Features of pregnancy course in women with chemoresistant tuberculosis (a literature review)

Туберкульоз – глобальна причина захворюваності серед жінок репродуктивного віку, що становить серйозну материнську та перинатальну небезпеку як у розвинених країнах, так і країнах, що розвиваються. Туберкульоз посідає 3 місце серед причин смертності жінок репродуктивного віку. При цьому спостерігається майже однакова частота як діагностики специфічного процесу у вагітних, так і вагітності у хворих жінок на туберкульоз. Нині у світі на цьому тлі лікування хіміорезистентного туберкульозу (ХРТБ) у вагітних залишається спірним.

According to the World Health Organization (WHO) [1], tuberculosis is one of the 10 causes of death of humanity worldwide (in 2017, about 1.3 million people died from tuberculosis, one third of whom were women). As of 2017, there are 558,000 people with rifampicin-resistant tuberculosis (RifTB), which is the most effective first-line drug, registered in the world, and 82 % have multidrug-resistant tuberculosis (MDR-TB). Successful treatment of patients with MDR-TB remains low -55 % and MDR-TB often ends with palliative care [2,3].
Tuberculosis is a global cause of morbidity among women of reproductive age, constituting a serious maternal and perinatal risk in both developed and developing countries [4][5][6][7][8]. Tuberculosis ranks 3rd among the causes of death in women of reproductive age [4]. At the same time, the frequency of diagnosing a specific process in pregnant women and pregnancy in women with tuberculosis is almost the same. Today, against this background, the treatment of chemoresistant tuberculosis (CR-TB) in pregnant women remains controversial [8][9][10].

Aim
To conduct a review of current literature sources in order to determine the characteristics of gestation in women with CR-TB, which will assist clinicians in the management of such patients.
The authors indicate that the prevalence of tuberculosis in pregnant Indian women is 1.16 cases per 1000 births and in 67 % of cases the specific process is extrapulmonary. It has been established that in pregnant women with tuberculosis, the risk of premature birth is 5 times higher and the risk of intrauterine growth retardation is 3 times higher. The authors recorded 4 % of maternal deaths during this period.
A. El-Messidi et аl., 2016 [6] in their retrospective cohort study (2003-2011, USA) determined the incidence trend of tuberculosis during pregnancy and studied the relationship between tuberculosis during pregnancy and complications in the mother and her fetus. The authors determined a significant increase in the incidence of tuberculosis in pregnant women from 1.92 to 4.06 cases per 10,000 births. At the same time, extrapulmonary forms of tuberculosis also prevailed. It has been definitely determined that pregnant women with tuberculosis were more likely to have chorioamnionitis, preterm delivery, postpartum anemia, pneumonia and acute respiratory distress syndrome in the newborn than pregnant women without tuberculosis. The researchers also emphasized the increased incidence of maternal mortality and a high incidence of congenital anomalies in newborns.
Researchers in South Asia [7] found that maternal tuberculosis is associated with an increased risk of a small-for-gestational-age birth, preterm birth, low birth weight infants and high perinatal mortality. The occurrence of these risks largely depends on the progression of tuberculosis, chemoresistance of mycobacterium tuberculosis (MBT) and adequacy of antimycobacterial therapy (AMBT). It has been established that maternal and obstetric complications most often develop in pregnant women, when tuberculosis is diagnosed in the 3rd trimester and the occurrence of preterm birth is 9 times higher. It was also pointed out that since abdominal tuberculosis in pregnant women is very difficult to diagnose because of its symptoms are masked by the pregnancy itself and the enlarged uterus, it has extremely unfavorable maternal and perinatal prognosis. The authors noted that very/extremely low birth weight was associated with fetal growth restriction in a pregnant woman with tuberculosis.
According to the literature [11], high incidence of severe premature birth and perinatal mortality is determined among pregnant women with tuberculosis who started treatment in the 3rd trimester.
Undoubtedly, a complete course of AMBT that is similar to treatment for non-pregnant women exists to achieve a successful pregnancy outcome in a woman with active TB. According to N. Jana et аl., 2012 [7], the risk of toxic reactions to AMBT in breastfed infants is low and may be minimized if the mother with tuberculosis takes medications immediately after breastfeeding. The authors also draw attention to the fact that the diagnosis of tuberculosis during pregnancy is often delayed due to the same symptoms of the specific process and pregnancy overlapping and physician reluctance to perform chest X-ray examination in pregnant women. At the same time, they point out that perinatal mortality among women with tuberculosis is 5 times higher.
Harbuziuk V. V. and Polova S. P. (2016) [12] investigated the features of gestation course in women with drug-susceptible tuberculosis. Thus, they found that the significant factors leading to pregnancy complications in women with tuberculosis were the following pathologies: endocrine (46.2 %), gynecological (36.5 %), somatic and infectious (75 %). It was found that complications in women with tuberculosis during childbirth occur 2.3 times more often than in somatically healthy pregnant women, and in those with destructive tuberculosis, this figure increases 4.8 times. The data obtained by these authors also indicated significant intrauterine growth retardation with signs of antenatal hypotrophy. They also found that a serious cause of the pregnancy complications in women with tuberculosis is anemia which occurs in 94.2 % of cases. They proved that obstetric complications in this category of patients are caused by morphological changes in the chorionic villi [13].
Mathad J. S. and A. Gupta (2012) [8] conducted a study of pregnancy and postpartum period influence on tuberculosis progression. As for the management of active tuberculosis in pregnant women and in the postpartum period, the authors distinguish the following. Breastfeeding of newborns is possible for MBT sputum smear negative women and in drug-susceptible form of tuberculosis. In terms of breastfeeding in women with CR-TB, the authors caution in this regard, since the data on the effect of second-line anti-tuberculosis drugs concentration in breast milk on newborns are insufficient.
J. Sugarman et аl., 2010 [9] indicate that the risk of premature birth is twice higher in pregnant women with tuberculosis, low birth weight as well as intrauterine growth retardation and an increase in the incidence of perinatal mortality are 6 times increased. These authors also indicate that chest X-ray examination involves minimal risk to a fetus, and therefore should be used in pregnant women. It is also emphasized that the treatment of a specific process for pregnant women with tuberculosis should be the same as for non-pregnant patients with tuberculosis.
Thus, E. Palacios et аl., 2009 [10] carried out a retrospective study of the treatment results and pregnancy outcomes in a group of women who received treatment for pulmonary CR-TB in Peru. Regarding the pulmonary CR-TB, the authors found that 61 % of cases were cured, 13 % of women died, 13 % refused treatment, and AMBT failure was determined in 5 % of cases. Regarding the course of pregnancy, it was found that in 10.5 % of cases, women experienced a clinical worsening of the specific process during pregnancy, 13.1 % of pregnancies resulted in miscarriages, pregnancy complications were determined in 21 % of cases, 1 infant (2.6 %) was stillborn, 1 infant (2.6 %) was born prematurely, 3 infants (7.8 %) were born with low birth weight, and fetal distress syndrome was diagnosed in 1 infant (2.6 %). None of the newborns was diagnosed with the teratogenic effect of anti-tuberculosis drugs which were administered to the mothers during pregnancy. It was established that effective treatment of tuberculosis in early pregnancy significantly reduces perinatal morbidity, and inadequate treatment of the specific process significantly increases both the risk of treatment failure and the enhancement of MBT resistance to anti-tuberculosis drugs. It was revealed that inadequate and uncontrolled AMBT may lead to fetal demise, congenital tuberculosis and postpartum infection of a newborn. As a result of the literature analysis, the researchers identified the following options for the management of pregnant women with CR-TB: withdrawal of CR-TB treatment, termination of pregnancy or continuation of CR-TB treatment during pregnancy. The authors themselves express support for complete course of adequate AMBT in pregnant women with pulmonary CR-TB without pregnancy interruption under medical supervision.
The article of M. Ünlü et аl., 2015 [14] provides a case of severe MDR-TB in a pregnant woman who received complete AMBT throughout the pregnancy and gave birth to a healthy child. At the same time, during the 8-month follow-up, the child did not exhibit any complications and there were no manifestations of second-line anti-tuberculosis drugs teratogenicity. On this basis, the authors strongly recommend not interrupting pregnancy in women with MDR-TB and administering a complete course of AMBT during pregnancy.
In their study, P. Tabarsi et аl., 2011 [15] observed 5 women with pulmonary MDR-TB, who became pregnant during treatment with second-line anti-TB drugs according to the drug sensitivity test. The results of their research showed that all women recovered and gave birth to healthy children. In this case, complications were observed neither during pregnancy nor during childbirth. Adverse reactions to anti-TB drugs were determined neither in the parturients nor in the newborns. Therefore, the authors also recommended a complete course of AMBT for MDR-TB during pregnancy indicating its safety and efficacy during pregnancy.
Deependra Kumar Rai claims in his work (2016) [16] that untreated tuberculosis poses a great risk to both a pregnant woman and a fetus. At the same time, the author points out that the treatment of drug-susceptible specific process should be prescribed according to the same scheme used for non-pregnant women with tuberculosis, with the exception of streptomycin. As for MDR-TB, the researcher recommends to terminate the pregnancy, since most of second-line anti-TB drugs are teratogenic.
In Ukraine, medical indications for artificial termination of pregnancy at 12-22 weeks' gestation are severe forms of tuberculosis: disseminated, progressive, chemoresistant, with severe complications (except for nervous system and acute meningeal tuberculosis, miliary tuberculosis) [17].
O. S. Hurskyi & S. P. Rolova (2013) [18] conducted a study of clinical and morphological disorders of the placental complex in 26 cases of artificial pregnancy termination for medical reasons in women with drug-susceptible newly diagnosed tuberculosis (NDTB) at 9-16 weeks' gestation. The researchers found that NDTB contributes to pathological course of pregnancy in women, causes threatened miscarriage and the risk of perinatal mortality.
S. P. Polova & V. V. Harbuziuk (2013) [19] conducted a study of the uteroplacental area structure during preterm birth in pregnant women with pulmonary tuberculosis. It was established that in pregnant women with tuberculosis, preterm birth was caused by morphological changes in the chorionic villi. At the same time, an ischemia of the placental intervillous space caused an impaired chorionic villi maturation and damage to the trophoblasts and chorionic villi as a result of uteroplacental inflammatory process in tuberculosis.
Yakovlev A. A. et. al., 2012 [20], studying a combined course of tuberculosis (in 80.5 % of cases -drug-susceptible tuberculosis, in 19.5 % -drug-resistant tuberculosis) and pregnancy in Omsk (the Russian Federation), found that tuberculosis caused 62.8 % of pregnancy complications cases (preeclampsia, anemia), 100% of complications in the postpartum period (decrease in contractile activity of the uterus, bloody vaginal discharge, postpartum endometritis), 49.3 % of complications in the fetus and newborns (low birth weight and neonatal pathology in 100 %). Coincidently, the tuberculosis process progression was diagnosed in 31.7 % of pregnant women and in 63.3 % of women in the postpartum period (the effectiveness of treatment for tuberculosis in the postpartum period was 27.3 %). It was also established that tuberculosis had a favorable course after pregnancy termination in the early stages in the overwhelming number of cases.
According to the scientific research of V. V. Harbuziuk (2019) [21], the incidence of preterm birth in women with tuberculosis is 63.1 %, which is significantly determined by the specific process activity and form (the risk of developing threatened premature birth was increased by 12.4 times in disseminated tuberculosis, by 7.2 times in fibrous-cavernous tuberculosis and by 4 times in focal tuberculosis) in 60.5 % of cases. These factors are accompanied by substantial changes in the hormonal function and microcirculation of the fetoplacental complex, persistence of pathogenic and conditionally pathogenic microorganisms in the parturient canal, an increase in immunodeficiency, a decrease in resistance to stress and an increase in anxiety.
Rohilla M. et аl., 2016 [22] studying the course and treatment of MDR-TB in pregnant women also indicate insufficient global experience in the use of second-line anti-TB drugs in pregnant women, which have a significant teratogenic effect, greatly complicating this issue. However, on the other hand, it is impossible not to treat MDR-TB. These researchers presented 2 clinical cases from their own observations: in the first case, a pregnant woman received second-line anti-tuberculosis drugs throughout her pregnancy and in the second case a pregnant woman started treatment in the last trimester. Both women gave birth to healthy children. A 6-month follow-up of both mothers and newborns revealed no complications and no adverse reactions. The authors emphasized that the management of pregnant women with MDR-TB should be based on an interdisciplinary approach including a team of physicians such as a pulmonologist (tuberculosis specialist), obstetrician, neonatologist, and public health expert. It was recommended that AMBT should be postponed until the second trimester in such patients in order to prevent the teratogenic effects of anti-TB drugs (provided that a patient is HIV-negative or not in critical condition).
According to A. Dudnyk and O. Pavelchuk (2016) [23], it was established that pregnant women with MDR-TB exhibit a higher incidence of unfavorable treatment and delivery outcomes compared to pregnant women with drug-susceptible tuberculosis (control group). Despite the fact that 100 % of pregnant women with drug-susceptible tuberculosis recovered, in women with MDR-TB, the recovery and mortality rates were 40 % each. Twenty percent of women with MDR-TB had an abortion (10 % had a miscarriage and 10 % had a pregnancy termination for medical reasons). With higher incidence in pregnant women with MDR-TB, diagnosis of pregnancy complications (30 % vs. 6.6 %) and adverse reactions to anti-TB drugs (60 % vs. 33.3 %) were observed. The situation being what it is, 60 % patients with MDR-TB who received second-line anti-TB drugs gave birth to healthy children, 10 % had a newborn with low birth weight and 10 % of infants were tuberculosis/HIV co-infected.
Laniado-Laborín R. et аl., 2018 [24] in their article also presented a clinical case of their own observation of MDR-TB course and treatment in a pregnant woman. The authors indicated that the woman completed a full-course of second-line AMBT and gave birth to a healthy child. Thus the treatment of MDR-TB in the pregnant woman was favorable for her and her newborn.
Prasad R. et аl., 2015 [25] indicate that, given the teratogenicity of second-line anti-TB drugs in pregnant women with MDR-TB, it is necessary to consider all risks and benefits of the therapy. At the same time, researchers also emphasize that the MDR-TB treatment should begin with the 2nd trimester of pregnancy. The choice of treatment should be based mainly on the MDR-TB severity, and termination of pregnancy should be performed if there is a risk to mother's life. Medical indications for termination of pregnancy are up to 20 weeks due to the possible serious risks for both a mother and fetus.
According to the latest WHO recommendation (2019) [1], such anti-TB drugs as amikacin, streptomycin, prothionamide and ethionamide are contraindicated during pregnancy. Information on the safety of bedaquiline and delamanid during pregnancy and breastfeeding is scarce. Therefore, in these cases, WHO recommends to carefully record the results of treatment, pregnancy and postpartum period while administering bedaquiline and delamanid. Congenital anomalies should be documented to assist in further recommendations for MDR-TB treatment during pregnancy.

Discussion
1. In pregnant women, incidence of extrapulmonary and pulmonary forms of tuberculosis is almost the same.
2. Chest X-ray examination in pregnant women should not be avoided, since the radiation risk for the fetus is insignificant when the abdominal cavity shielding.
3. In women with tuberculosis, childbirth occurs on average at the 38th week of pregnancy, and premature labor is associated with tuberculosis progression. 4. In pregnant women with tuberculosis, the incidence of chorioamnionitis, gestosis, premature birth, anemia, pneumonia, maternal and perinatal mortality is higher than in pregnant women without tuberculosis. 5. Newborns have an increased risk of premature birth, congenital tuberculosis, intrauterine growth retardation, congenital abnormalities, and distress syndrome. 6. A high frequency of these risks in pregnant women and newborns largely depends on tuberculosis progression, chemoresistance of mycobacterium tuberculosis and the adequacy of anti-mycobacterial therapy.
7. Untreated chemoresistant tuberculosis is associated with higher maternal mortality, an increased risk of vertical transmission of tuberculosis, spontaneous miscarriage, intrauterine growth restriction, premature birth, increased neonatal mortality.
8. Breastfeeding is possible if there is a sputum culture conversion in mother. The risk of toxic reactions to anti-tuberculosis drugs in breastfed infants is low and may be minimized if a mother with tuberculosis takes medications immediately after breastfeeding.
9. Medical indications for artificial termination of pregnancy at 12-22 weeks' gestation are severe forms of tuberculosis: disseminated, progressive, chemoresistant, with severe complications.

Conclusions
Considering the analysis of the literature, all pregnant women should be prescribed treatment for chemoresistant tuberculosis with second-line anti-tuberculosis drugs based on the drug sensitivity test starting from the second trimester (if a patient is HIV-negative or not in a critical state) with the exception of drugs such as amikacin, streptomycin, prothionamide and ethionamide. A timely and adequate anti-mycobacterial therapy is the key to successful pregnancy outcome. Pregnancy follow-up among women with chemoresistant tuberculosis should be based on an interdisciplinary approach including a team of physicians such as a tuberculosis specialist, obstetrician, neonatologist, and public health expert.
Prospects for further research. To present clinical cases of own observations of pregnancy course in women with СR-TB.