Hyperthyroidism (hyperthyroidism) is a group of autoimmune diseases that seriously affects pregnancy, with a prevalence of 0.1% to 1% during pregnancy, and can cause various adverse pregnancy outcomes, such as miscarriage, preterm delivery, intrauterine dysplasia and neonatal hyperthyroidism. In recent years, several societies have issued guidelines for the management of thyroid disorders in pregnancy, providing clinicians with more evidence for the treatment of thyroid disorders. However, because of the complexity of hyperthyroidism in pregnancy, its treatment is still controversial among different scholars and research groups.
Anti-thyroid drugs (ATDs) have been the treatment of choice for hyperthyroidism in pregnancy since their use in the 1940s. There are no randomized controlled studies of interventional treatment with ATDs for hyperthyroidism in pregnancy, but previous data suggest that carbimazole (CBZ), methimazole (MMI), and propylthiouracil (PTU) are close in efficacy in controlling hyperthyroidism in pregnancy. Therefore, the selection of ATDs in pregnancy is based more on the adverse effects of the drugs and the long-term effects on pregnancy outcomes, especially teratogenicity and severe hepatotoxicity. In this article, we discuss the selection and use of ATDs in pregnancy with regard to their adverse effects.
ATDs can cross the placenta
All ATDs are transmissible to the placenta and therefore carry similar risks, such as teratogenicity, effects on fetal thyroid development and function, and even hepatotoxicity, so various guidelines recommend the use of low doses of ATDs during pregnancy. In 1977, an in vivo trial of only seven pregnant women confirmed that PTU crossed the placenta in smaller amounts compared to CBZ/MMI. This is the only in vivo test to date, and subsequent animal studies have confirmed these findings. Traditionally, this is thought to be related to the fact that PTU binds more tightly to serum albumin than CBZ/MMI, and therefore theoretically transduces relatively less through the placenta. However, the transmission of CBZ/MMI and PTU through the placenta is not entirely protein-dependent. Some in vitro experiments have shown that CBZ/MMI and PTU are very similar to each other in full-term pregnancy. For pregnant women on PT therapy, the levels of PTU in cord blood are higher than maternal concentrations until full term. Furthermore, no differences in cord blood thyroid hormone and thyrotropin (TSH) concentrations have been found between mothers on PTU and CBZ/MMI at the time of delivery. In conclusion, the ability of PTU and CBZ/MMI to cross the placenta in late gestation may be similar, and it is not known which is more likely to cross the placenta in early gestation.
Adverse effects of ATDs
1. Teratogenicity
The teratogenicity of ATDs is still controversial because hyperthyroidism itself can cause congenital developmental abnormalities, especially cardiovascular and renal malformations. In 2008, a Japanese study showed that in a retrospective analysis of 2,137 pregnant women with hyperthyroidism in early pregnancy, the percentage of fetuses with hip dysplasia was as high as 20% and the percentage of fetuses with vomiting in pregnancy was as high as 12.8%. Therefore, the investigators concluded that women with Graves’ disease and vomiting in early pregnancy should be screened for fetal breech abnormalities. In addition, recent studies have shown that the overall prevalence of congenital malformations is not associated with thyroid status in early pregnancy.
As early as 1972, congenital hypoplasia of the fetal scalp (scalp defects) in early gestation caused by MMI has been observed. In fact, scalp hypoplasia may also be familial or spontaneous and is relatively rare in the absence of exogenous teratogenic agents, at 0.03%. In contrast, the prevalence of scalp rupture was significantly higher in newborns born after mothers were treated for MMI during gestation, which seems to indirectly prove the correlation between MMI and congenital scalp rupture. In addition, posterior nasal foramen atresia, tracheoesophageal fistula, gastrointestinal malformations (especially esophageal atresia), unclosed vitelline duct, umbilical hernia, nipple agenesis, developmental delay, and hearing loss have also been shown to be associated with CBZ/MMI use. However, these adverse effects were not seen in patients treated with PTU, suggesting a higher specificity of CBZ/MMI with embryonic developmental abnormalities. an analysis of 31 cases of embryonic developmental abnormalities due to CBZ/MMI reported in the literature by Bowman et al. found that such adverse effects were not significantly correlated with drug dose and maternal thyroid function levels, but neonatal perinatal mortality and preterm birth rates were significantly higher .
In 2010, Clementi et al. analyzed more than 18,000 cases of congenital malformations, 137 of which were associated with early gestational use of CBZ/MMI, which was associated with congenital postnasal foramen There was a strong association between atresia and umbilical hernia, which is consistent with the results of numerous other studies with smaller samples. In addition, this study found that PTU may be associated with visceral transposition, cardiac outflow tract defects, unilateral renal hypoplasia, and infertility, but in a smaller number of cases. More recently, a study from Japan comparing 1426 MMI-treated, 1578 PTU-treated, and 2065 normal pregnancies found a significantly higher rate of neonatal malformations in the MMI-treated group of 4.1% than in the PTU and control groups, with no difference between the latter two.
Overall, the current study data suggest that the correlation between CBZ/MMI and congenital malformations is high and that PTU has fewer such adverse effects. However, since the treatment rate of PTU in pregnancy is not as high as that of MMI, and PTU has been found to be more teratogenic to embryos in murine studies, and cases of scalp defects due to PTU have been reported in the past, the clinical use of PTU still needs to be kept vigilant.
2. Severe liver injury
Hepatic adverse reactions caused by PTU are more common and more serious than those caused by CBZ/MMI, which are mainly due to cholestasis, while PTU is associated with toxic hepatitis. In fact, the serious hepatotoxicity of PTU has received widespread attention after two meetings of the American Thyroid Association (ATA) and the Food and Drug Administration (FDA) in 2009. the FDA Adverse Reaction Reporting System database shows that 22 adults and 12 children have developed serious liver injury after PTU use in the past 20 years, and five of these adults and six of these children have undergone liver transplants. In addition, according to the United Network for Organ Sharing, from October 1987 to December 2007, 661 patients received liver transplants for drug-induced acute liver failure, and nearly 3% of these patients were due to PTU, which ranked fourth among all drugs causing liver transplants in children. Although a similar phenomenon was not found in some areas, the FDA classified PTU as a black box warning drug in 2010 based on the severity of the condition, and clinicians should closely evaluate its risk.
More importantly, liver failure due to PTU is unique in that its occurrence is difficult to predict because it is not significantly correlated with age, drug dose, or thyroid hormone levels at initial diagnosis. The relatively high rate of occurrence in women compared to men (male to female ratio of 1/8.3) may be related to the prevalence of hyperthyroidism in women and the subsequent increased use of PTU therapy. The need for routine and regular liver function testing in pregnant women is still controversial. Regular liver function tests may increase maternal anxiety and decrease patient compliance, and even if elevated liver enzymes occur after taking PTU, they often decrease or remain unchanged if the drug is continued. In addition, severe hepatotoxicity occurs rapidly and is often not detected in time by ordinary routine review.
Fortunately, severe liver failure due to PTU is relatively rare. It is estimated that about 0.1% of pregnant women in the United States may have severe liver injury with PTU. A total of 7 cases of toxic hepatitis due to PTU treatment during pregnancy have been reported in the literature, with 1 maternal death, 2 cases requiring liver transplantation, 2 cases of fetal death, 1 case of fetal developmental delay, and 1 case of neonatal hepatitis in a fetus after PTU use in a pregnant woman. Therefore, many scholars believe that the overall prognosis of PTU use in pregnant women with hepatotoxicity is poor, and even more so in fetuses.
3. Granulocyte deficiency
The most common adverse effects of ATDs are rash, gastrointestinal reactions and taste changes, which can also lead to granulocyte deficiency. Although more severe, granulocyte deficiency due to ATDs use during pregnancy is relatively rare compared to older adults, which may be related to the low dose of ATDs during pregnancy. A review of previous reports of granulocyte deficiency due to ATDs during pregnancy found that most of them were secondary to PTU therapy, which may be related to the increase in recommendations for PTU therapy during pregnancy in recent years.
Once granulocyte deficiency has occurred, it should be discontinued immediately and a complete blood count should be monitored and prophylactic antibiotics administered if necessary. Granulocyte colony-stimulating factor (GCSF) can help shorten the recovery period of granulocyte deficiency, but there are no rigorous controlled studies of its use in pregnant women. It has been found that miscarriage, stillbirth, abnormal offspring development, and amniotic fluid embolism in pregnant rabbits may be associated with GCSF. Although the risk of congenital malformations, etc., has not been confirmed for GCSF, human studies have shown that GCSF can cross the human placenta. Therefore, most scholars still recommend that GCSF should only be administered to pregnant women if the potential benefits of GCSF outweigh the potential risks to the fetus. GCSF treatment should only be given if the potential benefits of GCSF outweigh the potential risks to the fetus. In addition, there have been case reports of PTU being associated with the development of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis during pregnancy, which recovered after switching to MMI.
4. Effects on the fetal thyroid
Both CBZ/MMI and PTU have long been known to cause the development of fetal hypothyroidism and goiter. A 2012 systematic review study found no difference in the prevalence of neonatal hypothyroidism in pregnant women with hyperthyroidism treated with PTU compared to those treated with MMI. Therefore, overall, maintaining appropriate maternal thyroid hormone levels is more important than the choice of ATDs.
Use of ATDs during lactation
In general, CBZ/MMI is more appropriate for use during lactation due to the longer retention time of PTU and its risk of hepatotoxicity. 2012 ATA guidelines recommend that the dose of MMI should not exceed 20-30 mg/d and the dose of PTU should be less than 300 mg/d for breastfeeding female patients, which does not significantly affect infant thyroid function. For breastfeeding female patients taking ATDs, the infant should be screened for thyroid function and should be breastfed 3 to 4 h after dosing.
Strategies for the use of ATDs during pregnancy
In recent years, both the ATA and the American Association of Endocrinologists have recommended that PTU be used in early pregnancy and switched to CBZ/MMI by midterm, with thyroid function reviewed every 2 to 4 weeks after medication change. The reason for this is that this regimen reduces both the risk of congenital malformations that may be caused by CBZ/MMI and the serious liver injury caused by PTU, but there are still more controversial points. First, further studies are needed to determine when to change PTU to CBZ/MMI because fetal organ development is still incomplete by mid-gestation. Second, this regimen has not been confirmed by well-designed controlled clinical studies, and there are no data to show that it is effective in reducing PTU-induced hepatitis and CBZ/MMI-induced embryonic developmental abnormalities, and its effectiveness and utility remain unclear. Finally, this drug exchange regimen may cause dosing errors or lead to patient forgetfulness, negligence and poor compliance due to the cumbersome process, which in turn may be detrimental to thyroid function stability. Therefore, guidelines published by the ATA and the American Association of Clinical Endocrinologists in 2011 suggest that if PTU is used in early pregnancy without adverse effects, a switch to CBZ/MMI may not be necessary thereafter. The choice of medication for the lactation period remains controversial.
It is still unclear what treatment options are most appropriate for women with hyperthyroidism who are preparing to become pregnant. The latest ATA guidelines recommend taking CBZ/MMI to control thyroid function before pregnancy and switching to PTU only when pregnancy is diagnosed, but some scholars believe that the switch to PTU may increase the risk of CBZ/MMI, considering that patients may be negligent in changing medications and already taking CBZ/MMI at the first prenatal follow-up visit. Therefore, some patients who are ready to become pregnant in the short term and are treated with CBZ/MMI may be directly switched to PTU therapy. In the face of these controversies, more well-designed clinical studies are still needed to further clarify their effectiveness and safety.