstrum and Anania) is a high risk of pre-eclampsia, which often leads to premature delivery with its related morbidity, mortality, and high cost. The severity of the hypertension and other perinatal complications is greater in the more severely hypothyroid women. Early treatment and close monitoring to insure continued normalization of the thyroid function tests will result in prevention or a significant decrease in the perinatal complications. Those patients with concomitant illnesses, particularly diabetes, chronic hypertension, and anemia should have those illnesses properly treated and monitored as well.8,9 The reason that hypertension occurs more frequently in thyroid disorders is not yet fully known. Hypothyroid patients have reduced cardiac output and have increased peripheral resistance, probably secondary to an increase of sympathetic nervous tone an alpha-adrenergic response.32

 

The initial reports of physical developmental delay and lower intelligence quotients in the infants of hypothyroid mothers have not been confirmed by others. Follow-up examinations in seven of eleven children ranging to 3 years of age showed that they had no goiter, were euthyroid, and had negative antibody titers. Developmental milestones had been reached at the appropriate time of the examination.4 Liu et al.33 examined the intelligence quotients (IQs) of eight children whose mothers had been hypothyroid during early pregnancy and compared them with nine siblings who were not exposed to maternal hypothyroidism. The follow-up period was from 4-10 years in the children exposed to maternal hypothyroidism and from 4-15 years in the control siblings. All children had normal IQs, and there was no difference between the children exposed to maternal hypothyroidism and the group of sibling controls. The authors emphasize that even the child whose mother had the lowest thyroxine level had an IQ similar to his sibling. However, more cases and longer follow-up periods are needed to fully evaluate this issue. In the previously mentioned article by Pop et al.,31 lower IQs were found in a group of euthyroid women but who had elevated TPO-ab titers than in the children of TPO-ab negative women. Maternal hypothyroidism was not present, however, in this group of women. The mechanism by which the children may have been affected by the antibodies, as well as possible preventive measures, both deserve further investigation.

 

It is frequently stated that we still do not fully understand the role of thyroidal status that the mother may play in the development of the progeny. Several recent studies suggest that the thyroidal status of the mother and the small amounts of thyroid hormones that probably cross the placenta in humans may be more important than previously thought for fetal brain maturation.34-37 In animals, (particularly the rat) Morreale de Escobar et al. have shown that placental transfer of maternal thyroxine before the onset of fetal thyroid function is important for fetal brain maturation in early gestation 38,39 as well as near term.40 Bonet and Herrera 41 noted, also in the rat, that maternal thyroidectomy in early pregnancy greatly reduced the content of fetal pituitary growth hormone.41 How much of the animal studies that can be extrapolated to humans remains under investigation. Vulsma et al.34 studied 25 neonates born with complete inability to synthesize thyroxine (total organificatin defect or thyroid agenesis). In the cord serum of these affected neonates, T4 levels ranged from 35-70 µmol per liter. Those levels and the disappearance kinetics of T4 from the newborns during the days after delivery, suggested that it had a maternal origin. Vulsma et al. concluded that in infants with severe congenital hypothyroidism, substantial amounts of T4 were transferred from mother to fetus and probably mitigated, at least to some degree, the consequences of fetal hypothyroidism. The report of a very unusual case 42 has been added as additional evidence of the importance of transplacental transfer of T4 for fetal development and maturation. In this study, both mother and infant had Pit-I deficiency. Pit-I deficiency is very rare and only a few humans have been identified; this protein regulates hormone transcription, and it is confined to the nuclei of somatotropes, lactotropes, and thyrotropes. Both mother and fetus were hypothyroid because the mother was apparently noncompliant with her thyroxine replacement. The mother was found to be severely hypothyroid near term; the newborn was severely impaired. Although by the first year she had reached normal size, she remained profoundly retarded from a neurologic standpoint despite thyroxine replacement. The authors assume that the severe fetal retardation was caused by lack of transplacental passage of T4 from mother to fetus. However, in a fetus with lack of other anterior pituitary hormones, especially growth hormone, it is difficult to isolate the role of thyroxine alone in the developmental delay of this particular case.

 

The transient hypothyroxinemia that premature newborns may develop after birth has been reported to be a possible cause of impaired neurologic and mental development at 2 years old.36 It has been previously considered to be a benign developmental phenomenon, an expression of temporary hypothalamic-pituitary immaturity, or a manifestation of nonthyroidal illness; treatment has not been recommended because it was not thought to have long-lasting sequelae and that thyroxine replacement was not necessary. According to an editorial in the same issue of the New England Journal of Medicine,37 the main reason to withhold treatment in these neonates is the belief (erroneous according to the authors) that the human fetus does not need thyroid hormone before term. It is assumed that after delivery, these premature neonates no longer receive thyroxine from the mother and because of their immaturity, they cannot synthesize their own thyroxine. However, these infants are born to euthyroid women and whether any comparison to infants of hypothyroid mothers can be made is presently a matter of speculation. Premature infants may have many other problems because of organ immaturity that also may play a role in the development of their cognitive and motor abnormalities.

 

In humans, it is still poorly understood why some very hypothyroid women (even if untreated) may deliver seemingly normal infants. Most neonates with congenital hypothyroidism do not have symptoms or appear hypothyroid immediately after birth. This phenomenon was used as evidence that fetal development and maturation occurred independently from the mother when the human placenta was thought to be impermeable to the passage of thyroid hormones. However, the belief at present is that the reason why the fetuses with congenital hypothyroidism appear normal at birth is because of the T4 transferred from the mother, which is sufficient to prevent the manifestations of fetal hypothyroidism. It is only after birth, when the maternal T4 is no longer available, that hypothyroidism develops and will lead to potentially serious cognitive deficiencies if it is untreated. Nevertheless, we still we do not have an explanation for the lack of developmental and cognitive complications in the infants of hypothyroid mothers in the reports previously reviewed. It is unknown if there might be a maternal thyroid hormone threshold that would be important or if, in some cases, T4 may be inactivated to a greater extent by placental deiodinases 43 and may not be available to the fetus at some critical point. In view of the report by Pop et al.,31 the role of peroxidase thyroid antibodies deserves further study.

 

Another common complication of autoimmune thyroid disease during pregnancy, even if the mother is euthyroid, is postpartum thyroid dysfunction. As mentioned in the section of the cause of hypothyroidism, women with a previous history of postpartum thyroiditis are at higher risk of developing hypothyroidism and should be screened during subsequent pregnancies.

 
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Treatment
 

The improved outcome of pregnancy in hypothyroid women has been achieved through efforts to identify and treat these patients. They should be made euthyroid as soon as possible, and the euthyroidism should be maintained. Ideally, they should be euthyroid before pregnancy whenever possible, and the therapy should be read-justed as often as necessary to keep them euthyroid throughout because many patients require higher replacement doses during pregnancy.44-47 Treatment is simple and rewarding, and by preventing or reducing complications, it is also very cost-effective.

 

The patients who are euthyroid when they become pregnant and remain so throughout gestation are at low risk, and no special monitoring is needed besides periodic measurements of thyroid function tests. The main risk for those initially hypothyroid but who become euthyroid on treatment is pre-eclampsia (15-30%).7-9 Patients who are still hypothyroid at term have an even higher risk of pre-eclampsia and premature delivery (22-44%), as well as a risk of placental abruption and postpartum hemorrhage.7,8 According to one study,10 fetal distress in labor may occur in patients who were profoundly hypothyroid in early pregnancy, although their thyroid function tests improve with replacement. Antepartum fetal surveillance is not generally recommended for the maternal hypothyroidism alone unless it is indicated for other reasons (e.g., hypertension, diabetes mellitus, etc.). However, the total number of patients thus far published is still relatively small and from different institutions; therefore, additional experience needs to be accumulated before explicit recommendations can be formulated.

 

L-thyroxine has long been the drug of choice to treat hypothyroidism. Dessicated thyroid preparations were the main agents used until the 1960s and 1970s when the synthetic hormones became widely available. The hormonal content of the synthetic drugs is more reliably standardized, and they have replaced the desiccated thyroid tablets as the mainstay of therapy. The administration of T4 alone is preferable; T4 is deiodinated to T3 in the extrathyroidal tissues, therefore, it most closely resembles the normal physiologic process. Brand name prescriptions have usually been recommended because the bioavailability and bioequivalency of the generic formulations were considered to be too erratic and not interchangeable with the brand name preparations.48-50 Some studies do not find this situation to be the case,51 and the controversy has reached even the nonmedical press.52 Hopefully, additional studies will finally clarify the issue but, in the meantime, the treating physician will have to use his/her own judgment.

 

The recommended best time to take L-thyroxine is early in the morning, on an empty stomach. Some women, particularly in the first trimester, may not be able to tolerate medications at that time of day, and it is probably better to allow them to take the thyroxine later when they are not experiencing nausea or vomiting. Insisting on the administration of the medication early in the morning (regardless of the patients' symptoms) may lead to their skipping this important medication too often. Many pregnant women take ferrous sulfate during pregnancy, which may form insoluble ferric-thyroxine complexes resulting in a reduced absorption of thyroxine.21 The ingestion of these two medications should be separated by at least 2 hours. Other medications that may affect L-thyroxine requirements, and therefore the replacement dosage, are given in Table 2.

 

By the mid 1980s, reports started to appear indicating increased thyroxine requirements during pregnancy. Pekonen et al.44 observed 34 women through 37 pregnancies and noted that 13 (23%) needed readjustment. Many of these patients had been treated for thyroid carcinoma, and they were taking larger replacement doses than the average hypothyroid patient. Two women actually required a reduction of the dose because of symptoms of hyperthyroidism. Tamaki et al.45 reported that four women who underwent total thyroidectomy for carcinoma experienced a decrease in serum free T4 and an increase in serum TSH levels while they were being treated with constant thyroxine replacement doses.

 

Other studies have followed with more detailed analysis and confirming the need to increase the dose of L-thyroxine in many pregnant women. Mandel et al.46 observed 12 hypothyroid pregnant women throughout gestation, and they found that the replacement dosage needed to be increased in 9 (75%) of them. The mean dose increment was 45% (from 0.102 to 0.148 mg daily). The need for increased thyroxine replacement appeared in the first trimester, and it persisted throughout pregnancy. After delivery the requirements returned to prepregnancy levels. In this study, the magnitude of the increase was independent of the cause of hypothyroidism, and there were no adverse effects in the outcome of pregnancy.

 

Kaplan 47 studied a larger group of patients (65 women during 77 pregnancies). He divided them in two groups: 36 women were hypothyroid as the result of thyroidectomy, radio-iodine ablation, or both; in 29 other women, the cause of the hypothyroidism was chronic (Hashimoto's) thyroiditis. Six patients were lost to follow-up, and one was excluded because of poor compliance. All patients were known to be hypothyroid before pregnancy, and they took the same brand of levothyroxine throughout gestation. The replacement dose had to be increased in 76% of the women whose hypothyroidism was the result of thyroidectomy or radioiodine ablation, and it was increased in 47% of the women whose hypothyroidism was due to Hashimoto's thyroiditis. The need to increase the replacement dose occurred in the first trimester in most patients. However, one third of the women who had normal TSH levels in the first trimester required readjustment later in the pregnancy, thus, the need for follow-up throughout pregnancy was confirmed. The outcome of pregnancy was favorable in these patients due, at least in part, to the prompt readjustment of the thyroxine replacement dosage as soon as an elevated TSH level was detected. Based on these data, Kaplan suggests that the initial TSH level during pregnancy can be used to estimate the dose of L-thyroxine needed to normalize the elevated TSH: higher than normal but <10 µU/mL, 41 ± 24 µg of L-T4 daily. For serum TSH values between 10 and 20 µU/mL, 65 ± 19 µg daily and for TSH values >20 µU/mL, 105 ± 32 µg daily.

 

There has been speculation about the reason for the increased thyroxine requirements during pregnancy and the reasons they were not recognized earlier. Most authors agree that before the advent of sensitive TSH assays in the early to mid-1980s the replacement doses were too high and, therefore, sufficient to cover the increased requirements of pregnancy. It was not possible to separate normal from subnormal concentrations with the older TSH assays, but the newer assays can accurately measure the lower limits of the normal TSH range and even subnormal concentrations. As a consequence, the recommended replacement doses of L-thyroxine in hypothyroid patients have been greatly reduced because the therapeutic goal is to maintain the TSH in the normal range. Thus, the need for increased amounts of replacement becomes evident shortly after conception. Another possible reason for increased T4 requirements during pregnancy is the need to saturate the additional quantities of TBG that accumulate during the first trimester; in addition, decreased intestinal absorption of thyroxine may be a factor later in pregnancy.47 It also has been suggested that the very high enzymatic activity of placental inner-ring deiodinase may play a role in the increased clearance of T4 during pregnancy.53

 

Because most patients are already on therapy before conception, Kaplan's guidelines, as stated above, may be used to determine thyroxine readjustments. For those patients newly diagnosed in pregnancy, an initial dose of 2 µg/kg of actual body weight can be given because the total daily secretion of thyroxine is related to body mass. In the nonpregnant individual, doses above 1.6-1.7 µg/kg daily are considered suppressive. Therefore, the added amount takes into consideration the increased requirements of pregnancy; subsequent increments can be made according to the serum TSH level. An initial dose of 150 µg/day also is acceptable and additional adjustments are made according to TSH measurements afterwards (Table 5). When therapy is initiated during pregnancy or a dose change is made, subsequent measurements of thyroid function should be made every 4 weeks until the TSH returns to normal to make these patients euthyroid as soon as possible. Dose adjustments at less than 4-week intervals may lead to overtreatment; once they are euthyroid, they can be observed at less frequent intervals as detailed below. Most pregnant women are young and free of cardiovascular disease; therefore, it is safe to initiate treatment with full replacement doses as indicated.

Graphic Table 5

All pregnant women on thyroxine replacement therapy should be first checked at 6-8 weeks of gestation. Subsequent TSH levels should be measured at 16-20 weeks and at 28-32 weeks, with necessary readjustments made in the replacement dose. Those patients who had their thyroid removed or ablated are at higher risk of becoming hypothyroid during pregnancy and of needing larger dose increments. The goal of therapy is a normal serum TSH level. After delivery, the dosage of thyroxine should be reduced to the prepregnancy amount and a TSH measured 6-8 weeks postpartum to verify the adequacy of the dosage change. Afterwards, the patients may return to routine follow-up visits once or twice a year (or more often if there are other reasons). In the rare cases when the TSH cannot be used to guide thyroxine therapy (e.g., in hypothalamic or pituitary diseases), we recommend maintaining the free T4 index in the upper third of the normal range.

 

Those patients with a history of thyroid carcinoma are usually treated with larger, suppressive doses of levothyroxine because the growth of differentiated thyroid carcinomas may be dependent on thyrotropin.54 The goal of therapy is to inhibit thyrotropin secretion to undetectable levels (<0.10 mU/L) without inducing clinical symptoms of hyperthyroidism. The serum total and free T4 concentrations are maintained at the upper normal or slightly above the normal range. There is no need to change the goals of therapy during pregnancy in these patients. Pregnancy has not adversely influenced the long-term prognosis of differentiated thyroid carcinoma. Consequently, the outcome of pregnancy in these patients has been favorable even after the administration of high therapeutic doses of radioactive iodine, if certain precautions are taken.55

 
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Summary
 

Hypothyroidism during pregnancy occurs in 1/1600-2000 deliveries, according to the most recent publications. The most common causes are chronic autoimmune thyroid disease, radiodine-131 treatment, or surgical removal. The diagnosis is difficult to make on clinical grounds alone, even in advanced cases, and a high index of suspicion is needed. Some women are at high risk of developing hypothyroidism, and they should be screened. These women may have had previous treatment for hyperthyroidism; high-dose neck irradiation, evidence of thyroid autoimmunity, amiodarone therapy, suspected hypopituitarism, and type I diabetics. The best laboratory test is the serum TSH, followed, if elevated, by a free T4 index and a TPO-ab titer. Thyroid antibodies have been associated with an increased (double) risk of miscarriage and postpartum thyroiditis. Frequent (22-44%) pregnancy-induced hypertension leading to preterm delivery, and prematurity is the main complication observed in those still hypothyroid near term. Proper therapy eliminates or reduces the risk. No congenital anomalies have been reported in the most recent studies, and the data available shows that both physical and mental development have been normal until children are 10 years old. However, one study reported lower IQs in children of euthyroid women with positive TPO-ab than in children of TPO-ab negative mothers. Levothyroxine is the treatment of choice. Euthyroidism must be reached and maintained in a timely fashion. Many women need more thyroxine during pregnancy, and surveillance of thyroid function is needed throughout gestation to make dose adjustments when needed. During the postpartum periods the thyroxine requirements decrease to preconception levels.

 
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