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Does Hypothyroidism Increase The Risk Of Poor Neonatal Outcomes?

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Posted on Thu, 16 Jul 2015
Question: I am 9.5 weeks pregnant w twins through DE IVF. I was on 25 synthroid and 30 t3 per day up through last week when I increased to 50/day of the synthroid. My RE only ran tsh tests, which started low normal. When my tsh increased to 2.67 last week, I doubled my synthroid. My new OB decided to run my free t3 and free t4 for the first time this week and they were both extremely low. Ft4 was .6 mg/dl, which was at the very bottom of the reference range, and ft3 was 2, which was .3 below the reference range.

We understand that damage to fetal brain development occurs primarily from 6 to 8 weeks, so we are considering termination. Based on the many studies we've read, it appears fairly likely that one or both fetuses would wind up with significant cognitive impairment. Our OB is telling us not to worry, but we want the cold, hard truth so we can make an informed decision.

We appreciate your candor.
doctor
Answered by Dr. Shehzad Topiwala (47 minutes later)
Brief Answer:
Thyroid

Detailed Answer:
I follow what you are saying. The target TSH during the first trimester of pregnancy is 2.5

Your 2.67 is not much higher than that.

T3 is not recommended as a treatment for hypothyroidism ,by thyroid experts worldwide except in some very uncommon situations.

Free T4 and free T3 blood tests are also not recommended during pregnancy unless they have been systematically studied in pregnancy with reference ranges specifically during each trimester of pregnancy.

Most endocrinologists also would not be overly concerned about this mildly elevated TSH and low-appearing free T4. However I understand your concerns.

Unfortunately, there is no clear cut evidence in this domain at the present time to give you definite guidance as to whether or not termination is warranted.

So here is the current knowledge of the situation:

Regarding cognitive impairment — It is uncertain if the children of women with subclinical hypothyroidism are at risk for neuropsychological impairment. Observational studies suggest an association between subclinical hypothyroidism in pregnancy and impaired cognitive development in children. In one report of seven- to nine-year-old children, the mean intelligence quotient (IQ) score at age five years was slightly lower in 62 children whose mothers had high serum TSH concentrations (above 98th percentile for pregnancy, mean 13.2 mU/L) during the second trimester than in 124 children of mothers who had normal serum TSH concentrations (103 versus 107, p = 0.06) ; 15 percent of the former had a score of 85 or lower, as compared with 5 percent of the latter. In another study, 54 children born to mothers with mean TSH 7.81 mU/L in the first trimester (all treated with levothyroxine) had smaller hippocampal volume and lower scores on memory testing. (Hippocampus is a part of the brain)

In contrast to these findings, randomized trial data regarding neurocognitive outcomes in children of women with subclinical hypothyroidism are reassuring. As an example, in a randomized trial of screening for and treatment of thyroid dysfunction in early pregnancy, 21,846 pregnant women (gestational age 3.65 mU/L), serum free T4 below the 2.5th percentile, or both were treated with levothyroxine to achieve a TSH between 0.1 and 1.0 mU/L. Treatment was initiated in 4.6 percent of subjects at a median gestational age of 13 weeks. The majority of these patients had either an elevated TSH or a low free T4 (46 and 48 percent, respectively). In the control group, whose serum was stored until after delivery, there were similar proportions of patients with high TSH, low free T4, or both (48, 47, and 5 percent, respectively). IQ testing was performed in children of mothers in the screening and control groups who had tested positive for thyroid dysfunction. There was no difference in the IQ of the children at three years of age (100 versus 99.2). The proportions of children with IQ score <85 were 12.1 and 14.1 percent in the screening and control groups, respectively.

A difference between this randomized trial and the observational study is the fact that the mean serum TSH in the randomized trial was 3.8 mU/L , compared with 13.2 mU/L in the observational study. Thus, it is possible that the study population in the randomized trial included women with very mild hypothyroidism, where an effect of T4 therapy would be less likely to have been observed.

One limitation of the trial is that approximately 25 percent of children in each group did not complete psychological testing. In addition, it is uncertain if treatment earlier in gestation or testing of children at an older age would change the outcome. Additional randomized trials are needed to determine whether screening and treatment of subclinical hypothyroidism earlier in pregnancy (prior to 13 weeks) has any benefit on neurocognitive outcomes.

Some experts speculate that preterm delivery may explain some of the neurocognitive dysfunction (when found) in the children of women with subclinical hypothyroidism. However, an analysis of maternal thyroid function at delivery of preterm infants (born ≤34 weeks) and neurodevelopmental outcome assessed at 5.5 years of age demonstrated significant decrements in general cognition, verbal and perceptual performance subscales for each mU/L increment in maternal TSH.

Regarding your low free T4 levels ( ie Isolated maternal hypothyroxinemia) is defined as a maternal free T4 concentration in the lower 5th or 10th percentile of the reference range, in conjunction with a normal TSH. The effect of isolated maternal hypothyroxinemia on perinatal and neonatal outcome is unclear. In one study, maternal serum free T4 concentrations below the 2.5th percentile (with normal TSH) were not associated with adverse pregnancy outcomes. However, in one study, among the women with hypothyroxinemia and normal TSH (232 and 247 women in the first and second trimesters, respectively), there was an increased odds ratio for preterm labor (1.62, 95% CI 1.00-2.62), macrosomia (1.97, 95% CI 1.37-2.83), and gestational diabetes (1.70, 95% CI 1.02-2.84). In the Generation R study, maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery.

In some studies, infants and toddlers whose mothers had reduced serum free T4 concentrations (with normal TSH) during pregnancy (12 to 20 weeks) had lower mean intelligence, psychomotor, or behavioral scores compared with children born to women with normal thyroid function during gestation. As an example, in one study of 3727 mother-child pairs, the children of mothers whose free T4 was in the lowest 5 percent during the first trimester had IQ scores at six years that were 4.3 points lower than the children of mothers with higher free T4 concentrations. However, in the randomized trial described above, there was no difference in the IQ of children of mothers with low free T4 who did or did not receive T4 treatment before 20 weeks' pregnancy. Similar findings were noted in a case control study that examined children at age two years born to mothers who had second trimester free T4 levels less than 3rd centile versus those with free T4 levels between the 10th and 90th centile.
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Above answer was peer-reviewed by : Dr. Chakravarthy Mazumdar
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Answered by
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Dr. Shehzad Topiwala

Endocrinologist

Practicing since :2001

Answered : 1663 Questions

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Does Hypothyroidism Increase The Risk Of Poor Neonatal Outcomes?

Brief Answer: Thyroid Detailed Answer: I follow what you are saying. The target TSH during the first trimester of pregnancy is 2.5 Your 2.67 is not much higher than that. T3 is not recommended as a treatment for hypothyroidism ,by thyroid experts worldwide except in some very uncommon situations. Free T4 and free T3 blood tests are also not recommended during pregnancy unless they have been systematically studied in pregnancy with reference ranges specifically during each trimester of pregnancy. Most endocrinologists also would not be overly concerned about this mildly elevated TSH and low-appearing free T4. However I understand your concerns. Unfortunately, there is no clear cut evidence in this domain at the present time to give you definite guidance as to whether or not termination is warranted. So here is the current knowledge of the situation: Regarding cognitive impairment — It is uncertain if the children of women with subclinical hypothyroidism are at risk for neuropsychological impairment. Observational studies suggest an association between subclinical hypothyroidism in pregnancy and impaired cognitive development in children. In one report of seven- to nine-year-old children, the mean intelligence quotient (IQ) score at age five years was slightly lower in 62 children whose mothers had high serum TSH concentrations (above 98th percentile for pregnancy, mean 13.2 mU/L) during the second trimester than in 124 children of mothers who had normal serum TSH concentrations (103 versus 107, p = 0.06) ; 15 percent of the former had a score of 85 or lower, as compared with 5 percent of the latter. In another study, 54 children born to mothers with mean TSH 7.81 mU/L in the first trimester (all treated with levothyroxine) had smaller hippocampal volume and lower scores on memory testing. (Hippocampus is a part of the brain) In contrast to these findings, randomized trial data regarding neurocognitive outcomes in children of women with subclinical hypothyroidism are reassuring. As an example, in a randomized trial of screening for and treatment of thyroid dysfunction in early pregnancy, 21,846 pregnant women (gestational age 3.65 mU/L), serum free T4 below the 2.5th percentile, or both were treated with levothyroxine to achieve a TSH between 0.1 and 1.0 mU/L. Treatment was initiated in 4.6 percent of subjects at a median gestational age of 13 weeks. The majority of these patients had either an elevated TSH or a low free T4 (46 and 48 percent, respectively). In the control group, whose serum was stored until after delivery, there were similar proportions of patients with high TSH, low free T4, or both (48, 47, and 5 percent, respectively). IQ testing was performed in children of mothers in the screening and control groups who had tested positive for thyroid dysfunction. There was no difference in the IQ of the children at three years of age (100 versus 99.2). The proportions of children with IQ score <85 were 12.1 and 14.1 percent in the screening and control groups, respectively. A difference between this randomized trial and the observational study is the fact that the mean serum TSH in the randomized trial was 3.8 mU/L , compared with 13.2 mU/L in the observational study. Thus, it is possible that the study population in the randomized trial included women with very mild hypothyroidism, where an effect of T4 therapy would be less likely to have been observed. One limitation of the trial is that approximately 25 percent of children in each group did not complete psychological testing. In addition, it is uncertain if treatment earlier in gestation or testing of children at an older age would change the outcome. Additional randomized trials are needed to determine whether screening and treatment of subclinical hypothyroidism earlier in pregnancy (prior to 13 weeks) has any benefit on neurocognitive outcomes. Some experts speculate that preterm delivery may explain some of the neurocognitive dysfunction (when found) in the children of women with subclinical hypothyroidism. However, an analysis of maternal thyroid function at delivery of preterm infants (born ≤34 weeks) and neurodevelopmental outcome assessed at 5.5 years of age demonstrated significant decrements in general cognition, verbal and perceptual performance subscales for each mU/L increment in maternal TSH. Regarding your low free T4 levels ( ie Isolated maternal hypothyroxinemia) is defined as a maternal free T4 concentration in the lower 5th or 10th percentile of the reference range, in conjunction with a normal TSH. The effect of isolated maternal hypothyroxinemia on perinatal and neonatal outcome is unclear. In one study, maternal serum free T4 concentrations below the 2.5th percentile (with normal TSH) were not associated with adverse pregnancy outcomes. However, in one study, among the women with hypothyroxinemia and normal TSH (232 and 247 women in the first and second trimesters, respectively), there was an increased odds ratio for preterm labor (1.62, 95% CI 1.00-2.62), macrosomia (1.97, 95% CI 1.37-2.83), and gestational diabetes (1.70, 95% CI 1.02-2.84). In the Generation R study, maternal hypothyroxinemia was associated with a 2.5-fold increased risk of premature delivery. In some studies, infants and toddlers whose mothers had reduced serum free T4 concentrations (with normal TSH) during pregnancy (12 to 20 weeks) had lower mean intelligence, psychomotor, or behavioral scores compared with children born to women with normal thyroid function during gestation. As an example, in one study of 3727 mother-child pairs, the children of mothers whose free T4 was in the lowest 5 percent during the first trimester had IQ scores at six years that were 4.3 points lower than the children of mothers with higher free T4 concentrations. However, in the randomized trial described above, there was no difference in the IQ of children of mothers with low free T4 who did or did not receive T4 treatment before 20 weeks' pregnancy. Similar findings were noted in a case control study that examined children at age two years born to mothers who had second trimester free T4 levels less than 3rd centile versus those with free T4 levels between the 10th and 90th centile.