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Original Studies |
Endocrine Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, I.R. Iran
Address correspondence and requests for reprints to: Prof F. Azizi, P.O. Box 19395-4763, Tehran, I.R. Iran.
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Abstract |
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Mean ± SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 ± 4.1 to 11.6 ± 4.4 and from 20.5 ± 4.7 to 9.8 ± 1.5 when treated with 20 mg MMI. Values for FT3I decreased from 462 ± 52 to 194 ± 52 with 10 mg MMI and from 481 ± 92 to 171 ± 38 with 20 mg MMI. FT4I and FT3I were normal from the third to the twelfth months. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The lowest T4 and T3 values were 108 and 1.87 nmol/L, and the highest TSH value was 4.0 mU/L. Serum MMI levels in infants were less than 0.03 µg/mL. Six mothers receiving 20 mg MMI had increased serum TSH concentrations ranging from 26 – 135 mU/L after 1 month of treatment. Their infants were euthyroid with serum TSH values less than 2.6 mU/L. At 48–74 months of age, height, weight, FT4I, FT3I, TSH, and antithyroid antibody titers were not different than controls. The mean IQ was 107 ± 14 vs. 106 ± 16 (Goodenough test) and 103 ± 10 vs. 103 ± 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. Similarly, there was no difference in verbal and performance IQ and their components between infants of thyrotoxic lactating mothers and control children.
No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Methods |
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Selection of lactating mothers with thyrotoxicosis and control subjects
One hundred thirty-nine thyrotoxic lactating mothers and their infants were, studied. Fifty-one thyrotoxic lactating mothers were treated with 5–20 mg MMI during pregnancy and were allowed to continue taking 5 mg MMI during breast-feeding. Eighty-eight thyrotoxic lactating mothers were diagnosed as hyperthyroid within 2–8 months of delivery (24% from 3–4 and 76% from 5–8 months pospartum). Twenty-seven thyrotoxic lactating mothers (31%) had a history of thyrotoxicosis before pregnancy. All had overt symptoms and signs of thyrotoxicosis including weakness, fatigue, weight loss, nervousness, tachycardia, hyperactivity, diffuse goiter, warm and moist skin, stare, lid lag, and tremor. We excluded cases with mild symptoms and signs of thyrotoxicosis and those with T3/T4 ratio less than 20 ng/µg or a sedimentation rate of over 30 mm/h. However, we did not perform thyroid RAI uptake measurements because all mothers were breast-feeding. Therefore, definitive distinction between Graves’ hyperthyroidism and destructive thyrotoxicosis could not be made. We identified 38 normal breast-fed infants, 2–8 months of age, whose mothers were euthyroid, without acute or chronic illnesses, who had attended health maintenance clinics; blood samples had been ordered by pediatricians for different reasons not related to thyroid disease.
For evaluation of physical and neuropsychological development, we recruited 14 children of thyrotoxic lactating mothers and 17 controls between the age of 48 and 74 months. To counter the effect of parentral education and socioeconomic status, the control group consisted of children with parenetral education and socioeconomic levels close to children of thyrotoxic lactating mothers. Using the two-factor index of social position scores of Hollingshead (13), the computed scores were 28 ± 6 and 29 ± 5 (not significant) for parents of case and control groups, respectively.
Study procedures
Fifty-one women who were treated with MMI during pregnancy were allowed to continue breast-feeding, and their infants were evaluated monthly until 6 months after delivery. MMI therapy was continued until 12 months after delivery in all but one mother, and the average number of lactating months per infant while a mother was taking MMI was 11 months in this group. Of 88 thyrotoxic lactating mothers who were first diagnosed and treated after delivery, 46 mothers received 5 mg MMI twice a day during the first 2 months, and 42 mothers were given 10 mg MMI twice a day during the first month and 5 mg twice daily during the second month of therapy. All 88 mothers received a maintenance dose of 5–10 mg MMI from the third until the twelveth months after initiation of therapy. Mothers were allowed to continue breast-feeding, with supplements given to infants older than 6 months of age. The average number of lactating months per infant while a mother was taking MMI was 13 months in this group. Mothers and their infants were evaluated before and at 1, 2, 4, 8, and 12 months after initiation of MMI therapy. At each visit, symptoms of hyper- or hypothyroidism were sought and both mother and infant were examined and blood samples collected for thyroid function tests. In six infants 5–6 month of age, blood samples for MMI measurment were obtained 2 h after breast-feeding. Mothers were on 10 mg MMI twice a day and instructed to take 10 mg 2 h before breast-feeding.
Forteen children of thyrotoxic lactating mothers and 17 controls were recruited at 48–74 months of age. Histories and physical examinations were performed, and height and weight were recorded. Blood and urine samples were collected for thyroid function tests and urinary iodine measurment, respectively. The intelligence quotient (IQ) was evaluated by Wechsler Preschool and Primary School of Intelligence (WPPSI) and Goodenough tests (14, 15). WPPSI provides a full-scale score, a verbal score, and a performance score, and scores on 11 subtests. IQ tests were performed by the same psychologist, to minimize subjective interpretation of the tests. The psychologist did not know whether the children were from thyrotoxic lactating mothers treated with MMI or control children.
The study was approved by the appropriate human research review committee, and informed consent was obtained from the parents of each child.
Assay methods
Serum T4 and T3 were measured by RIA, and serum TSH by IRMA. T3-resin uptake was measured, and FT4 and FT3 indices were calculated (16). All kits were Spectria, obtained from Orion Diagnostica (Finland). We measured antithyroid peroxidase (TPO) and antithyroglobulin (Tg) antibodies by immunoenzymometric assay (Radium, Italy). The urinary iodine level was measured by a digestion method (17). Serum MMI concentration was determined using high-performance liquid chromatography with electrochemical detection (18). The sensitivity of the MMI assay was 0.03 µg/mL (263 nmol/L).
Reference ranges of serum parameters for euthyroid adult subjects are: T4, 58–167 nmol/L; T3, 1.2–3.1 nmol/L; TSH, < 0.1–5.0 mU/L; FT4I, 4.5–12.5; FT3I, 70–200; anti-TPO, < 100 IU/mL; anti-Tg, < 100 IU/mL.
Statistical analysis
Geometric means and SD are used to summarize the results. We compared continuous variables using the unpaired and paired Student’s t tests and Z test.
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Results |
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The infants of 51 mothers with thyrotoxicosis during pregnancy who were maintained on 5 mg MMI daily had normal serum T4, T3, and TSH concentrations from 1–6 months postpartum.
Table 1
demonstrates the FT4I and FT3I
values before and after MMI therapy in 46 thyrotoxic lactating mothers
first treated after delivery with 10 mg MMI daily and their infants.
After 1 month of therapy, 29 of 46 (63%) had a normal FT4I, one had a
low FT4I and an increased TSH, and 16 had an elevated FT4I. Mean FT4I
decreased from 19.4 ± 4.1 to 11.4 ± 6.4 (P
< 0.001). Two months after treatment with 10 mg MMI daily, only two
thyrotoxic lactating mothers had FT4I values above the normal range and
the mean of the FT4I had decreased to 8.7 ± 2.6. The mean FT3I
decreased from 642 ± 58 to 194 ± 52 in the first month and
to 167 ± 29 in the second month of therapy (P <
0.001). Twenty-one (46%) and six (13%) thyrotoxic lactating mothers
had elevated FT3I at 1 and 2 months of MMI treatment, respectively. All
thyrotoxic lactating mothers had normal FT4I and FT3I from the third
month up to the twelfth month after initiation of therapy. In the
infants, serum T4, T3, and TSH concentrations
before and 1 month after MMI administration to their mothers were all
within the normal range and did not change significantly over the
following month of observation: T4, 157 ± 33 vs.
154 ± 24 nmol/L; T3, 3.04 ± 0.29 vs.
2.96 ± 0.25 nmol/L; and TSH 1.6 ± 0.7 vs.
1.5 ± 0.8 mU/L, before and after MMI treatment, respectively
(Fig. 1). The lowest serum T4
and T3 concentrations in the MMI group were 122 and 1.83
nmol/L, respectively, and the highest TSH concentration was 3.6
mU/L.
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). By the
end of the first month of therapy, seven patients had abnormal thyroid
function tests: in one patient the serum T4 was 174 and
T3 was 3.99 nmol/L; and in one patient the serum
T4 was normal and the serum T3 elevated to 3.76
nmol/L; and five thyrotoxic lactating mothers had increased serum TSH
and decreased FT4I (Table 2). The dose of
MMI was appropriately adjusted and the serum FT4I, FT3I, and TSH
concentrations remained within the normal range in all thyrotoxic
lactating mothers until 1 yr after the onset of MMI treatment. Serum
T4, T3, and TSH concentrations in 42 breast-fed
infants 1 month after maternal MMI therapy with 20 mg daily were all
within normal limits. The values were: T4, 152 ± 19
and 148 ± 24 nmol/L; T3, 3.11 ± 0.29 and
3.04 ± 0.32 nmol/L; and TSH, 1.8 ± 1.4 and 2.4 ± 1.9
mU/L, before and after MMI therapy of their mothers, respectively (Fig. 1). The lowest serum T4, T3, and the highest
TSH concentrations in this group were 108 nmol/L, 1.87 nmol/L, and 4.0
mU/L, respectively. The serum MMI level in all six infants was less
than 0.03 µg/mL (293 nmol/L), 2 h after they were
breast-fed.
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Six thyrotoxic lactating mothers had low serum T4 and
high serum TSH concentrations 1 month after MMI therapy (five receiving
20 mg and one receiving 10 mg daily). Only two mothers complained of
weight gain and weakness. Serum T4, T3, and TSH
concentrations in all six infants were in the normal range (Table 2).
All six mothers required MMI at reduced doses until the end of 12
months of therapy.
Two mothers continued 20 mg/day MMI for 2 months. The serum T4, T3, and TSH serum concentrations in their infants were 9.8 and 10 µg/dL, 200 and 230 ng/dL, and 2.8 and 3.2 mU/L, respectively.
Psychological testing in the children
There was no significant difference in age, sex, height, weight, serum T4, T3, and TSH and urinary iodine concentrations and anti-Tg and anti-TPO titers between 14 children of thyrotoxic lactating mothers and 17 control children. Individual values for all children were within the normal range (only one child in the control group had an elevated anti-TPO level of 150 IU/mL). Information concerning parental education, socioeconomic status, number of sibilings, and number of hours spent for sports and outdoor activities were similar in both groups.
Table 3 shows the results of IQ
scores with Goodenough and Wechsler tests. There were no significant
differences in full-scale, verbal, and performance IQ scores between
children of thyrotoxic lactating mothers and those from the control
group. Subscales of verbal and performance IQ scores are shown in Fig. 2. Scores in all subsets of verbal IQ (information,
vocabulary, mathematics, similarities, comprehension, and sentences)
and performance IQ (animal house, picture completion, mazes,
geometric design, and block design) were similar in both groups of
children.
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Discussion |
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More than 50 yr ago, it was reported that the concentration of thiouracil in milk was three times higher than the plasma concentration (19). These data were extended by inference to the newer antithyroid drugs, propylthiouracil (introduced in 1946) and MMI (introduced in 1949), and for many decades the use of antithyroid drugs for the treatment of thyrotoxicosis in breast-feeding mothers was abandoned (1, 20). Women taking either of these drugs were advised by their physicians not to breast-feed for the fear of causing hypothyroidism in the infant. In 1979, Low et al. (2), and in 1980, Kampmann et al. (5), reported that less than 0.1% of the administered dose of propylthiouracil was detected in the milk of lactating women. Since these observations, there have been a few reports describing the use of propylthiouracil in the treatment of thyrotoxicosis in breast-feeding mothers (5, 6, 7, 8). A total of 15 infants have had normal thyroid function tests while their mothers were being treated with 50–300 mg propilthiouracil daily.
There has been more scepticism in the use of MMI and carbimazole during breast-feeding, because studies of excretion of these compounds in the milk have demonstrated a milk to plasma drug ratio of approximately 1 (3, 4). It is estimated that after a single dose of 40 mg MMI the breast-fed infant may receive as much as 70 µg MMI, an amount that could theoretically affect the infant’s thyroid function (7). However, Lamberg et al. (11) reported 11 infants whose mothers were treated with carbimazole in dosages ranging from 5–15 mg daily during pregnancy and were permitted to breast-feed after delivery. All 11 newborns had normal serum TSH and T4 concentrations during the 3 weeks of study, and two infants continued to have normal values at 3 and 4 months of age during continued breast-feeding. The dose of carbimazole used in this study was equivalent to 3.3–10 mg MMI daily. We have previously reported that in 35 infants of lactating mothers with thyrotoxicosis who were receiving 5–20 mg MMI daily, serum concentrations of T4, T3, and TSH were within the normal range 1 month after the initiation of therapy (12). Thyroid function tests in the six breast-fed infants whose mothers were receiving 20 mg MMI daily for the first month, 10 mg for the second month, and 5 mg for an additional 4 months remained within normal range.
In the present study, we have extended our experience in a larger number of lactating mothers with thyrotoxicosis treated with MMI and their breast-feeding infants. We have observed that MMI treatment of 88 lactating women, who developed thyrotoxicosis 2–8 months after delivery, for 1 yr does not cause alterations in thyroid function of their infants. Of interest are the results of thyroid function tests in infants whose mothers had biochemical evidence of hypothyroidism 1 month after MMI treatment. Serum T4, T3, and TSH concentrations remained within the normal range in all six children while their mothers had marked increase in serum TSH concentrations.
It has been shown that mean peak milk MMI concentrations after a dose of 40 mg is 0.72 ± 0.07 µg/mL at 1 h (4) and following a 15-mg dose is 0.32 ± 0.1 µg/mL at 2 h (21). The half-life of MMI in milk is 4.2 ± 0.8 h, and the mean MMI concentration decreases to 0.03 ± 0.01 µg/mL after 12 h. From the available data (4, 7, 21), it can be calculated that following a 20-mg dose of MMI, the infant may receive approximately 35 µg MMI. This amounts to 5 µg/kg for a 5-month-old infant weighing 7 kg (or 350 µg MMI in a 70-kg man). Therefore, it is not surprising that in the present study the serum MMI levels in the infants were less than 0.03 µg/mL.
The administration of a low-dose of 10 mg MMI daily resulted in normalization of thyroid function for most of the thyrotoxic mothers after 1 month of therapy. This finding is in agreement with our previous observations that thyrotoxic patients in Iran respond well to lower doses of both MMI and propylthiouracil (22, 23). We have suggested that environmental iodine intake may affect the response to antithyroid drugs. Others have also reported that euthyroidism can be achieved by low-dose MMI treatment in thyrotoxic patients, although the control of hyperthyroidism is slower in comparison with larger doses (24).
We have also shown that physical growth, thyroid function, and IQ scores are similiar in children whose mothers received MMI while breast-feeding compared with control children between 48 and 74 months of age. However, due to small sample size in both groups, we can not conclude with certainity that no differences between two groups exist. It is of interest that IQ scores in all children whose mothers received MMI while breast feeding are within the normal range of 91–130, that was observed in 73 Tehranian schoolchildren tested by our group in another study (25).
Thyroid hormone is essential for brain development during intrauterine life and brain function after birth. It plays important roles in neurogenesis, neuronal migration, axon and dendrite formation, myelination, synaptogenesis, and the regulation of specific neurotransmitters (26, 27). Therefore, lack of thyroid hormone any time from midgestation through the first few years of life may disturb neural connectivity and reduce the capability of neural transmission, affecting intellectual function and mental processes. The integrity of the hypothalamic-pituitary-thyroid axis in both mother and fetus during pregnancy and that of the newborn during the first 2 yr of life is of great importance. Subtle but important alterations in neuropsychological development have been reported in children born of mothers with undiagnosed hypothyroidism during pregnancy (28) and in children who were diagnosed with congenital hypothyroidism by screening programs and treated within the first 2 months of life (29). In addition, it has been suggested that transient neonatal hyperthyrotropinemia may adversely affect long-term intellectual development, at least in iodine-deficient regions (30) (Azizi, F., M. Afkhami, A. Sarshar, M. Nafarabadi, submitted for publication). Therefore, normal thyroid function and an unaltered IQ score and its subscales in children of MMI-treated thyrotoxic lactating mothers suggest that the use of MMI during breast-feeding did not cause thyroid dysfunction during the neonatal period and that subsequent preformance on neuropsychological tests remained normal.
On the basis of the present findings and other reports in the current literature, we conclude that both propylthiouracil and MMI can be safely administered during lactation. However, the potential risk of thyroid dysfunction in rare instances may exist, and careful monitoring of both mother and infant must be carried out. Serum T4 and TSH determinations every 4 weeks while the thyrotoxic lactating mothers are taking initial doses of an antithyroid drug is reasonable.
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Acknowledgments |
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Received January 24, 2000.
Revised May 12, 2000.
Accepted June 5, 2000.
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References |
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), and in 17 controls (
). There is no statistical difference in
the subsets of verbal IQ (A) and perfomance IQ (B) between the two
groups.