Thyroid
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Levothyroxine (T4) is compatible with all stages of pregnancy. Untreated or undertreated maternal hypothyroidism is associated with low birth weight secondary to medically indicated preterm delivery, preeclampsia or placental abruption (1), and with lower neuropsychological development of their offspring (2).
FETAL RISK SUMMARY
T4 is a naturally occurring thyroid hormone produced by the mother and the fetus. It is used during pregnancy for the treatment of hypothyroidism (see also Liothyronine [T3] and Thyroid). Earlier investigations concluded that there was negligible transplacental passage of T4 at physiologic serum concentrations (3–8), but a 1989 study found that sufficient amounts of T4 cross the placenta to protect the congenital hypothyroid fetus and newborn (see below) (9). A 1994 review summarized the evidence that T4 crosses to the embryo and fetus throughout gestation (10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 554 newborns had been exposed to levothyroxine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 25 (4.5%) major birth defects were observed (24 expected). Specific data were available for six defect categories, including (observed/expected) 5/6 cardiovascular defects, 0/1 oral clefts, 0/0.3 spina bifida, 1/2 polydactyly, 1/1 limb reduction defects, and 1/1 hypospadias. These data do not support an association between the drug and congenital defects.
In a study of 25 neonates born with an autosomal recessive disorder that completely prevents iodination of thyroid proteins and thus the synthesis of T4, the thyroid hormone was measured in their cord serum in concentrations ranging from 35 to 70 nmol/L (9). Because the newborns were unable to synthesize the hormone, the T4 must have come from the mothers. The investigators then studied 15 newborns with thyroid agenesis and measured similar cord levels of T4. The mean serum half-life of T4 in the neonates was only 3.6 days, indicating that T4 would be below the level of detection between 8 and 19 days after birth. Although the amounts measured were below normal values of T4 (80–170 nmol/L), the amounts were sufficient to protect the infants initially from impaired mental development. A possible mechanism for this protection may involve increased conversion of T4 to T3 in the cerebral cortex in hypothyroid fetuses, and when combined with a decreased rate of T3 degradation, the net effect is to normalize intracellular levels of the active thyroid hormone in the brain (9).
Several reports have described the direct administration of T4 to the fetus and amniotic fluid (2,7,9,11–15). In almost identical cases, two fetuses were treated in the 3rd trimester with IM injections of T4, 120 mcg, every 2 weeks for four doses in an attempt to prevent congenital hypothyroidism (2,7). Their mothers had been treated with radioactive iodine (I131) at 13 and 13.5 weeks’ gestation. Both newborns were hypothyroid at birth and developed respiratory stridor, but neither had physical signs of cretinism. At the time of the reports, one child had mild developmental retardation at 3 years of age (7). The second infant was stable with a tracheostomy tube in place at 6 months of age (11). In a third mother who inadvertently received I131 at 10–11 weeks’ gestation, intra-amniotic T4, 500 mcg, was given weekly during the last 7 weeks of pregnancy (12). Evidence was found that the T4 was absorbed by the fetus. A male infant who developed normally was delivered. In a study to determine the metabolic fate of T4 in utero, 700 mcg of T4 were injected intra-amniotically 24 hours before delivery in five full-term healthy patients (13). Serum T4 levels were increased in all infants. Intra-amniotic T4, 200 mcg, was given to eight women in whom premature delivery was inevitable or was indicated to enhance fetal lung maturity (14). The patients ranged in gestational age between 29 and 32 weeks. No respiratory distress syndrome was found in the eight newborn infants. Delivery occurred 1–49 days after the injection. The dimensions of a large fetal goiter, secondary to propylthiouracil, were decreased but not eliminated within 5 days of an intra-amniotic 200-mcg dose of T4 administered at 34.5 weeks’ gestation (15). Serial lecithin:sphingomyelin (L:S) ratios before and after the injection demonstrated no effect of T4 on fetal lung maturity.
In a large prospective study, 537 mother–child pairs were exposed to levothyroxine and thyroid (desiccated) during the 1st trimester (16, pp. 388–400). For use anytime during pregnancy, 780 exposures were reported (16, p. 443). After 1st trimester exposure, possible associations were found with cardiovascular anomalies (nine cases), Down’s syndrome (three cases), and polydactyly in blacks (three cases). Because of the small numbers involved, the statistical significance of these findings is unknown and independent confirmation is required. Maternal hypothyroidism itself has been reported to be responsible for poor pregnancy outcome (17–19). Others have not found this association, claiming that fetal development is not directly affected by maternal thyroid function (20). However, untreated maternal hypothyroidism during pregnancy has been shown to result in lower scores relating to intelligence, attention, language, reading ability, school performance, and visual–motor performance in children 7–9 years of age (21).
Combination therapy with thyroid–antithyroid drugs was advocated at one time for the treatment of hyperthyroidism but is now considered inappropriate (see Propylthiouracil).
BREASTFEEDING SUMMARY
Levothyroxine (T4) is excreted into breast milk in low concentrations. The effect of this hormone on the nursing infant is controversial (see also Liothyronine and Thyrotropin). Two reports have claimed that sufficient quantities are present to partially treat neonatal hypothyroidism (22,23). A third study measured high T4 levels in breastfed infants but was unsure of its significance (24). In contrast, four competing studies have found that breastfeeding does not alter either T4 levels or thyroid function in the infant (25–28). Although all of the investigators on both sides of the issue used sophisticated available methods to arrive at their conclusions, the balance of evidence weighs in on the side of those claiming lack of effect because they have relied on increasingly refined means to measure the hormone (29–31). The reports are briefly summarized below.
In 19 healthy euthyroid mothers not taking thyroid replacement therapy, mean milk T4 concentrations in the 1st postpartum week were 3.8 ng/mL (22). Between 8 and 48 days, the levels rose to 42.7 ng/mL and then decreased to 11.1 ng/mL after 50 days postpartum. The daily excretion of T4 at the higher levels is about the recommended daily dose for hypothyroid infants (22). An infant was diagnosed as athyrotic shortly after breastfeeding was stopped at age 10 months (23). Growth was at the 97th percentile during breastfeeding, but the bone age remained that of a newborn. In this study, mean levels of T4 in breast milk during the last trimester (12 patients) and within 48 hours of delivery (22 patients) were 14 and 7 ng/mL, respectively (23). A 1983 report measured significantly greater serum levels of T4 in 22 breastfed infants than those in 25 formula-fed babies, 131.1 vs. 118.4 ng/mL, respectively (24). The overlap between the two groups, however, casts doubt on the physiologic significance of the differences.
In 77 euthyroid mothers, measurable amounts of T4 were found in only 5 of 88 milk specimens collected over 43 months of lactation, with 4 of the positive samples occurring within 4 days of delivery. Concentrations ranged from 8 to 13 ng/mL (25). A 1980 report described four exclusively breastfed infants with congenital hypothyroidism who were diagnosed between the ages of 2 and 79 days. Breastfeeding did not hinder making the diagnosis (26). Another report, evaluating clinical and biochemical thyroid parameters in hypothyroid infants, found no differences between breastfed (N = 12) and bottle-fed (N = 33) babies. These results lead to the conclusion that breast milk does not offer protection against the effects of congenital hypothyroidism (27). In a 1985 study, serum concentrations of T4 were similar in breastfed and bottle-fed infants at 5, 10, and 15 days postpartum (28).
The discrepancies described above can be partially explained by the various techniques used to measure milk T4 concentrations. Japanese researchers failed to detect milk T4 using four different methods of radioimmunoassay (RIA) (29). Using three competitive protein-binding assays, highly variable T4 levels were recovered from milk and a standard solution. Although the RIA methods were not completely reliable because recovery from a standardized solution exceeded 100% with one method, the researchers concluded that milk T4 concentrations must be very low and had no influence on the pituitary–thyroid axis of normal babies. No difficulty was encountered with measuring serum T4 levels, which were not significantly different between breastfed and bottle-fed infants (29). Swedish investigators using RIA methods also failed to find T4 in milk (30). A second group of Swedish researchers used a gas chromatography–mass spectrometry technique to determine that the concentration of T4 in milk was <4 ng/mL (31).
Levothyroxine breast milk levels, as determined by modern laboratory techniques, are too low to protect a hypothyroid infant completely from the effects of the disease. The levels are also too low to interfere with neonatal thyroid screening programs (28). The American Academy of Pediatrics classifies levothyroxine as compatible with breastfeeding (32).
References
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