To our knowledge, no other studies have compared the clinical features and TB treatment outcome among pregnant women after IVF-ET and naturally pregant women. In this study, we observed similar baseline characteristics (such as: age, TB history, history of BCG vaccination, contact history of TB, education level, HBsAg positive and HCV antibody positive) of pregnant women with tuberculosis after in vitro fertilization and embryo transfer (IVF-ET) and natural pregnancy. The onset period of patients with IVF-ET was earlier than the time of patients with natural fertilization (115th vs. 147th, p>0.05).
Generally speaking, TB symptoms during pregnancy were not much different from those of non-pregnancy TB. Cough, cough with phlegm and fever are still the main clinical manifestations. But we found the incidents of fever among pregnant women with IVF-ET was significantly higher than that among pregnant women with natural fertilization, which suggests that pregnant women with tuberculosis after IVF-ET are more likely to have systemic symptoms (tuberculosis toxemia).
During pregnancy, the mother uses a complex network of hormones, immune cells and cytokines to immunoregulate the various physiological processes of pregnancy. The specific and non-specific immune tolerance between the mother and the fetus are the main factors for maintaining the success of the pregnancy. Hormones such as progesterone, estrogens and human chorionic gonadotropin have very important effect on early pregnancy which play essential roles in the immune crosstalk at the maternal-fetal interface15,16. Studies have shown specific immunity is suppressed in pregnant women, including the decrease in the number of T cells, the decline in T-cell functions and the change Th1/Th2 cytokine towards Th2 bias, which enhance the maternal-fetal immune tolerance but impair responses against some pathogens17–19. IVF is widely used to treat infertility. The clinical pregnancy rate and embryo growth rate are closely related to the receptivity of the endometrium, and are affected by ovarian steroid hormones, particularly estradiol and progesterone20.In the process of controlled ovarian hyperstimulation (COH) and luteal phase, progesterone needs to be injected daily21. Glucocorticoids, acting as immunomodulators to influence cell-mediated immunity and reduce inflammation, have been used to improve folliculogenesis and the intrauterine environment22. Therefore, once a woman becomes pregnant, especially after IVF-ET, the changes in the immune function of the body are not conducive to the control and elimination of mycobacterium tuberculosis. Our study also shows the lymphocyte count, CD4 T cell count, CD8 T cell count of pregnant women in the IVF-ET group were significantly lower than those in natural pregnancy group and the proportion of military tuberculosis of pregnant women in the IVF-ET group at admission were higher than those in natural pregnancy group.
In the published literature, there are few studies on the side effects of tuberculosis treatment in pregnant women, especially liver toxicity. Our study showed severe hepatotoxicity was significantly more frequent in pregnant women after IVF-ET compared to those in natural pregnancy. It is speculated that it may be related to pregant women after IVF-ET who are mostly twin pregnancies leading to liver overload, and pregnant women are mostly hematological disseminated tuberculosis patients, with severe symptoms of infection and poisoning, and DILI is more likely to occur. Temporary drug withdrawal or change anti-tuberculosis treatment regimen due to DILI was more frequent in pregant women after IVF-ET than those in nature fertilization. The usual recommendation is restart with rifampin with or without ethambutol, then add isoniazid after 3-7 days, and to continue treatment, if liver function tests are normal. In case of prolonged or severe hepatotoxicity, add other second-line medication (Levofloxacin, Linezolid, Prothionamide, etc.) and discontinue pyzinamide23.
A 2017 meta-analysis5 showed tuberculosis in pregnancy has a greater impact on fetus than on pregnant women, compared with pregant women without TB, pregnant women with active TB tended to have a higher risk of death(OR 4.1, 95%CI 0.65-25.2), was associated with increased odds of preterm birth (OR 1.7, 95%CI 1.2-2.4) and perinatal death (OR 4.2, 95%CI 1.5-11.8). Pregnancy with hematogenous disseminated tuberculosis can cause chorioamnionitis due to severe tuberculosis toxemia and mycobacterium tuberculosis spreading along the blood to infect the placenta24,25, leading to miscarriage (spontaneous abortion, inevitable abortion) and fetal death. We also found that the proportion of artificial abortion among naturally pregnant tuberculosis patients is higher, mainly because most of them have unplanned pregnancies, and the others were worried about the side effects of drugs, although there is evidence that the use of these first-line antituberculous drugs in pregnancy are considered safe for the mother and the foetus26.
Our study had several limitations. First, the study is a retrospective study, and it is impossible to determine whether maternal tuberculosis was infected during pregnancy or caused by recurrence of old lesions in the body, and this may involve different interventions, especially for women who are about to undergo IVF-ET. If active tuberculosis is caused by re-infection, the measures taken are to protect pregnancy women during pregnancy. If it is caused by the reignition of old lesion, detailed tuberculosis screening work is required before IVF-ET. If infertility is caused by congenital tuberculosis, anti-tuberculosis treatment should be initiated immediately and if congenital tuberculosis and active tuberculosis in other parts are ruled out, women infected mycobacterium tuberculosis might need to receive preventive treatment. These measures may reduce the incidence of tuberculosis during pregnancy and abortion rate of pregnant women. We will do further research on these issues next.