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H
ypothyroidism occurs during pregnancy rel- atively frequently. A nation-wide US survey showed that 4.6% of the population 12 years old and older had hypothyroidism and that 4.3% of all women suff ered from thyroid disease or goitre, or were taking thyroid medication.1 Routine prenatal screening showed that 2.2% of pregnant women in their second trimester had thyroid-stimulating hor- mone (TSH) levels at or above 6 mU/L.2 Pregnant patients with hypothyroidism are at increased risk of obstetric complications, such as fetal death, gestational hypertension, placental abruption, and poor perinatal outcome. Adequate treatment withthyroid hormones greatly reduces the frequency of these maternal complications.3
Until 12 weeks’ gestation, before the fetal thyroid begins to produce thyroid hormones, the devel- oping brain is critically dependent on circulating levels of maternal thyroxine (T4).4 A recent trial demonstrated that thyroid insufficiency in preg- nant rats disrupted migration of neurons in the fetal cortex and hippocampus, leading to aberrant location of neurons in the adult off spring’s brain.5 Children born to women with high serum TSH concentrations at 17 weeks’ gestation who were not treated for hypothyroidism had 7-point lower IQs Alejandro A. Nava-Ocampo, MD, MSC Offi e P. Soldin, PHD, MBA Gideon Koren, MD, FRCPC
Hypothyroidism during pregnancy
ABSTRACT
QUESTION I have a 27-year-old patient diagnosed with hypothyroidism in the 8th week of pregnancy. She received conflicting opinions regarding risk for her baby and wants to get more information. I also found conflicting information in the literature. How should I advise her?
ANSWER Pregnant patients with untreated hypothyroidism are at increased risk of obstetric complications. Adequate treatment with thyroid hormones greatly reduces the frequency of these complications. Observational studies suggest that children whose mothers had hypothyroxinemia in early pregnancy have lower IQs than matched controls. Another study has shown that even if levothyroxine therapy is started after the fi rst trimester, there is an excellent chance children will have normal neuropsychologic development.
RÉSUMÉ
QUESTION Une de mes patientes de 27 ans qui en est à sa huitième semaine de grossesse vient de recevoir un diagnostic d’hypothyroïdie. Les avis qu’on lui a donnés concernant le risque pour son enfant sont contradictoires et elle veut avoir plus d’information. J’ai moi aussi trouvé des renseignements confl ictuels dans les ouvrages scientifi ques.
Quels conseils devrais-je lui donner?
RÉPONSE Les patientes enceintes dont l’hypothyroïdie n’est pas traitée présentent un risque accru de complications obstétriques. Un traitement adéquat au moyen d’hormones thyroïdiennes réduit considérablement la fréquence de telles complications. Des études par observation laissent entendre que les enfants dont la mère a souff ert d’hypothyroxinémie au début de sa grossesse ont un quotient intellectuel plus bas en comparaison des sujets de contrôle. Une autre étude a fait valoir que même si une thérapie à la lévothyroxine est commencée après le premier trimestre de la grossesse, il y a d’excellentes chances que ces enfants aient un développement neuropsychologique normal.
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than matched controls.6 A prospective cohort study has shown that low levels of free thyroxine (fT4) at 12 weeks’ gestation are associated with impaired psychomotor development at 10 months old.7
Treatment
Two thyroid hormones, levothyroxine (L-T4) and liothyronine (L-T3), are available in Canada.
Liothyronine can be used occasionally when quick onset of action is required, but is less desirable for chronic replacement therapy because it requires frequent dosing and because it produces a tran- sient elevation in triiodothyronine concentrations.
A desiccated hormone preparation, derived from animal thyroids, is also available in Canada. It con- tains both thyroxine and triiodothyronine, but because it has highly variable biologic activity, it is not recommended as the primary alternative for thyroid hormone therapy. Levothyroxine is consid- ered a safe and eff ective replacement treatment for hypothyroid pregnant patients and is not terato- genic. A large population-based case-control study found that only 12 babies were born with major malformations to mothers with a history of hypo- thyroidism who were being treated with thyroid hormones during pregnancy.8 Th ese cases had no homogenous pattern of defects.
It is generally accepted that severe maternal hypothyroidism during the second trimester can result in irreversible neurologic defi cits. Maternal hypothyroxinemia (fT4 below the lowest 10th per- centile and TSH within the reference range of 0.15 to 2.0 mU/L) at later stages can lead to less severe, and partially reversible, fetal brain damage.
Even partial treatment of maternal hypothyroid- ism during pregnancy appears to be benefi cial for off spring.6 A recent cohort study found that infant neurodevelopment was not adversely aff ected by hypothyroxinemia during the first trimester if fT4 concentrations were subsequently corrected.9 Should we then treat all pregnant women with high TSH levels but no clinical hypothyroidism? We believe this decision must await results of random- ized controlled trials of treatment.
Dose adjustment of L-T
4during pregnancy
Several studies have now confirmed that L-T4 requirements in most women with existing hypo- thyroidism increase substantially during pregnancy.
Absorption of T4 occurs in the small intestine; it can absorb from 50% to 80% of the dose.10 An empty stomach improves absorption. Sucralfate, cholestyr- amine resin, and aluminum hydroxide can interfere with L-T4 absorption. Concomitant administration of drugs that induce hepatic cytochrome P450 (CYP) enzymes, mainly CYP3A4, such as phenytoin, carba- mazepine, and rifampin, enhance biliary excretion of L-T4. Hormonal and physiologic changes could indi- cate a need to adjust dosages during pregnancy.
Special attention should be paid to prenatal vita- mins because they contain iron and calcium, both of which potently inhibit absorption of L-T4.11,12 A recent study found L-T4 dosage adjustments were not required if prenatal vitamins were taken 4 hours after ingesting L-T4.13
Therapeutic drug monitoring of L-T
4Because adverse eff ects for both mother and baby are not due to high serum TSH per se but to low free T4 concentrations, decisions regarding treat- ment should be based on serum free T4 concentra- tions rather than on serum TSH concentrations.14 If the L-T4 dose was increased during pregnancy, it should be reduced gradually after delivery and thy- roid function evaluated repeatedly.
Levothyroxine and breastfeeding
The quantity of thyroid hormone transferred into human milk is too low to aff ect plasma thyroid hor- mone levels in neonates.15 Th e American Academy of Pediatrics considers L-T4 compatible with breastfeed- ing and has reported that no observable change is seen in nursing infants whose mothers are taking L-T4.16 References
1. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al.
Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994):
National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-99.
2. Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, et al. Maternal
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thyroid defi ciency and pregnancy complications: implications for population screening.
J Med Screen 2000;7:127-30.
3. Glinoer D. Management of hypo- and hyperthyroidism during pregnancy. Growth Horm IGF Res 2003;13(Suppl A):S45-54.
4. Contempre B, Jauniaux E, Culvo R, Jurkovic D, Campbell S, de Escobar GM. Detection of thyroid hormones in human embryonic cavities during the fi rst trimester of pregnancy.
J Clin Endocrinol Metab 1993;77:1719-22.
5. Lavado-Autric R, Auso E, Garcia-Velasco JV, Arufe M del C, Escobar del Rey F, Berbel P, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitec- ture of the progeny. J Clin Invest 2003;111:1073-82.
6. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid defi ciency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55.
7. Pop VJ, Kuijpens JL, van Baar AL, Verker KG, van Son MM, de Vijlder JJ, et al. Low mater- nal free thyroxine concentrations during early pregnancy are associated with impaired psy- chomotor development in infancy. Clin Endocrinol 1999;50:149-55.
8. Khoury MJ, Becerra JE, d’Almada PJ. Maternal thyroid disease and risk of birth defects in off spring: a population-based case-control study. Paediatr Perinat Epidemiol 1989;3:402-20.
9. Pop VJ, Brouwers EP, Vader HL, Vulsna T, van Baar AL, de Vijlder JJ. Maternal hypothy- roxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003;59:282-8.
10. Hays MT. Localization of human thyroxine absorption. Th yroid 1991;1:241-8.
11. Campbell NR, Hasinoff BB, Stalts H, Rao B, Wong NC. Ferrous sulfate reduces thyroxine effi cacy in patients with hypothyroidism. Ann Intern Med 1992;117:1010-3.
12. Singh N, Singh PN, Hershman JM. Eff ect of calcium carbonate on the absorption of levo- thyroxine. JAMA 2000;283:2822-5.
13. Chopra IJ, Baber K. Treatment of primary hypothyroidism during pregnancy: is there an increase in thyroxine dose requirement in pregnancy? Metabolism 2003;52:122-8.
14. Poppe K, Glinoer D. Th yroid autoimmunity and hypothyroidism before and during preg- nancy. Human Reprod Update 2003;9:149-61.
15. Van Wassenaer AG, Stulp MR, Valianpour F, Tamminga P, Ris Stalpers C, de Randamie JS, et al. Th e quantity of thyroid hormone in human milk is too low to infl uence plasma
thyroid hormone levels in the very preterm infant. Clin Endocrinol 2002;56:621-7.
16. American Academy of Pediatrics, Committee on Drugs. Th e transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
Motherisk questions are prepared by the Motherisk Team at the Hospital for Sick Children in Toronto, Ont. Dr Nava- Ocampo and Dr Soldin are members and Dr Koren is Director of the Motherisk Program. Dr Koren, a Senior Scientist at the Canadian Institutes for Health Research, is supported by the Research Leadership for Better Pharmacotherapy during Pregnancy and Lactation and, in part, by a grant from the Canadian Institutes for Health Research.
Do you have questions about the safety of drugs, chemi- cals, radiation, or infections in women who are pregnant or breastfeeding? We invite you to submit them to the Motherisk Program by fax at (416) 813-7562; they will be addressed in future Motherisk Updates.
Published Motherisk Updates are available on the College of Family Physicians of Canada website (www.cfpc.ca). Some articles are published in The Motherisk Newsletter and on the Motherisk website (www.motherisk.org) also.
