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Q1: Would more aggressive monitoring of the maternal thyroid status and fetal condition in the unsuccessful pregnancies have led to a better outcome?
A more aggressive management of maternal thyroid status is definitely expected to improve the fetal outcome. A higher incidence of congenital malformation, neonatal mortality, and low birthweight infants is seen in untreated Graves' disease.1Hyperthyroid untreated mothers had the highest incidence of fetal anomalies (6%) making it clear that treatment and monitoring is of paramount importance.1 An equal and low rate (1%) of fetal anomalies had been reported to mothers rendered euthyroid by antithyroid drugs and monitored throughout the pregnancy in comparison to euthyroid untreated mothers with Graves' disease.1 2
Q2: Is it likely that the difference in the outcome of those unsuccessful pregnancies was related to the maternal uncontrolled thyroid state or to the circulating antibody levels?
In one word it is difficult to tell which of the two, untreated thyroid status or high circulating level, is more important. To the authors it looks that both are equally important. Thyroid stimulating immunoglobulins can cross the placenta freely and can affect the developing fetus adversely. Also there is a possibility that after the definitive treatment of the hyperthyroidism with radioactive iodine the antibody titre had dropped, and this had favoured the baby.
Q3: What are the three crucial factors for the successful outcome in this case?
The three crucial factors in the above case are careful planning before conception, close supervision, and joint management.
Graves' disease diagnosed during pregnancy needs careful monitoring, maintaining an euthyroid state with TSH in the normal range. A block and replacement regimen of antithyroid drugs and thyroxine is not an option as thyroxine does not cross the placenta but antithyroid drugs do freely. For obvious reasons radioactive iodine is contraindicated in pregnancy. Therefore antithyroid drugs are the main option. The dose of antithyroid drugs should be as low as possible to keep the free thyroxine in the upper level and serum TSH in the lower level of the normal range.2 Most studies show both propylthiouracil and carbimazole can be used in pregnancy.3 4 Although propylthiouracil is preferred, especially in the United States, an advantage has not been proved. In a recently conducted study the incidence of major congenital malformations in mothers treated with propylthiouracil and carbimazole was reported to be 3% and 2.7% respectively.4 As propylthiouracil is more protein bound, it is secreted less in milk and is usually preferred during breast feeding.
Thyroid disease in pregnancy is not uncommon.
Untreated Graves' disease has unfavourable outcome both to mother and the baby.
Maternal free thyroxine should be kept in the upper normal range.
Measuring TSHRAb is important to predict neonatal hyperthyroidism.
Careful planning before conception, close supervision, and joint management is important for a successful outcome.
The situation is different when Graves' disease is diagnosed before conception. Every effort should be made to make the mother euthyroid before conception. This will obviously reduce the effect of maternal hyperthyroidism on the developing fetus. Even when the mother is clinically and biochemically euthyroid, she may have plenty of TSHRAb that can cross the placenta and affect the baby. In our patient, there was no evidence of maternal hyperthyroidism in the previous pregnancies resulting into stillbirths. It is clear from the postmortem results that stillbirths were due to intrauterine Graves' disease. TSHRAb was not monitored in the previous pregnancies.
Due consideration should be given the fetal thyroid state. The problems encountered are growth retardation, stillbirth, and fetal Graves' disease. All the four risk factors found to be associated with poor maternal-fetal outcome (maternal hyperthyroidism, a history of Graves' disease for more than 10 years, the onset of Graves' disease before the age of 20 years, and positive TSHRAb during pregnancy) were present in our patient.5 Fetal Graves' disease is suspected by growth retardation, goitre on ultrasound scan, and fetal tachycardia. It is treated by giving antithyroid drugs to the mother. In cases where the mother is euthyroid, she should be given thyroxine to prevent the development of hypothyroidism from antithyroid medication given for the fetus. The best time to perform subtotal thyroidectomy, if required, is the second trimester. In cases where radioactive iodine is given, the patient should not conceive for at least four months after the radioactive iodine.
In conclusion, untreated/unsupervised Graves' disease in pregnancy can have adverse effects on mother and baby. Our patient, who presented with juvenile hyperthyroidism initially, illustrates the importance of careful supervision of thyroid status during pregnancy, even when there is apparently no maternal problem.