Opposite Variations in Maternal and Neonatal Thyroid Function ...

Whereas the consequences of extremes in iodine intake are well described, much less is known about the effect of more moderate variations in maternal iodine intake on fetal thyroid function. The present study performed in Denmark with mild to moderate iodine deficiency dealt with the effect of maternal iodine supplementation on thyroid function in the mother at term and in the fetus/neonate. Serum was collected consecutively from pregnant women at term (n = 144) and from cord blood (n = 139). Forty-nine women had a regular intake of vitamin and mineral tablets with iodine (150 μg/day) during pregnancy, and 95 took no artificial iodine supplementation. Iodine supplementation (+I) induced opposite variations in thyroid function in the mother and the fetus. In +I mothers, TSH was 7.6% lower than in mothers with no supplementation (P < 0.05). In cord blood, on the contrary, TSH was 27.3% higher in the +I group (P < 0.05). The variations were caused by opposite shifts in TSH frequency distribution in mothers and neonates. The association between iodine supplementation and high serum TSH in the neonates was further substantiated by an inverse correlation between thyroglobulin and TSH in cord blood (P < 0.001), whereas no specific pattern was observed in the mothers. High serum thyroglobulin was a marker of low iodine intake in both mothers and neonates. The results suggest that the fetal thyroid, at least in areas of mild iodine deficiency, is more sensitive to the inhibitory effect of iodine than hitherto anticipated.
IODINE IS AN essential component of thyroid hormones, and the normal function of the thyroid gland, as well as the tendency to develop abnormalities in thyroid gland function and structure, depends greatly on the iodine intake of the subject (1–3). Both low and high iodine intake levels may lead to disease. This is particularly observed in the fetus, where, on the one hand, severe iodine deficiency of the mother may lead to insufficient thyroid hormone synthesis in both the mother and fetus and may be accompanied by developmental brain injury (4). On the other hand, excess iodine given to the mother may block thyroid function in the fetus, leading to hypothyroidism and goiter (5, 6).
Whereas the consequences of extremes in iodine intake are well described, much less is known about the effect of more moderate variations in maternal iodine intake on fetal thyroid function. In Denmark, the basic iodine intake corresponds to mild to moderate iodine deficiency (7–9), as also found in many other European countries (10). The present study dealt with the effect of maternal iodine supplementation, taken as iodine-containing vitamin/mineral tablets (150 μg iodine/tablet), on thyroid function in the mother at term and in the fetus/neonate evaluated by cord blood analyses. The study revealed a diverse effect of iodine, with facilitated thyroid function in the mother and inhibited thyroid function in the child.
Materials and Methods
Healthy pregnant women with no previous history of thyroid disease were consecutively recruited when admitted for delivery in departments of obstetrics in 5 different regions of Denmark (Aarhus, Randers, Aalborg, Copenhagen, and Ringkoebing). Approximately 30 women were studied in each region (total n = 152). The vitamin and mineral supplementation during pregnancy was recorded, with special care being taken to obtain information on the iodine content of supplements. Women with a regular daily intake of a multivitamin and mineral tablet containing iodine (150 μg) during pregnancy (+I = iodine group; n = 50) and women with no artificial iodine supplementation (no I = no iodine group; n = 96) continued in this study, whereas women who had a history of intermittent iodine supplementation (n = 6) were excluded. The participants were instructed to continue their previous vitamin and mineral supplementation during the puerperal period, and urinary iodine was measured in a spot urine sample on day 5 after delivery. The median urinary iodine concentration was 60 μg/L (57.5 μg/g creatinine) in the +I group and 34.5 μg/L (39 μg/g creatinine) in the no I group. Notably, these values are influenced by the start of lactation during the period of sampling, as previously discussed (8). All of the mothers breast-fed their children during at least the puerperal period. Iodine was measured in urine collected from the neonates on day 5 as previously described (9). The median urinary iodine concentration in the neonates was 63 μg/L in the +I group and 31 μg/L in the no I group.
The age and parity of the mothers in relation to iodine supplementation are presented in Table 1. There were no statistically significant differences between the +I group and the no I group.
Table 1.
Parity and age of the women and gestational age and birth weight of the neonates
Blood samples (n = 144 available) were taken from the mothers by standard puncture of a cubital vein shortly after admission for labor. Closure of the umbilical cord was performed within the first minute after delivery, and mixed cord blood (n = 139) was sampled from the placental part immediately after. In one cord blood sample the amount of serum was limited, which precluded some of the analyses. Blood samples were centrifuged shortly after sampling, and serum was stored at −20 C until analysis.
Reagents for measurements of total T4 (RIA; reference range, 60–140 nmol/L), total T3 (RIA; 1.2–2.7 nmol/L), and T3 uptake test (T3 test; 0.8–1.2) were supplied by Farmos (Turko, Finland). TSH was measured by an immunoluminometric assay (Berilux, Behring Werke, Marburg, Germany; detection limit, 0.01 mU/L; reference range, 0.40–4.0 mU/L) as previously described (11), and free T4 was determined by a two-step method (RIA-gnost-FT4, Behring Werke; reference range, 9–24 pmol/L). Thyroglobulin antibodies (Tg-ab) were measured by a very sensitive radioimmunoprecipitation assay (detection limit, 20 U/L; Medical Research Council standard reference code A 65193) (12), and thyroglobulin (Tg) was determined by an immunoluminometric assay (Behring Werke; detection limit, <1 μg/L), including recovery measurement. Because Tg-ab may influence Tg values (13, 14), Tg values from samples with Tg-ab values more than 200 U/L (mothers, n = 1; cord blood, n = 2) were excluded. Tg-ab levels below 200 U/L have previously been found not to interfere with Tg measurement using this assay (2). In all assays, samples from the +I group and the no I group were combined in random order. Samples from a mother and child pair were measured in the same assay. Iodine in urine was measured in duplicate by the cerium/arsenic method, after alkaline ashing, by a modification of the method of Wilson and van Zyl (15). Recovery of added 127I and 125I was more than 95% and was not corrected for.
The statistical package of social sciences (SPSS, Inc., Chicago, IL) was used to calculate median, 25–75% percentiles, and range for testing differences between groups (Mann-Whitney rank test and Fisher’s exact test) and for correlation (Spearman test). A 5% level of statistical significance was used. The protocol was reviewed and approved by the local ethical committees.
Results
Thyroid hormone levels in maternal serum collected shortly before delivery and in serum from cord blood are shown in Table 2. The mothers in the +I group had a 7.6 lower serum TSH, a higher free T4, and a lower serum Tg than the mothers in the no I group. The neonates showed a pattern different from that of the mothers. Overall, serum TSH was higher, T3 was lower, and free T4 and Tg were higher in the neonates than those in the mothers. In contrast to the mothers, the +I group of neonates had a 27.3% higher serum TSH level than the no I group. The variations in free T4 and Tg in relation to iodine supplementation were similar to those observed in the mothers. When the T3/T4 ratios in individual samples were calculated, no significant differences between the +I group and the no I group were observed in the mothers and the neonates.
Table 2.
Iodine supplementation and thyroid parameters in mothers and in cord blood
The opposite variations in serum TSH in mothers and neonates are further depicted in Fig. 1 showing the frequency distributions of TSH in relation to iodine supplementation. The iodine-supplemented group was shifted to the left in the mothers and to the right in the neonates, e.g. a serum TSH below 1 mU/L was nearly twice as common in iodine-supplemented mothers as in non-supplemented mothers, whereas the frequency of TSH levels below 5 mU/L in neonates from iodine-supplemented mothers was less than half that in neonates from non-supplemented mothers. Correspondingly, a TSH level greater than 10 mU/L was found in 41% of the neonates from the+ I group vs. 31% from the no I group. Although some of the TSH values were outside the reference range, all individuals had normal thyroid hormone values, and no evidence of overt thyroid dysfunction was found.
Frequency distribution of serum TSH values in mothers and neonates in relation to iodine supplementation during pregnancy.
The association between iodine supplementation and high serum TSH in the neonates was further substantiated by the inverse correlation between Tg and TSH in cord blood (Spearman’s r = −0.25; P < 0.001) shown in Fig. 2a. In contrast, no specific pattern was observed in the mothers (Spearman’s r = 0.017; P = 0.84; Fig. 2b). Neonates with high serum TSH levels had, in general, low serum Tg levels. Figure 3 shows the inverse correlation between iodine in urine in the newborns and Tg in cord blood (Spearman’s r = −0.41; P < 0.001), demonstrating the role of high serum Tg as a marker of low iodine intake. Serum Tg was nearly twice as high in the no iodine group as in the iodine-supplemented group (Table 2), and a positive correlation was observed between Tg in mothers and neonates (Spearman’s r= 0.44; P < 0.001; Fig. 4).
A small subset of the mothers investigated had Tg antibodies in serum. In general, the measured antibody levels were higher in cord serum, leading to twice as many serum values above the level of detection (Table 2). No differences related to iodine supplementation were observed, nor was there any difference in gestational age and birth weight between neonates from the two groups (Table 1).
Discussion
The pregnant women participating in the present study had been recommended to take vitamin and mineral supplementation as part of normal pregnancy care, and more than 90% of the women had followed this advise. The recommendation did not include the iodine content of the tablets, and more or less by chance approximately one third of the women investigated had taken tablets with 150 μg iodine, whereas the rest had taken tablets without iodine. Apart from the differences related to iodine intake, no basic differences between the two groups of mothers were observed.
Iodine supplementation was associated with variations in maternal thyroid function similar to those previously observed by us (16) and by Glinoer et al. in a study from Belgium (17). There was a slightly lower TSH, a slightly higher free T4, and a much lower serum Tg in mothers receiving iodine. This pattern is in accordance with the conclusions drawn from the previous studies also performed in areas of mild iodine deficiency. A relative lack of iodine during pregnancy leads to a slightly impaired synthesis of thyroid hormones and a compensatory increase in serum TSH. The variation is normalized by iodine supplementation. Similar, although more profound, abnormalities, which are also corrected by iodine supplementation, have been observed in pregnant women living in areas with more severe iodine deficiency (18, 19).
Surprisingly, we observed a very different pattern in cord blood. Iodine-supplemented mothers gave birth to neonates with a nearly 30% higher serum TSH, not a lower serum TSH as in the mothers. Generally, there was an opposite shift in the distribution of TSH in mothers and neonates after iodine supplementation. This points to an inhibitory effect of the iodine on fetal thyroid function as opposed to the facilitating effect in the mother.
The difference between the mother and the fetus was further substantiated by the correlation between TSH and Tg in samples. Although no specific pattern was observed in the mothers, there was a clearly negative correlation in cord blood samples. This means that cord sera with high TSH did not have high Tg levels, which is a marker of iodine deficiency. On the contrary, they had low Tg levels. Low Tg levels in serum were found to correlate to a high iodine intake in both the neonate and the mother, and this has also been shown in many other studies (16, 17).
Iodine has an inhibitory action on many processes in the thyroid gland (20). The results indicate that the fetal thyroid is more susceptible to such iodine inhibition than the adult thyroid. A similar difference between dam and offspring has been demonstrated experimentally in the rat by Theodoropoulos et al. (6). In humans such a difference has been demonstrated repeatedly when larger amounts of iodine are given to the mother (20). A special case is the use of iodine in vaginal disinfectants in pregnancy or before labor. This may induce transient hypothyroidism in the neonate despite normal thyroid function of the mother (21–23).
The high TSH level in iodine-supplemented neonates was not paralleled by major alterations in serum T4 and T3. In general, this was not expected, as variations in serum TSH are normally much larger than the corresponding changes in serum concentrations of thyroid hormones. Due to the balance of pituitary/thyroid feedback regulation, levels of thyroid hormones responsible for the increase in TSH in cord blood should be only slightly suppressed. The results of our study suggest that the peripheral thyroid hormone responsible for the increase in serum TSH was T3, which tended to be lower in the iodine-supplemented group. T4 in cord serum was slightly increased after iodine supplementation, which may be secondary to a higher iodine supply for thyroid hormone synthesis (24) and to the increase in TSH. The mechanism of TSH regulation around the time of delivery is only partly known (4). In general, the neonatal period is characterized by a rapid increase in serum T3 and serum TSH. Notably, exactly similar variations in TSH, T4, and T3 were observed in a study from China on children with normal and with high iodine intake due to differences in the iodine content of drinking water (25). Children with high iodine intake had higher serum TSH, higher serum T4, and slightly lower serum T3 levels.
Our previous study of iodine supplementation in pregnancy included a considerably smaller number of subjects (16). There was no significant effect of iodine on cord blood TSH. The supplementation study performed by Glinoer et al. included 180 pregnant women. The average serum TSH level in cord blood was 14% higher after iodine supplementation, but the difference was not statistically significant (17). Notably, iodine supplementation induced a significant fall in serum TSH in the mothers in both studies, supporting the present conclusion of a different outcome in mothers and neonates.
The results of the present study suggest that iodine supplementation of the mother will, in general, not improve fetal thyroid function in areas such as Denmark with mild iodine deficiency. A slight inhibitory effect may be expected, which is probably not of clinical significance. It should be stressed that in areas of severe iodine deficiency, iodine supplementation of pregnant women is of uttermost importance to protect fetal brain development (19, 26).
The above conclusion is somewhat in contrast to the findings of studies suggesting that a high frequency of elevated serum TSH found by screening in neonates can be used as an indicator of iodine deficiency (27, 28). Probably the areas studied have been more iodine deficient than ours were. Moreover, we obtained data from a limited number of subjects compared to neonatal screening programs, which may identify more outliers. Another notable difference is that we studied variations in cord blood, whereas neonatal screening for hypothyroidism is most often performed around day 5 after birth. Finally, it should be considered whether some of the cases of transient TSH elevation observed in iodine- deficient areas might have been due to iodine excess from, for example, the use of iodine-containing disinfectants in the mothers. In one study from Hamburg, iodine contamination during perinatal life was found in 17.6% of 79,871 neonates (29), and iodine contamination has been found to be a very frequent cause of transient neonatal hypothyroidism in some areas with low basic iodine intake (30–32). The iodine load to the mother has mainly been due to iodine-containing vaginal disinfectants, which are, in general, not used in Denmark.
Even if the present study gives no evidence of improved neonatal thyroid function after iodine supplementation to pregnant women in areas of mild iodine deficiency, adequate iodine intake during pregnancy is important, because the consequences of iodine deficiency for brain development are severe (4). The results of the present study cover only the immediate perinatal period, and iodine supplementation may well be important during other parts of fetal and postnatal life. Iodine intake may vary over time and between subjects, and a population intake level near the lower limit of safety may put some neonates at risk, even if not observed in the present study. Furthermore, the inhibitory effect of an iodine load on fetal and neonatal thyroid function seems to be much lower in populations with an iodine intake corresponding to recommended levels (33).
In conclusion, we observed that moderate iodine supplement during pregnancy facilitated thyroid function in the mothers, but inhibited thyroid function in the neonates. The results suggest that the fetal thyroid, at least in areas of mild iodine deficiency, is more sensitive to the inhibitory effect of iodine than hitherto anticipated.
This work was supported by the Music Publishers Agnes and Knut Mørks Foundation.
1
Laurberg
P
,
Pedersen
KM
,
Vestergaard
H
, Sigurdsson G.
1991
High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland.