Table 2.
Primary Safety Outcome and Secondary Maternal and Infant Outcomes through Week 48 after Delivery.*
| Outcome | Immediate Group | Deferred Group | Incidence Rate Difference (95% CI) |
||
|---|---|---|---|---|---|
| no./total no. (%) |
incidence rate per 100 person-yr |
no./total no. (%) |
incidence rate per 100 person-yr |
||
| Primary outcome† | |||||
| Intention-to-treat population | 72/477 (15.1) | 15.03 | 73/479 (15.2) | 14.93 | 0.10 (−4.77 to 4.98) |
| Per-protocol population | 64/376 (17.0) | 16.00 | 69/388 (17.8) | 16.71 | −0.71 (−6.27 to 4.85) |
| Secondary maternal outcomes | |||||
| Any grade 3 or 4 adverse event | 144/477 (30.2) | 34.95 | 136/479 (28.4) | 31.26 | 3.69 (−4.07 to 11.45) |
| Hepatotoxicity‡ | 29/477 (6.1) | 5.80 | 34/479 (7.1) | 6.69 | −0.89 (−3.98 to 2.19) |
| Peripheral neuropathy | 1/477 (0.2) | 0.19 | 0/479 (0.0) | 0.00 | 0.19 (−0.19 to 0.57) |
| Death | 2/477 (0.4) | 0.40 | 4/479 (0.8) | 0.78 | −0.39 (−1.33 to 0.56) |
| Death due to hepatitis after receiving isoniazid§ | 1/477 (0.2) | 0.20 | 1/479 (0.2) | 0.20 | 0.00 (−0.54 to 0.55) |
| Permanent discontinuation of trial regimen because of toxic effects§ | 16/477 (3.4) | 3.16 | 28/479 (5.8) | 5.48 | −2.32 (−4.88 to 0.23) |
| Tuberculosis¶ | 3/477 (0.6) | 0.60 | 3/478 (0.6) | 0.59 | 0.01 (−0.94 to 0.96) |
| Secondary infant outcomes | |||||
| Any grade 3 or 4 adverse event | 191/445 (42.9) | 70.74 | 192/464 (41.4) | 65.75 | 4.99 (−8.69 to 18.67) |
| HIV infection | 3/439 (0.7) | 0.79 | 7/458 (1.5) | 1.75 | −0.96 (−2.54 to 0.61) |
| Infant death: 0–48 wk after birth | 11/445 (2.5) | 2.99 | 17/464 (3.7) | 4.42 | −1.43 (−4.17 to 1.32) |
| Neonatal death: 0–7 days after birth∥ | 4/445 (0.9) | — | 5/464 (1.1) | — | — |
| Tuberculosis** | 0/445 (0.0) | 0.54 | 1/464 (0.2) | 0.52 | 0.02 (−1.02 to 1.07) |
All analyses were performed on an intention-to-treat basis unless otherwise specified. Incidence rates were used to summarize the outcomes, given that the follow-up period of observation was expected to vary from 48 weeks to 74 weeks, depending on the duration of gestation at entry. The noninferiority margin was an upper boundary of the 95% confidence interval for the difference in the rate of the primary outcome between the two groups of less than 5 events per 100 person-years.
The primary safety outcome was a maternal adverse event of grade 3 or higher that was possibly, probably, or definitely related to isoniazid or placebo (as adjudicated by an independent end-point review committee, whose members were unaware of the trial-group assignments) or permanent discontinuation of the trial regimen because of toxic effects, whichever occurred earlier. The intention-to-treat population included all women who underwent randomization. The per-protocol population included all eligible enrolled women who completed the trial regimen according to the protocol, who died during the treatment period, and who permanently discontinued the trial regimen because they met criteria for discontinuation as specified in the protocol, and all women in whom tuberculosis developed.
Hepatotoxicity was defined as an elevation of grade 3 or higher in liver-enzyme levels (alanine aminotransferase [ALT], aspartate aminotransferase, or total bilirubin); a grade 2 or higher elevation in total bilirubin and ALT levels; or a grade 2 or higher elevation in ALT level with symptomatic clinical hepatitis.
The analysis of this outcome was a post hoc analysis. Additional details are provided in Table S5 in the Supplementary Appendix.
Of the six cases of tuberculosis adjudicated by the independent end-point review committee, four were confirmed cases of pulmonary tuberculosis and two were probable cases of pulmonary tuberculosis. Three cases were in women who had positive IGRA status at entry, one case was in a woman with indeterminate status at entry, and one case was in a woman whose IGRA status changed from negative to positive before tuberculosis diagnosis (Table S6 in the Supplementary Appendix).
Incidence rates are not reported for this category because of the short follow-up time.
The calculation of the incidence rates in this category includes deaths from unknown causes (two in the immediate group and one in the deferred group).