Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials

Ruth N Moro, Nigel A Scott, Andrew Vernon, Naomi K Tepper, Stefan V Goldberg, Kevin Schwartzman, Chi-Chiu Leung, Neil W Schluger, Robert W Belknap, Richard E Chaisson, Masahiro Narita, Elizabeth S Machado, Marta Lopez, Jorge Sanchez, Margarita E Villarino, Timothy R Sterling, Ruth N Moro, Nigel A Scott, Andrew Vernon, Naomi K Tepper, Stefan V Goldberg, Kevin Schwartzman, Chi-Chiu Leung, Neil W Schluger, Robert W Belknap, Richard E Chaisson, Masahiro Narita, Elizabeth S Machado, Marta Lopez, Jorge Sanchez, Margarita E Villarino, Timothy R Sterling

Abstract

Rationale: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy.

Objectives: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H).

Methods: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date.

Results: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively.

Conclusions: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Keywords: latent tuberculosis infection treatment; pregnancy outcomes; safety assessment.

Figures

Figure 1.
Figure 1.
Pregnancy events safety assessment. This figure shows the total number of participants who were enrolled in the PREVENT TB and the iAdhere trials. Certain groups were excluded to select women of reproductive age who were evaluated in this analysis. In addition, pregnancies in which the estimated date of conception occurred after the last study dose were excluded to identify pregnancies that had been exposed to the study drugs. *Reasons for ineligibility: false positive TST (n = 3), lack of sensitivity test for the index case (n = 4), negative tuberculosis culture of the source (n = 31), isoniazid and rifapentine resistant of the source (n = 53), tuberculosis at enrollment (n = 1). †One participant reported 2 pregnancies (EDC occurred before and after the LD for each pregnancy). 3HP = 12-dose once-weekly regimen of isoniazid (900 mg) plus rifapentine (900 mg); 9H = 9-month daily isoniazid (300 mg); EDC = estimated date of conception; LD = last study dose; TST = Tuberculin Skin Test.

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