Thyroid disorders in pregnancy

Transcription

1 Current bstetrics & Gynaecology (2003) 13, 45^51 c 2003 Elsevier Science Ltd doi: /cuog available online at on Thyroid disorders in pregnancy Joanna C. Girling Consultant bstetrician and Gynaecologist, West Middlesex University Hospital, Twickenham Road, Isleworth, MiddlesexTW76AF, UK KEYWRDS cretinism; hyperthyroidism; hypothyroidism Summary The physiological changes of pregnancy and the presence of the second patient, the fetus, mean that the management of thyroid disease in pregnancy is not the same as outside pregnancy. These adaptations and di erences in management will be discussed. c 2003 Elsevier Science Ltd INTRDUCTIN Thyroid diseases are the commonest cause of endocrine dysfunction in women of childbearing age. bstetricians will frequently see women with thyroid disease and so a good understanding of the pathophysiology of the problems and their clinical management is essential.this article will outline the relevant physiological changes of pregnancy, including the important aspects of fetal thyroid function, and discuss management options for the commonest causes of abnormal thyroid function in pregnancy. MATERNAL PHYSILGY In a normal pregnancy, iodine crosses the placenta, thyroxine (t4) is transferred only in the rst trimester and triiodothyronine (t3) and thyroid stimulating hormone (TSH) do not cross at all. A number of physiological changes occur: * Thyroxine binding globulin (TBG). nly free thyroxine (ft4) and free triiodothyronine (ft3) are biologically active. However, more than 99% of these hormones are protein-bound and therefore inactive. TBG concentration almost triples in the rst 20 weeks of pregnancy due to oestrogen-driven glycosylation of TBG, which extends the half-life from 15 min to 3 days. In order to ensure that an euthyroid state remains, total thyroid hormone production increases, but the levels of ft4 and ft3 remain approximately the same. When assessing thyroid function in pregnancy, total t4 and total t3 measurements are unreliable. * Human chorionic gonadotrophin (hcg). hcg and TSH share identical a subunits and have similar b subunits Correspondence to: JCG.Tel.: ; Fax: ; joanna.girling@wmuh-tr.nthames.nhs.uk and receptors. hcg itself is a collection of many similar molecules with a range of thyrotropic activities. In the rst trimester, a hormone spillover syndrome may occur in which high levels of hcg stimulate the TSH receptor, giving a biochemical pro le of hyperthyroidism; therefore, thyroid function tests should be interpreted particularly carefully at this stage of pregnancy. This scenario is more common in multiple pregnancy and in pregnancies where there is a higher proportion of the most thyrotropic forms of hcg, such as those complicated by trophoblastic disease or hyperemesis gravidarum. * Iodine de ciency. Extrathyroidal iodine is in dynamic equilibrium with the thyroid and kidneys. The increased glomerular ltration rate of pregnancy results in greater renal loss and the increase in total t4 requires greater uptake into the thyroid. Together these can increase the frequency or severity of iodine de ciency and may account for the physiological goitre of pregnancy. Transplacental iodine transport can exacerbate these problems, although in women with severe iodine de ciency maternal iodine trapping mechanisms over-ride fetal demands, resulting in cretinism. * De-iodination of thyroid hormones. Three de-iodinase enzymes control the metabolism of t4 to the more active t3 and the deactivation of both hormones to inactive compounds. These enzymes are important for local regulation of thyroid hormone concentrations. De-iodinase 111 occurs in the placenta, its concentration increasing with gestation. It inactivates t4 and t3 by removing molecules of iodine, which are then readily available for transport to the fetus. This may contribute to the fall in circulating hormone levels that seems to occur in the third trimester and to the lack of transfer of t4 to the fetus beyond the rst trimester.

2 46 CURRENTBSTETRICS & GYNAECLGY Table 1 Pregnancy-speci c reference ranges for thyroid function tests Not pregnant 1sttrimester 2nd trimester 3rd trimester Free thyroxine (pmol/l) 11^23 11^22 11^19 7^15 Free triiodothyronine (pmol/l) 4^9 4^8 4^7 3^5 Thyroid stimulating hormone (mu/l) 0^4 0^1.6 1^1.8 7^7.3 FETALTHYRID PHYSILGYAND THE EFFECTF MATERNALTHYRID STATUS Fetal thyroid function begins by the end of the rst trimester. Prior to that, there is evidence that normal development of the fetal brain is dependent upon maternally-derived t4, which is converted intracellularly to t3. Such t4 has been detected from 5.8 weeks gestation, and by 11weeks its concentration is 100 times greater than that in the maternal circulation. Maternal hypothyroxinaemia at this stage may have adverse e ects on subsequent fetal brain development (see below). Fetal ft4 and total t4 reach adult levels by 36 weeks gestation, fetal TSH is greater than adult TSH and fetal t3 remains low.the relatively high levels of t4 allow intracellular conversion to t3 in the fetal brain. When fetal thyroid dysfunction occurs, maternally derived t4 is essential for normal neurological development. Placental perfusion studies have demonstrated that in normal pregnancy at term, very little (0.008%) maternal t4 crosses to the fetal side. However, inhibition of placental de-iodination of t4 enhances transfer 2700-fold, so that fetal levels reach 30% of maternal concentrations. In pregnancy complicated by fetal thyroid dysfunction, de-iodinase 111 is inhibited, allowing additional transfer of t4 to the fetus, reduced fetal peripheral de-iodination of t4 and enhanced intracellular activation to t3 in the fetal brain, so protecting it from permanent damage. ASSESSMENT F THYRID FUNCTIN IN PREGNANCY As for the case outside pregnancy, the assessment of thyroid function depends upon a combination of clinical features and biochemical results. In pregnancy it is particularly di cult to detect subtle clinical changes in thyroid status because of the diverse symptoms and signs of pregnancy.there is a greater dependence upon biochemical measures. In addition, the potential implications to the fetus of inadequate or inappropriate treatment mean that tight control of maternal thyroid disease should be maintained (see below). Reference ranges for thyroid function in pregnancy are shown in Table 1. The absolute values should not be used, rather the equivalent adjustment must be made to the non-pregnant ranges used in an individual hospital. These data are the best that are currently available.they are not based on large numbers of women and simple, and possibly inadequate, statistical analysis was used. I am currently determining a valid set of reference ranges, which hopefully will clarify this area. Bearing this in mind, ft4, ft3 and TSH should be requested when assessing maternal thyroid function; total t4 and t3 should not be used in pregnancy. When deciding whether to change the treatment dose, more weight should be placed upon ft4 and ft3 levels than on TSH, since these re ect both the actual thyroid status and, in the rst trimester, the availability of hormone for fetal transfer. In women with hypothyroidism, TSH may remain elevated, despite normal ft4 and ft3 levels, for some time after the correct dose of t4 has been initiated, although poor compliance must be considered since this can give a similar picture. Conversely, TSH may remain suppressed once ft4 and ft3 levels return to normal in hyperthyroidism. Free thyroxine concentration seems to fall in the second half of pregnancy, the lower limit of normal being below the non-pregnant reference range in the third trimester. TSH often increases at the same time. This does not usually indicate the onset of hypothyroidism nor the need to increase the dose of t4 in established cases of hypothyroidism. Increasing concentrations of type 11 de-iodinase enhance the intracellular conversion of t4 to t3, thereby raising, at the cellular level, the thyroid activity for a given concentration of ft4. In an evolutionary sense, this economy of maternal metabolism prior to the exertions of labour and lactation may enhance self-preservation. IDINE DEFICIENCY Iodine de ciency results in cretinism in newborns, goitre in adults and reduced reproductive success in women. Worldwide, more than 1 billion people are a ected by iodine de ciency and more than 20 million have adverse neurological sequelae following fetal iodine deprivation. Neurological endemic cretinism is the leading preventable cause, worldwide, of mental retardation, and it has a major negative e ect on the economy of a icted areas. Approximately 2^10% of individuals in iodine-de cient

3 THYRID DISRDERS IN PREGNANCY 47 populations are a ected. In these populations, a mild degree of mental retardation is ve times more common than cretinism itself, resulting in a left shift of the intelligence quotient (IQ) distribution curve by10 points. Cretinism is characterized by deaf^ mutism, intellectual de ciency, spastic motor disorder and, in some cases, hypothyroidism. Although the precise pathophysiology of the insult to the neurological system is poorly understood, the combination of maternal iodine de ciency and hypothyroxinaemia with, as a consequence of the former, fetal hypothyroidism, lasting throughout the pregnancy are devastating to the fetus. The developing cochlea, cerebral neocortex and basal ganglia are most sensitive to iodine de ciency and all are growing rapidly during the second trimester. In myxoedematous cretinism, hearing, speech and motor function are spared, and the clinical picture is similar to that of untreated congenital hypothyroidism: the degree of maternal iodine deprivation is less severe and the mother is capable of transferring either su cient iodine or t4 or both to the fetus at the critical stages of neurological development to ensure normal development of these functions. In areas of endemic iodine de ciency, the usual maternal ndings are goitre in association with normal t3, low or very low t4 and raised TSH. Neurological cretinism is common in the o spring, suggesting that maternal t3 alone is insu cient to protect the fetal brain and that fetal deprivation of iodine and, possibly, maternal t4 may be important with regard to the long-term neurological e ects in the o spring (see above). This is not surprising because fetal brain utilizes t3 derived from intracellular t4. A single oral dose of iodine administered to women possibly up to 12 months before conception or until the end of the second trimester normalizes maternal TSH and t4 and improves fetal neurological status. It is likely, therefore, that iodination of drinking water, salt or our, or annual administration of iodine to women of reproductive age would have a major reduction in the incidence of this devastating condition. Amongst 5000 Senegalese women with moderate iodine de ciency there was no delay in the age of menarche. Iodine de ciency was associated, in a dose-dependent manner, with an increased incidence of both repeated (three or more) miscarriage and stillbirth. Thus, 49% of women with severe iodine de ciency, 27%withmoderate,22%withmildand21%withnone, had one of these outcomes. Malnutrition and illiteracy signi cantly worsened the reproductive outcome in iodine-de cient women. Pre-pregnancy iodine supplementation improves pregnancy outcome, reducing pregnancy loss from 24% to 16% in Papua New Guinea and reducing stillbirth from 18 per 1000 to 9 per 1000 in Zaire. HYPEREMESIS GRAVIDARUM In up to 60% of cases of hyperemesis gravidarum (HG) requiring prolonged or repeated admission to hospital, thyroid function tests are abnormal, with either an elevated ft4 (sometimes up to 80 pmol/l) or a suppressed TSH or both. In one recent study, ft4 returned to normal by 15 weeks gestation and TSH by 19 weeks. This is due to the stimulation of the TSH receptor by hcg moieties with increased thyrotropic activity. Therefore, although the total hcg concentration as measured by routine laboratory assays may not be elevated, increased proportions of pro-thyrotropic hcg molecules result in a situation of temporary biochemical thyrotoxicosis. Recently, a genetic mutation of thetsh receptor, making it unusually sensitive to hcg, has been described in a mother^ daughter pair who both had recurrent severe HG. Treatment is centred on correcting the metabolic insults of prolonged vomiting, and on minimizing further vomiting. There is no place for the use of antithyroid medication, since the thyroid abnormality is not of intrinsic thyroid overactivity and it is short-lived and self-limiting. If antithyroid medication is used for hcg-induced hyperthyroidism, it is either ine ective or extremely high doses are required to achieve biochemical euthyroidism. Since these agents cross the placenta (see hyperthyroidism, below), they could render the fetus hypothyroid. Since true hyperthyroidism may occasionally present with the sole complaint of vomiting, thyroid function tests should be monitored to ensure that they return to normal. The clinical picture of hyperemesis is quite di erent from that of thyrotoxicosis. The typical patient with hyperemesis is washed out, tired, lacking in energy and de ated; there is no goitre, tremor or eye signs; if present, tachycardia is secondary to dehydration, weight loss to poor nutritional intake and warm peripheries to the vasodilatation of pregnancy; the symptoms are clearly of recent onset, do not antedate the pregnancy and improve as the vomiting settles. If there is clinical doubt concerning the di erential diagnosis of the thyroid dysfunction, the absence of thyroid antiperoxidase, antithyroglobulin and TSH receptor autoantibodies supports the diagnosis of hyperemesis. HYPERTHYRIDISM Conception is unusual in untreated thyrotoxicosis, but as the condition improves, libido and fertility return.the incidence of thyrotoxicosis is 2 per 1000 pregnancies, 95% of cases being due to Graves disease.if a new diagnosis of hyperthyroidism is suspected in the rst trimester of pregnancy, hyperemesis gravidarum and molar pregnancy should be considered.

4 48 CURRENTBSTETRICS & GYNAECLGY Typically, Graves disease ares in the rst trimester and puerperium. During the second and third trimester there is a reduced requirement for antithyroid medication and 30% of women can discontinue treatment. After delivery the majority of these women need to increase the dose and or recommence therapy in order to avoid a relapse.these changes re ect alterations in the titre of thyroid receptor stimulating antibodies and a change from stimulatory to inhibitory antibodies as pregnancy advances. Clinical assessment of disease activity The clinical assessment of thyroid disease activity is di cult in pregnancy due to overlap between the symptoms of pregnancy and those of hyperthyroidism (seetable 2). Failure to gain weight despite a good appetite together with maternal tachycardia that does not slow with Valsalva manoeuvre may be helpful indicators of hyperthyroidism. Eye signs and pretibial myxoedema do not re ect disease activity, although onycholysis does. Pregnancy outcome If thyrotoxicosis is well controlled, the outcome for mother and baby is good. However, when control is inadequate, maternal and fetal complications (such as thyroid storm, cardiac failure, hypertensive disease of pregnancy, small for gestational age infants, preterm labour and stillbirth) are increased. utcome is worst for those pregnancies in which control is never achieved, intermediate when euthyroidism occurs during the pregnancy and best when thyrotoxicosis is controlled before conception. Treatment of thyrotoxicosis in pregnancy Radioactive iodine Radioactive iodine is totally contraindicated during pregnancy and lactation, or in women contemplating pregnancy in the near future. It crosses the placenta freely throughout pregnancy and irreversibly destroys the fetal thyroid gland. Surgery Surgery may be used for failed medical therapy, compressive symptoms due to goitre and suspicion of, or de nite diagnosis of, thyroid cancer. It is usually carried out in the second trimester. Medical therapy Propylthiouracil (PTU) and carbimazole are the rst-line choices for treatment of thyrotoxicosis in pregnancy and are equally e ective at achieving euthyroidism. They block thyroid hormone synthesis and have an immunosuppressive e ect, reducing the titre of TSH receptor antibodies and thereby directly in uencing the course of Graves disease.contrary to earlier beliefs, both drugs cross the placenta in similar amounts. Treatment should be titrated against maternal wellbeing and biochemistry, aiming for ft4 at the upper limit of normal for pregnancy, in order to minimize the dose required. Propranolol may Table 2 verlap between clinical symptoms ofthyroid disease and pregnancy Pregnancy Hyperthyroidism Hypothyroidism Heat intolerance Increased appetite Nausea Palpitations Tachycardia Tremor Sweating Warm palms Goitre Amenorrhoea Weight gain Carpal tunnel syndrome Fluid retention Constipation Loss of concentration Tiredness

5 THYRID DISRDERS IN PREGNANCY 49 be used safely in pregnancy if required to control tremor, anxiety or tachycardia. * Teratogenesis. PTU and carbimazole are safe in pregnancy. Early reports suggested that PTU caused aplasia cutis of the fetal scalp, but this association is now thought to be spurious or at worst extremely weak. Pregnancies where thyrotoxicosis is controlled by thionamides have less congenital abnormality than those where thyrotoxicosis is untreated or partially treated, suggesting that not only are the thionamides not teratogenic but also that they can reduce the risk of abnormality that thyrotoxicosis itself causes. * Fetal and neonatal e ectsof medical therapy. Carbimazole and PTU may each cause fetal hypothyroidism. Although this risk does not directly correlate with dosage, treatment should aim at using the lowest e ective dose. Since they do not inhibit deiodinases 11 or 111, normal intracellular t3 levels are maintained in the developing fetal brain, provided that there is su cient iodine available. Approximately 10 ^20% of babies whose mothers are taking thionamides at delivery have transient asymptomatic hypothyroidism that resolves by day 5. This may mask neonatal hyperthyroidism, a potentially dangerous but rare condition, which usually presents at 7^10 days of age (see below). A total of 1^2% of babies have small goitres that resolve quickly. * Long-term e ectson o spring. Four small studies of 101 children have demonstrated comparable physical and psychological development and thyroid size and function in children exposed to thionamides in utero compared with children whose mothers had thyroidectomy to control hyperthyroidism. * Lactation. Small amounts of both PTU (0.025^ 0.077%) and carbimazole (0.47%) cross the breast. However, at normal doses this does not cause hypothyroidism nor prevent the recovery from neonatal hypothyroidism caused by in utero transfer of drugs. If doses above 15 mg carbimazole or 150 mg PTU are needed, the dose should be split, and neonatal wellbeing monitored clinically and biochemically. * Blocking replacement regime. This entails giving a high dose of antithyroid medication to suppress maternal thyroid activity and TSH-receptor antibody titre, and adding t4 to correct the resulting hypothyroidism, the aim being to achieve control more quickly and with a lower relapse rate. This regimen should not be used in pregnant women since the high dose of thionamide crosses the placenta, but the additional t4 does not (see above). ut of 20 cases recorded in pregnancy, cord TSH was increased and one baby had a goitre. In addition, outside pregnancy, it is now apparent that it is not more e ective than traditional therapy. Neonatal Graves disease Transplacental passage of maternal TSH receptor stimulating antibodies (half-life = 21days) in women with active Graves disease may occasionally cause fetal or neonatal Graves disease. The literature describes a 2^10% risk of neonatal Graves disease although in clinical practice it seems much lower. Presentation is usually at 7^10 days of age, when the e ect of transplacental thionamides has waned. Cord thyroid function tests should be recorded to provide a baseline and the paediatricians informed of the delivery; local protocols will dictate surveillance and monitoring. Parents should be aware of the symptoms of neonatal thyrotoxicosis and have a low threshold for seeking medical advice. New developments Exciting recent work on microchimerism of fetal origin in women with autoimmune and other thyroid diseases raises the possibility that fetal cells may be implicated in chronic graft-versus-host disease, resulting in maternal thyroid disease. The implications of pregnancy may be even more long-lasting than previously thought. HYPTHYRIDISM Hypothyroidism a ects 9 per 1000 pregnancies, and is usually due to Hashimoto s thyroiditis or following hyperthyroidism. Clinical assessment It is di cult to di erentiate clinically between the symptoms of pregnancy and those of hypothyroidism (seetable 2). Biochemical assessment, with an interpretation of results against pregnancy-speci c ranges is required. Management of hypothyroidism in pregnancy t4 therapy is the mainstay of medical treatment in pregnancy. t4 is safe in pregnancy and lactation; there is no evidence of teratogenicity, or that signi cant amounts pass into breast milk. The dose of t4 should be titrated against the biochemical results. Thyroid function tests should be measured at 8 ^12 week intervals when the thyroid dose is stable and the woman is clinically and biochemically euthyroid, the rst assessment being made as early in pregnancy

6 50 CURRENTBSTETRICS & GYNAECLGY as possible and ideally before conception as well (see below). Testing is required more frequently if the dose is being adjusted, usually every 4 ^6 weeks, but probably 2 weekly if undertreatment occurs in the rst trimester. Some authorities have recommended a blanket increase in t4 to 200 mg daily in pregnancy, although the logic for this is unclear. thers have found that most patients needed an increased dose, which was reduced again after delivery. In my experience, only 20% of women with hypothyroidism need to increase their t4 dosage; invariably they had been undertreated prior to conception and they continued on the same increased dose postnatally.the remaining 80% of women who are euthyroid at booking remain so throughout pregnancy without a change in dose. Neonatal outcome Substantial, but old, data suggest that untreated hypothyroidism is associated with stillbirth, prematurity, congenital abnormality and reduced IQ. Recent data indicate that untreated hypothyroxinaemia in the rst trimester is associated with a loss of 7 IQ points at the age of 7^9 years compared with the o spring of euthyroid women, and that maternal treatment with t4 at this gestation (when t4 is able to cross the placenta) provides fetal brain protection (see above). Ideally, therefore, maternal t4 therapy should be optimized before conception or failing that as early as possible in pregnancy. Although thyroid peroxidase and antithyroglobulin autoantibodies cross the placenta they do not a ect fetal thyroid development. Therefore Hashimoto s hypothyroidism is not usually associated with fetal or neonatal thyroid dysfunction. TSH receptor blocking antibodies may, rarely, cause fetal or transient neonatal hypothyroidism; incidence has been estimated at 1 in neonates or 2% of cases of congenital hypothyroidism. Women who are hypothyroid following treatment for thyrotoxicosis, may still have TSH receptor stimulating antibodies and so have a small risk of neonatal thyrotoxicosis, as discussed above. A retrospective review of 13 babies with neonatal encephalopathy whose mothers either took t4 or had thyroid disease (including hypothyroidism and hyperthyroidism), or both, suggested that t4 caused neonatal encephalopathy. However, half of the babies had other risk factors for encephalopathy and when the babies were separated into di erent groups, encephalopathy was no longer associated with t4 use. In addition, there is no biologically plausible reason why t4 itself should cause neonatal encephalopathy. Doctors must not be deterred from prescribing t4 for pregnant women in the appropriate dose when clinically indicated. PSTPARTUM THYRIDITIS Postpartum thyroiditis (PPT) is a subacute destructive autoimmune condition strongly related to antiperoxidase antibodies, occurring in the rst year postpartum. It may present as either hyperthyroidism or hypothyroidism, or most often as a purely biochemical phenomenon. Its prevalence in clinical practice is much lower than the 2^17% described in clinical trials. In clinically apparent cases, any or all of the three phases may occur: hyper-thyroidism at 1^3 months postpartum, hypothyroidism 3^ 8 months postpartum and euthyroidism by 1 year. The former occasionally requires treatment with b blockers (but never with thionamides since t4 synthesis is not raised). The hypothyroidism is more likely to need treatment, with t4, although the symptoms may be vague and di cult to distinguish from other postnatal problems; t4 should be withdrawn once the baby is 1 year old. Follow-up thyroid tests are important since a small proportion of women will have permanent hypothyroidism and 5% per year will develop it subsequently, while 70% will get PPT following subsequent pregnancies. There is insu cient evidence to support calls for routine screening for PPT with thyroid autoantibodies. Women with PPT usually present to general practitioners (GPs) and not to obstetricians. Unless GPs are aware of the condition, women may be given other diagnoses, such as Hashimoto s hypothyroidism or depression. The most common, and increasingly frequent, situation in which I see women with PPT is when they conceive their next pregnancy and attend the obstetric medicine clinic with a history compatible with PPT but on long-term treatment with t4. THYRID NDULES AND CANCER Most reports of thyroid nodules in pregnancy exaggerate the frequency of malignancy, which is likely to be much lower than the 30 ^50% risk recorded by endocrinologists, otolaryngologists and head and neck surgeons. In an unselected obstetric population, 18 women with thyroid nodules were referred to bstetric medicine clinics, giving an approximate incidence of1in 2500 pregnancies; none were malignant. Apart from avoiding tests utilizing radioactive iodine, investigation of thyroid nodules is not altered by pregnancy, being based on clinical and biochemical assessment, ultrasound, chest X-ray and ne needle aspiration. Surgery may be undertaken if required and suppressive doses of t4 used if indicated. Thyroglobulin is elevated in normal pregnancy and cannot be used to detect recurrence of thyroid cancer.

7 THYRID DISRDERS IN PREGNANCY 51 PRACTICE PINTS * Biochemical assessment of thyroid function must be with reference to pregnancy-speci c ranges. Placental de-iodinases contribute to changes in maternal thyroid function during pregnancy and enhance the transfer of iodine to the fetus. * Placental transfer of thyroxine (t4) occurs in the rst trimester, when it is required for fetal brain development. Beyond then, the fetal thyroid functions independently. Euthyroid women with hypothyroid fetuses have placental adaptation allowing t4 transfer beyond the rst trimester thus protecting the fetal brain. * Maternal iodine transfer is essential for normal fetal thyroid function. Iodine de ciency causes severe neurological cretinism, which can be prevented by iodine supplementation prepregnancy or up to the second trimester. * Hyperemesis gravidarum is often associated with hyperthyroidism that resolves spontaneously and does not need speci c treatment. * Hyperthyroidism generally has a good fetal and maternal outcome provided that it is treated optimally, usually with propylthiouracil or carbimazole. * Inadequate treatment of hypothyroidism prior to conception and in the rst trimester may have adverse neurological sequelae for the o spring. * There is no place for screening for postpartum thyroiditis. FURTHER READING Dillon JC, Milliez J. Reproductive failure in women living in iodine de cient areas of West Africa. Br J bstet Gynaecol 2000; 107: 631^ 636. Girling JC. Thyroid disease in pregnancy. In: de Swiet M (ed.) Medical Disorders in bstetric Practice, 4th edn. xford: Blackwell, Girling JC, de Swiet M. Thyroxine dosage during pregnancy in women with primary hypothyroidism. Br J bstet Gynaecol 1992; 99: 368 ^370. Girling JC, de Swiet.Maternal thyroid disease: a risk factor for newborn encephalopathy. Br J bstet Gynaecol 2001; 108: 769^770. Momotani N, Noh JY, Ishikawa N, Ito K. E ects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves hyperthyroidism. J Clin Endocrinol Metab1997; 82: 3633^3636. Mortimer RH, Galligan JP, Addison RS, Roberts MS. Maternal to fetal thyroxine transmission in the human term placenta is limited by inner ring deiodination. J Clin Endocrinol Metab1996; 81: 2247^2249. PopVJ, Kuijpens JL, van Baar Al et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol 1999; 50: 149 ^155. Srivatsa B, Srivatsa S, Johnson KL et al. Microchimerism of presumed fetal origin in thyroid specimens from women: a case control study. Lancet 2001; 358: 2034^2038. Tan JYL, Loh KC, Yeo GSH, CheeYC. Transient hyperthyroidism of hyperemesis gravidarum. Br J bstet Gynaecol 2002; 109: 683^688. Tonglet R, Bourdoux P, MingaT, Ermans AM. E cacy of low oral doses of iodized oil in the control of iodine de ciency in Zaire. N Engl J Med1992; 326: 236 ^241. RESEARCH DIRECTINS * Accurate reference ranges for thyroid function tests are required. * Fetoplacental adaptations need to be investigated. * The impact of genetics on thyroid disease requires further study.