Impact of Tuberculosis Preventive Treatment on Adverse Pregnancy Outcomes in women living with HIV in Uganda: A Quasi-experimental study using routine care data

Impact of Tuberculosis Preventive Treatment on Adverse Pregnancy Outcomes in women living with HIV in Uganda: A Quasi-experimental study using routine care data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of Tuberculosis Preventive Treatment on Adverse Pregnancy Outcomes in women living with HIV in Uganda: A Quasi-experimental study using routine care data Joseph Musaazi, Christine Sekaggya-Wiltshire, Stella Zawedde-Muyanja, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7170241/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The World Health Organization recommends tuberculosis preventive treatment (TPT) for people living with HIV, including pregnant women. However, data on the safety of TPT during pregnancy particularly from routine care settings in high tuberculosis (TB) burden countries remain limited. We evaluated the association between TPT exposure and adverse pregnancy outcomes among pregnant women living with HIV (WLHIV) in Uganda. Methods: We conducted a quasi-experimental study using routinely collected data from five public urban primary health care facilities in Kampala, Uganda. We included pregnant WLHIV on antiretroviral therapy (ART) between 2016 and 2023. The primary outcome was a composite of adverse pregnancy outcomes: miscarriage, stillbirth, low birth weight, congenital anomalies, or maternal/neonatal death. The primary exposure was 6-months isoniazid TPT (IPT) during pregnancy. Analyses used inverse probability of treatment weighting (IPTW) using logistic regression model to adjust for confounding and multiple imputation for handling missing data. Results: Analysis included 521 pregnant WLHIV, 44% were exposed to IPT during pregnancy. Overall, 10.0% experienced an adverse pregnancy outcome, with no significant difference between IPT-exposed and unexposed groups (10.3% vs. 9.6%; p = 0.81). Adjusted IPTW analysis showed no significant association between IPT exposure and adverse outcomes (pooled weighted odds ratio 1.04; 95% CI: 0.69–1.58). Sensitivity and subgroup analyses yielded consistent results. Conclusion: We found no evidence that 6-month isoniazid TPT increases the risk of adverse pregnancy outcomes. However, limitations in outcome and adverse event documentation from routine care may affect these findings. Strengthening pharmacovigilance and clinical reporting is essential to safeguard maternal and neonatal health as TPT coverage expands in high TB/HIV burden settings. Tuberculosis Preventive Treatment (TPT) Pregnancy Outcomes Women Living with HIV (WLHIV) Isoniazid Preventive Therapy (IPT) Sub-Saharan Africa Routine Programmatic Data Figures Figure 1 Figure 2 INTRODUCTION The World Health Organization (WHO) recommends tuberculosis preventive treatment (TPT) for people living with HIV (PLHV) including pregnant women, to reduce the risk of developing active tuberculosis( 1 ). However, some studies show that pregnancy is associated with increased risk of hepatoxicity in women living with HIV( 2 ), with higher risk among those exposed to isoniazid preventive therapy (IPT) compared to those not exposed( 3 ). For instance, the IMPAACT P1078 randomized controlled trial, conducted across 13 sites in 8 high TB-burden countries reported a higher risk of adverse pregnancy outcomes in a composite outcome that included stillbirth or spontaneous abortion, low birth weight, preterm delivery, and congenital anomalies among women who initiated IPT during pregnancy (24%) versus those who deferred initiation until postpartum (17%) ( 4 ). Conversely, a systematic review that included the IMPAACT P1078 trial reported mixed findings. Of the five studies reviewed, only the P1078 trial, a randomized controlled trial, identified a significantly increased risk of adverse pregnancy outcomes associated with IPT exposure during pregnancy, whereas the remaining observational studies found no such association ( 3 ). These divergent findings highlight ongoing uncertainty about the safety of IPT during pregnancy, particularly in real-world settings. Uganda bears a high burden of both TB and HIV. According to the 2023 joint United Nations programme on HIV/AIDS (UNAIDS), HIV prevalence among Ugandan women aged 15–49 years is 6.6%, nearly double that of men (3.6%) ( 5 ). The 2015 Uganda National TB Survey estimated TB incidence at 198 cases per 100,000 population ( 6 ). TB during pregnancy or the postpartum period has been associated with serious outcomes, including spontaneous abortion, low birth weight, preterm delivery ( 7 ), and perinatal mortality( 8 ). Following WHO recommendations, the Uganda Ministry of Health (MoH) adopted TPT for high-risk populations in 2021, including pregnant women living with HIV (WLHIV), based on the presumption that benefits outweigh potential risks ( 9 , 10 ). By 2023, TPT uptake and completion rates among PLHIV in Uganda had surpassed 90%, with higher completion observed among women than men ( 11 , 12 ), reflecting both strong program implementation and national commitment to TB control. Despite these gains, data on TPT safety during pregnancy remain limited, especially from routine care settings in high-burden countries. While both clinical trials and observational studies have assessed safety ( 3 , 4 , 13 , 14 ), evidence from real-world programmatic data remains scarce. Although the P1078 trial demonstrated a modest increase in adverse outcomes with pregnancy-initiated IPT, WHO and Uganda-MoH recommends TPT for pregnant WLHIV especially residing in high TB burden settings, emphasizing that the benefits outweigh the risks. This study aimed to evaluate the association between the tuberculosis preventive therapy (IPT) use during pregnancy and adverse pregnancy outcomes including spontaneous abortion or miscarriage, stillbirth, low birth weight, congenital anomalies, and maternal or neonatal death among pregnant WLHIV. Using routinely collected programmatic data, we assessed both the prevalence of adverse outcomes and the potential impact of TPT exposure during pregnancy. METHODS Study design, population and setting Study design and population We conducted a quasi-experimental study using routinely collected clinical data from five public primary health care facilities in Kampala Capital City Authority, Uganda. The clinics provide free care and treatment for people living with HIV (PLHV) through the President's Emergency Plan for AIDS Relief (PEPFAR) program, including antiretroviral treatment, and prophylaxis for opportunistic infections and tuberculosis, and antenatal services. The clinics maintain registers for the TPT program, antenatal and post-partum visits; other individual clinical data is collected into the Uganda electronic medical record (EMR) system. The study population included pregnant women living with HIV (WLHIV), aged 15 years and older, who initiated antiretroviral therapy (ART) between January 2016 and December 2023, coinciding with the rollout of the HIV Test and Treat strategy and expanded TPT provision in Uganda( 15 ). We excluded women with missing ART initiation dates, those with a ≥ 12-month gap in HIV clinic attendance, and women who initiated TPT before starting ART to minimize confounding due to the absence of ART’s protective effect against TB at the time of TPT initiation. The study sites were purposively selected due to the relative completeness and reliability of their clinical documentation compared to other facilities in the region. Kampala was selected as the study setting due to its high burden of both HIV and tuberculosis (TB) relative to other regions in Uganda. Programmatic Implementation of TPT in Uganda In 2015, the Uganda-MoH adopted and expanded the WHO recommendation to provide TPT to all people at risk of developing active TB. This includes all PLHV including pregnant women without active TB, and household contacts of individuals with confirmed TB disease. From 2015 until 2021, isoniazid monotherapy, taken daily for six months, was the only available TPT option recommended for asymptomatic PLHIV in Uganda( 16 ). In 2021, the Uganda-MoH rolled out revised national TPT guidelines, incorporating rifamycin-based shorter-course regimens to improve uptake and adherence ( 9 ). Between 2018 and 2023, the Uganda-MoH intensified efforts to expand TPT coverage among PLHV through a series of strategic interventions. In July 2019, the Uganda-MoH launched a 100-day accelerated IPT scale-up campaign aimed at initiating 300,000 PLHV on TPT and achieve > 90% completion rate among those initiated( 17 ). In 2021, the Uganda-MoH updated national guidelines that integrated TPT into the routine HIV care package for all PLHV without symptoms of TB ( 9 ). These guidelines endorsed the use of shorter-course, rifamycin-based TPT regimens alongside isoniazid monotherapy, to improve adherence and programmatic uptake. While earlier TPT guidelines in Uganda permitted isoniazid use at any stage of pregnancy, the 2021 revision introduced more restrictive criteria for TPT provision in pregnant WLHV. Under the new guidance, TPT during pregnancy was recommended only for those with CD4 counts < 200 cells/mm³, WHO stage III or IV HIV disease, or a history of contact with a person with bacteriologically confirmed pulmonary TB. For all other pregnant WLHIV, TPT initiation was advised to be deferred until three months postpartum ( 9 ). Data extraction and collection Between July 2020 to March 2021, trained research assistants abstracted demographic, clinical, and pregnancy data from TPT, maternity and antenatal registers using a structured abstraction tool programmed in Open Data Kit (ODK)( 18 ). To ensure data quality, built-in validation checks were applied within the ODK tool. Additional quality assurance measures included training research assistants in standardized data abstraction procedures and conducting daily reviews of the collected data. Additional data were obtained directly from the Uganda Electronic medical records (EMR) database system ( 19 ) using a pre-defined abstraction guide. Data from the different sources were linked using the patient's unique HIV clinic identifier number. The specific data variables extracted are described in section below. To select study participants, systematic random sampling was employed at each of the five health facilities. The sampling interval was calculated by dividing the total number of eligible patients at each facility by the number of participants allocated to that site. Outcome measure and covariates The primary outcome was a composite measure of adverse pregnancy outcomes, defined as the occurrence of any of the following: spontaneous abortion/miscarriage, stillbirth, low birth weight, congenital anomalies, neonatal death, or maternal death. Individual pregnancy outcomes were assessed as secondary outcomes. The denominator was all pregnant WLHIV included in the study. For participants with multiple pregnancy events, the most recent pregnancy was used for analysis. The pregnancy event date was estimated as the first clinic visit at which pregnancy was recorded. Preterm birth was excluded from the composite outcome due to a lack of documented data in the reviewed pregnancy records. Definitions of individual pregnancy outcomes Spontaneous Abortion (miscarriage) The loss of a fetus before 20 gestation weeks of pregnancy. Stillbirth The death of a fetus at or after 20 weeks of pregnancy. Low Birth Weight Babies born weighing less than 2,500 grams (5 pounds, 8 ounces). Congenital Anomalies in an Infant Also known as birth defects, these are structural or functional abnormalities that occur during intrauterine life and can be identified prenatally, at birth, or later in life. Major anomalies to be defined according to the Metropolitan Atlanta Congenital Defects Program of the Centers for Disease Control and Prevention( 27 ). Neonatal Mortality The death of a live-born baby within the first 28 days of life. Maternal Mortality The death of a woman during pregnancy, childbirth, or within 42 days of termination of pregnancy, from any cause related to or aggravated by the pregnancy or its management. The primary exposure was tuberculosis preventive therapy (TPT) using 6-months isoniazid prophylaxis during pregnancy, which was the only regimen available during the study period. A secondary analysis further classified TPT exposure by trimester: no exposure, 1st trimester (< 13 weeks), 2nd trimester (13–28 weeks), and 3rd trimester (29–40 weeks), in accordance with national guidelines ( 20 ) and previous studies ( 4 , 14 ). Potential covariates included both clinical and reproductive factors. Clinical variables comprised viral load (copies/mL), nadir CD4 count at ART start (cells/µL), ART regimen type at the time of pregnancy, ART duration in months, WHO HIV clinical stage (I/II vs III/IV), body mass index (BMI, kg/m²) and, ART initiation calendar year before and after September 2018 to coincides with dolutegravir-based ART regimen roll-out in Uganda. Viral load during pregnancy was defined as the closest measurement within 12 months before or 6 months after the pregnancy event date. Baseline CD4 count at ART start was defined as any test conducted within 6 months before or 3 months after ART start. Reproductive factors included maternal age (in years), gestational age (in weeks) at first antenatal care (ANC) visit, parity, gravidity, number of ANC visits, and anemia. Information on other maternal health conditions such as preeclampsia, hypertension, diabetes, and sexually transmitted infections (including syphilis) were limited or inconsistently recorded and therefore excluded from the analysis. Pre-pregnancy weight was defined as the most recent recorded weight within six months prior to the first documented pregnancy visit. Sample size and statistical power A total sample size of 538 pregnant WLHIV (269 per group) was estimated to provide 80% power to detect a ≥ 10 percentage-point difference in adverse pregnancy outcomes between exposed and unexposed groups, assuming a baseline risk of 17% in the unexposed group ( 4 ), with a two-sided alpha of 0.05 and a Pearson Chi-square test. Statistical analysis Descriptive statistics (frequencies, percentages, means with standard deviations, or medians with interquartile ranges) were used to summarize participant characteristics. For longitudinal variables such as weight, missing values were imputed using last observation carried forward (LOCF). The primary outcome; any adverse pregnancy outcome was compared between women exposed and unexposed to TPT during pregnancy using the Pearson Chi-square test. To address confounding, inverse probability of treatment weighting (IPTW) using stabilized propensity scores was applied, followed by weighted logistic regression models for effect estimation. Missing data were addressed using multiple imputation by chained equations (MICE) with five imputations via predictive mean matching for continuous and logistic model for binary variables. Details of the imputation models used for each covariate with missing values are provided in Supplementary Section, Table S1. Subgroup analyses were conducted based on CD4 count (< 200 vs ≥ 200 cells/µL), viral load (< 200 vs ≥ 200 copies/mL), age (< 25 vs ≥ 25 years), ART initiation year (< 2018 vs ≥ 2018), and BMI (< 18.5, 18.5–<25, ≥ 25 kg/m²), selected based on clinical relevance and prior evidence. Pregnancy weight was defined as the most recent weight within six months prior to the first recorded pregnancy visit. Sensitivity analyses included unadjusted, covariate-adjusted, and Firth penalized logistic regression models, the latter used to address sparse outcomes. Firth regression was not used in the primary analysis due to incompatibility with imputed datasets. Statistical significance was set at 5% level. RESULTS Participants description A total of 521 pregnant women living with HIV were included in this analysis (Table 1 ). Of these, 227 (44%) had used IPT for TPT during pregnancy, while 294 (56%) had not. Among those who used IPT, 139 (61%) started IPT in 1st trimester, 58 (26%) in the 2nd trimester, and 30 (13%) in the 3rd trimester. In the IPT unexposed group, 149 (51%) had completed IPT course before the onset of pregnancy, and 145 (49%) had never received IPT. Overall, the median age at current pregnancy was 28 years (interquartile range [IQR] 24 to 31 years), 50.3% (238/473) had ≥ 2 prior live births, 0.6% were in HIV WHO stage 3 or 4, with median time on ART of 22 months (IQR: 0 to 53 months). At their first recorded antenatal visits, the median gestation age was 24 weeks (IQR: 18 to 30 weeks), implying that majority of the women had their first ANC visit in their 2nd trimester (Table 1 ). Table 1 Pregnant women living with HIV’ characteristics at first antenatal visit by TPT exposure status during pregnancy* Characteristics Total TPT Unexposed group TPT Exposed group P-value N = 521 N = 294 N = 227 Age in years, median (IQR) † 28 (24, 31) 28 (24, 32) 28 (24, 31) 0.403‡ Parity ≥ 2 births† 238 (50.3) 125 (48.4) 113 (52.6) 0.374 BMI in Kgs/m 2 , median (IQR) † 24.9 (22.3, 27.8) 24.9 (22.2, 27.8) 24.9 (22.7, 27.5) 0.750‡ WHO HIV stage 3/4, n (%) † 3 (0.6) 1 (0.4) 2 (0.9) 0.469 Gestation age at first ANC visit in weeks, median (IQR) 24 (18, 30) 23 (18, 30) 26 (20, 32) 0.013‡ CD4 count at ART start, in cells/mL, median (IQR) † 408 (243, 584) 413 (215, 586) 396 (268, 584) 0.820‡ Nadir CD4 count < 200 cells/mL, n (%) 73 (18.7) 45 (21.2) 28 (15.6) 0.158 Viral load at pregnancy † < 200 copies/mL, n (%) 299 (89.2) 163 (88.1) 136 (90.7) 0.452 < 1000 copies/mL, n (%) 308 (91.9) 168 (90.8) 140 (93.3) 0.444 ART start after 2018 †¥ 142 (32.1) 50 (21.3) 92 (44.4) < 0.001 ART duration in months, median (IQR) † 22 (0, 53) 25 (6, 56) 16 (0, 46) < 0.001‡ ART duration ≥ 2 years, n (%) † 245 (48.9) 144 (52.6) 101 (44.5) 0.072 ART regimen at pregnancy ¶ DTG based 33 (6.7) 21 (7.7) 12 (5.4) 0.559 EFV based 444 (89.5) 240 (87.9) 204 (91.5) NVP based 10 (2.0) 7 (2.6) 3 (1.3) ATV/r or LPV/r 9 (1.8) 5 (1.8) 4 (1.8) * Number of women exposed to TPT during pregnancy in: 1st trimester (n = 139), 2nd trimester (n = 58), and 3rd trimester (n = 30). Among the unexposed group, n = 149 had completed TPT before pregnancy onset, n = 145 had never been exposed to TPT. † Missing values: age (n = 3), parity (n = 48), BMI (n = 38), WHO stage (n = 47), nadir CD4 (n = 130, 25%), Viral load (n = 186, 36%), ART duration (n = 20, 4%), 5 of those with ART start date had no regimen specified. ‡ P-values derived using Man-Whitney Wilcoxon rank-sum test to comparing medians across groups, else P-values were derived using Pearson Chi-square test ¥ ART initiation calendar year before and after September 2018 to coincides with dolutegravir-based ART regimen roll-out in Uganda. This stratification helped to explore whether there’s interaction between TPT exposure before versus after DTG-based regimen DTG roll-out in Uganda. ¶ ART regimen at pregnancy, 97% were on TDF based regimen on overall (96% in unexposed group, 98% in exposed group). Pregnancy outcomes Of the 521 enrolled participants, pregnancy outcome data were available for 472 (90.6%) (Table 2 ). Among those with complete data, 47 women (10.0%) experienced at least one adverse pregnancy outcome. There was no statistically significant difference in the prevalence of adverse pregnancy outcomes between women exposed to TPT during pregnancy and those unexposed (22/213, 10.3% versus 25/259, 9.6% respectively, p-value = 0.81). After adjusting for potential confounding using inverse probability of treatment weighting (IPTW), and completing missing values using multiple imputation, the pooled weighted estimates still showed no evidence for an increased risk of adverse pregnancy outcome due to TPT exposure during pregnancy (pooled weighted odds ratio [OR], 1.04; 95% confidence interval [CI], 0.69 to 1.58; p = 0.84) (Table 3 ). The distribution of composite adverse pregnancy outcomes across categories of covariates is detailed in Supplementary Section, Table S2. Sensitivity analyses yielded consistent results; re-running the analysis using Firth penalized logistic regression which accounts for sparse data bias, it further revealed no effect of TPT exposure during pregnancy on risk of adverse pregnancy outcome (adjusted OR, 1.08; 95% CI, 0.59 to 1.97). Similarly, conventional complete case analysis and covariate-adjusted logistic regression with multiply-imputed data showed no significant association (Table 3 ). Low birth weight was the most frequent adverse outcome, occurring in 16 of 472 participants (3.4%), but was not significantly different between the TPT-exposed and TPT-unexposed (p-value = 0.53). The overall median birth weight was 3200 g (IQR, 3000 to 3500 g). Additionally, there was no significant association between TPT exposure and other individual pregnancy outcomes; spontaneous abortion, stillbirth, neonatal or maternal deaths (all p-values were ≥ 0.20) (Table 2 , Fig. 1 ). Among women who received TPT during pregnancy, the highest prevalence of adverse outcomes was observed in those who initiated TPT in the third trimester (6/29; 20.7%), compared with those who initiated in the first (12/130; 9.2%) or second trimester (4/54; 7.4%). However, this difference did not reach statistical significance (p-value = 0.38) (Fig. 1 , Supplementary Section Table S3). Stillbirth was the most frequently observed adverse event among those who initiated TPT in the third trimester (Supplementary Section, Table S4). In exploratory subgroup analyses (Fig. 2 ), there was no significant interactions effect of being on TPT during pregnancy, and selected covariates which included; timing of ART initiation, HIV viral load at the first antenatal visit, or baseline CD4 count (all interaction p > 0.10). Table 2 Pregnancy outcomes by TPT-exposure status during pregnancy Pregnancy outcomes¶ TPT-exposed n (%) N = 213 TPT-unexposed n (%) N = 259 Risk difference (%) P-value† Non-adverse outcome 191 (89.7) 234 (90.3) N/A 0.81 Adverse outcome 22 (10.3) 25 (9.6) 0.7 (-4.8,6.1) Specific adverse outcomes Low birth weight (< 2500g) 6 (2.8) 10 (3.8) -1.0 (-4.3, 2.2) 0.53 Spontaneous abortion or miscarriage 3 (1.4) 6 (2.3) -0.9 (-3.3, 1.5) 0.47 Stillbirth 6 (2.8) 2 (0.7) 2.0 (-0.4, 4.5) 0.09 Neonatal death 0 1 (0.4) -0.4 (-1.1, 0.4) 0.37 Maternal death 0 2 (0.7) -0.8 (-1.8, 0.3) 0.20 Other anomalies: Difficulty in breathing 7 (3.3) 4 (1.5) 1.7 (-1.1, 4.6) 0.21 ¶ Analysis performed on n = 472 women who had pregnancy outcomes, 49/521 (9%) had missing pregnancy outcome. †Pearson Chi-square P-value comparing adverse pregnancy outcomes between women exposed to TPT during pregnancy versus those who were not. % denote column percentages Table 3 Weighted odds ratios and 95% confidence intervals for the impact of Isoniazid TPT monotherapy taken during pregnancy on adverse pregnancy outcomes Odds Ratio (95% CI) P -value Primary analysis IPTW weighted Logistic regression model¥ 1.04 (0.69, 1.58) 0.84 Sensitivity analyses Unadjusted Logistic regression model (complete case)¶ 1.08 (0.59, 1.97) 0.81 Unadjusted Logistic regression model (imputed) 1.08 (0.60, 1.96) 0.80 Covariates-adjusted Logistic regression model † 1.01(0.51, 12.00) 0.97 Firth penalized logistic regression model ‡¶ 1.08 (0.59, 1.97) 0.81 OR = odds ratio; IPTW = inverse probability of treatment weighting; TPT = tuberculosis preventive therapy. ¥ Pooled Odds Ratios and their 95% confidence intervals (95%CI) were estimated from Pooled Weighted Logistic Regression. Propensity scores used to generate Inverse Probability Treatment Weighted (IPTW) weights were calculated using a logistic regression model with covariates: maternal age, body mass index, anemia during antenatal care, ART duration, CD4 < 200, viral load < 200, ART regimen timing (pre/post-September 2018), and parity ≥ 2. Missing data were completed using Multiple Imputation with chained equations using 5 imputations, via predictive mean matching for continuous and logistic model for binary variables. See Table S1 for details on specific imputation models used. ¶ Complete case estimates analyzed on 472 participants (excluding 49 with missing pregnancy outcomes) †Covariate-adjusted logistic regression model included the same variables as the PS model. ‡Firth penalized logistic regression model used to reduce sparse data bias. Adverse pregnancy outcomes defined as proportion of composite outcome that includes any of the following: spontaneous abortion/miscarriage, stillbirth, preterm delivery, low birth weight, congenital anomalies, neonatal death, or maternal death. Discussion This study contributes to the body of knowledge about safety of TPT during pregnancy. Using routinely collected programmatic data from urban HIV clinics in Uganda, we evaluated the association between TPT exposure during pregnancy and adverse pregnancy outcomes. We found no statistically significant increase in the risk of composite or individual adverse outcomes that included; spontaneous abortion or miscarriage, stillbirth, low birth weight, congenital anomalies, maternal, or neonatal death among WLHIV on antiretroviral therapy (ART) who received IPT. These findings were consistent across causal inference models and sensitivity analyses, supporting their robustness. We did not observe evidence of effect modification by maternal viral load during pregnancy, baseline CD4 count, or timing of IPT initiation in relation to the rollout of dolutegravir-based ART in Uganda. However, the study may have been underpowered to detect interaction effects, limiting our ability to assess heterogeneity in IPT safety across subgroups. Low birth weight emerged as the most common adverse outcome, consistent with findings from the IMPAACT P1078 trial, which attributed low birth weight to maternal factors such as poor nutrition and smoking( 14 ). Unfortunately, our dataset lacked information on these potential confounders, limiting exploration of their role in our cohort. Although statistically non-significant, we observed slightly higher proportions of stillbirth and congenital anomalies of about 2 percentage points higher among IPT-exposed women. Notably, four of the six stillbirths occurred among those initiating IPT in the first trimester, a period critical to fetal development ( 21 ). These signals underscore the need for continued pharmacovigilance and larger studies to assess the safety of IPT during early pregnancy ( 22 ). We also noted a higher frequency of adverse outcomes among women initiating IPT in the third trimester. Late IPT initiation may reflect delayed antenatal care, a known risk factor for poor outcomes such as stillbirth and preterm birth ( 23 , 24 ). These findings highlight the need to promote early antenatal attendance and ensure timely initiation of preventive therapies like IPT to improve pregnancy outcomes. Our results align with observational studies from sub-Saharan Africa ( 13 , 25 , 26 ), and a systematic review by Hamada et al. ( 3 ), all suggesting no increased risk of adverse pregnancy outcomes with IPT. For instance, Taylor et al. ( 25 ) found no association between IPT and adverse outcomes in Botswana, while Salazar-Austin et al. ( 26 ) and Kalk et al. ( 13 ) reported lower risks of adverse outcomes among IPT recipients in cohorts in South Africa. However, these studies are subject to residual confounding, as are ours, due to limited adjustment for key maternal risk factors. In contrast, Theron et al. ( 14 ), using data from the IMPAACT P1078 randomized trial, reported significantly higher rates of composite adverse pregnancy outcomes among women initiating IPT during pregnancy versus postpartum. That study had strong internal validity, with a large sample size (925 mother–infant pairs), conducted in 8 high TB countries, and rigorous adjustment for confounders. While our study used causal inference methods to minimize bias, unmeasured factors such as syphilis, hepatitis co-infection, multiple gestation, and other comorbidities were often undocumented and could still influence outcomes. Absence of increased risk of adverse pregnancy outcomes may reflect lower baseline risk in our cohort, as all women were already on ART at conception, and achieved viral suppression during pregnancy, factors known to protect against adverse outcomes and potentially mitigate adverse pregnancy outcomes. A major strength of this study is its use of routine electronic medical record (EMR) data from multiple high-burden HIV/TB clinics in Uganda, enhancing generalizability in similar programmatic settings. Such data allow for practical evaluation of intervention safety within routine care, informing policy in contexts where randomized trials may not be feasible. Nonetheless, several limitations warrant consideration. First, misclassification and underreporting are possible, particularly for early pregnancy losses, preterm births, congenital anomalies, and maternal deaths, which may be inconsistently documented. Second, selection bias may have occurred, as most women initiated antenatal care in the second trimester, potentially excluding early losses. Third, key confounders such as syphilis, hepatitis, multiple gestation, nutritional status, and smoking were not available, limiting our ability to adjust for all relevant risk factors ( 14 ). Finally, our modest sample size limited power to detect small or rare effects, though linked EMR data across several clinics enhances the external validity of our findings. Conclusion Our findings show no evidence that 6-month isoniazid monotherapy TPT, delivered through routine HIV and antenatal care in Uganda, increases the risk of adverse pregnancy outcomes. However, interpretation should consider limitations such as limited statistical power and incomplete outcome documentation inherent to routine programmatic data. As TPT scale-up continues especially among pregnant women in high TB/HIV burden settings strengthening pharmacovigilance systems and ensuring systematic documentation of adverse events and relevant risk factors is essential. These efforts are critical to safeguarding maternal and neonatal health while supporting national and global goals for TB prevention among vulnerable populations, including women living with HIV. Abbreviations WHO World Health Organization HIV Human Immunodeficiency Virus AIDS Acquired Immune Deficiency Syndrome TB Tuberculosis TPT Tuberculosis Preventive Treatment IPT Isoniazid Preventive Therapy ART Antiretroviral Therapy PLHV People Living with HIV WLHIV Women Living with HIV Uganda MoH-Uganda Ministry of Health EMR Electronic Medical Record IPTW Inverse Probability of Treatment Weighting Declarations Ethics approval and consent to participate The AIDS Support Organization Research Ethics Committee (TASOREC), Kampala, Uganda (number: TASOREC/085/19-UG-REC-009) and the Uganda National Council for Science and Technology, Kampala, Uganda (UNCST number: HS729ES) granted ethical approval for the study. Due to the retrospective study design and that this was a public health surveillance, the need for patient informed consent was waived by the Ethic Committee. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests Funding The programme was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control (CDC) and Prevention (terms of Cooperative Agreement NU2GGH002022). Support for data collection was provided by the Fogarty International Center, National Institutes of Health (grant #2D43TW009771-06 ‘HIV and co-infections in Uganda’); and European & Developing Countries Clinical Trials Partnership (EDCTP) – East Africa TB NODE (Grant number: EDCTP-RegNET2015-1104). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number 2D43TW009771-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author Contribution JM – conceptualized the research idea and proposal, wrote the methodology, project administration, data collection supervision, data curation, data validation, formal analysis and writing the initial manuscript draft. JM, BC – acquired the funding for data abstractionCS, BC, NB, MSA – supervised project activitiesJM, CS, BC, NB, MSA, YCM, SZM, PMN – Proposal and manuscript review & editing Acknowledgement The authors thank various staff from the Infectious Diseases Institute (Kampala, Uganda) for their contributions: Dr Andrew KAmbugu, Dr Stephen Okoboi, J Nabbaale, A Nanvuma, G Banturaki, EJ Akumu, E Katunguka; D Kirumira, J Masika, C Kaidu, P Asiimwe, M Atugonza, NM Juma (research assistants); staff at the Kampala Capital City Authority (KCCA) Directorate of Public Health and Environment office in Uganda: D Okello, P Nazziwa; and staff and in-charges at the six KCCA healthcare facilities who assisted in retrieval of patients’ records. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. References World Health Organization. Global tuberculosis report 2023. Geneva; 2023. Ouyang DW, Shapiro DE, Lu M, Brogly SB, French AL, Leighty RM, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS. 2009;23(18):2425–30. Hamada Y, Figueroa C, Martín-Sánchez M, Falzon D, Kanchar A. The safety of isoniazid tuberculosis preventive treatment in pregnant and postpartum women: systematic review and meta-analysis. Eur Respir J. 2020;55(3). Gupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, et al. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019;381(14):1333–46. HIV/AIDS JUNPo. UNAIDS Country Specific factsheets for Uganda 2023 [Available from: https://www.unaids.org/en/regionscountries/countries/uganda Uganda Ministry of Health. The Uganda National Tuberculosis Prevalence Survey, 2014–2015. 2017 23 August 2017. Mathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect diseases: official publication Infect Dis Soc Am. 2012;55(11):1532–49. Gupta A, Nayak U, Ram M, Bhosale R, Patil S, Basavraj A, et al. Postpartum Tuberculosis Incidence and Mortality among HIV-Infected Women and Their Infants in Pune, India, 2002–2005. Clin Infect Dis. 2007;45(2):241–9. Uganda Ministry of Health. Guidelines for Programmatic Management of Latent TB Infection in Uganda; A Health Worker Guide. 2021. World Health Organization. Global tuberculosis report 2022. Geneva; 2022. Lukoye D, Gustavson G, Namuwenge PM, Muchuro S, Birabwa E, Dejene S, et al. Tuberculosis Preventive Therapy among Persons Living with HIV, Uganda, 2016–2022. Emerg Infect Dis. 2023;29(3):609–13. Musaazi J, Sekaggya-Wiltshire C, Okoboi S, Zawedde-Muyanja S, Senkoro M, Kalema N, et al. Increased uptake of tuberculosis preventive therapy (TPT) among people living with HIV following the 100-days accelerated campaign: A retrospective review of routinely collected data at six urban public health facilities in Uganda. PLoS ONE. 2023;18(2):e0268935. Kalk E, Heekes A, Mehta U, de Waal R, Jacob N, Cohen K, et al. Safety and Effectiveness of Isoniazid Preventive Therapy in Pregnant Women Living with Human Immunodeficiency Virus on Antiretroviral Therapy: An Observational Study Using Linked Population Data. Clin Infect diseases: official publication Infect Dis Soc Am. 2020;71(8):e351–8. Theron G, Montepiedra G, Aaron L, McCarthy K, Chakhtoura N, Jean-Philippe P, et al. Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus. Clin Infect diseases: official publication Infect Dis Soc Am. 2021;72(11):e784–90. Uganda Ministry of Health. Consolidated guidelines for Prevention and Treatment of HIV in Uganda. 2016. Uganda Ministry of Health. Isoniazid Preventive Therapy in Uganda - A Health worker's guideline. 2014. Uganda Ministry of Health. 100-Day Accelerated Isoniazid Preventive Therapy Scale Up Plan. 2019. Kit OD. Open Data Kit documentation. [Available from: https://docs.opendatakit.org Uganda Ministry of Health METS. Uganda Electronic Medical Records (EMR) System User Manual [Available from: https://github.com/METS-Programme/ugandaemr-usermanual Uganda Ministry of Health. Essential Maternal and Newborn Clinical Care Guidelines for Uganda. Kampala. 2022 May, 2022. Moore K, Persaud V, Torchia M, Keith L, Moore TVN. Torchia: The Developing Human. Clinically Oriented Embryology. 11th edition. Elsevier, 20202020. Shafi J, Virk MK, Kalk E, Carlucci JG, Chepkemoi A, Bernard C, et al. Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment, and Findings from Low- and Middle-Income Countries: A Scoping Review. Drug Saf. 2024;47(10):957–90. Raatikainen K, Heiskanen N, Heinonen S. Under-attending free antenatal care is associated with adverse pregnancy outcomes. BMC Public Health. 2007;7:268. Bater J, Lauer JM, Ghosh S, Webb P, Agaba E, Bashaasha B, et al. Predictors of low birth weight and preterm birth in rural Uganda: Findings from a birth cohort study. PLoS ONE. 2020;15(7):e0235626. Taylor AW, Mosimaneotsile B, Mathebula U, Mathoma A, Moathlodi R, Theebetsile I, et al. Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy. Infect Dis Obstet Gynecol. 2013;2013:195637. Salazar-Austin N, Cohn S, Lala S, Waja Z, Dooley KE, Hoffmann CJ, et al. Isoniazid Preventive Therapy and Pregnancy Outcomes in Women Living With Human Immunodeficiency Virus in the Tshepiso Cohort. Clin Infect diseases: official publication Infect Dis Soc Am. 2020;71(6):1419–26. Centers for Disease Control and Prevention (CDC). The Metropolitan Atlanta Congenital Defects Program (MACDP) 2024 [updated May 16, 2024. Available from: https://www.cdc.gov/birth-defects/tracking/?CDC_AAref_Val=https://www.cdc.gov/ncbddd/birthdefects/macdp.html Additional Declarations No competing interests reported. Supplementary Files SUPPLEMENTARY.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7170241","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507693608,"identity":"c448cdb2-f571-45ab-aebb-ae042c94158b","order_by":0,"name":"Joseph Musaazi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYBACxgYIzcPPzGBwgDQtks3EaoEDoHoD4lQyTztj/OFHTZ2M8XHmjQcYamwYDM4vIOCw2Tlmkj3H2HjMDrMVHGA4lsZgcOMBYS0MPGw8QC08BgcYGw4DtRwgqMX4459/EjzGzSRoMZDmbTPgMWCGaTnfQEhLWpm0bF8CjwTILwnH0ngkb+DXwWA4O3nzxzff6uz5+w9v/vChxkaO7zwBhxmiuCIBGKcMEgn4tchjCvETsGUUjIJRMApGHAAAlOlBRwmiadgAAAAASUVORK5CYII=","orcid":"","institution":"Infectious Diseases Institute, Makerere University College of Health Sciences","correspondingAuthor":true,"prefix":"","firstName":"Joseph","middleName":"","lastName":"Musaazi","suffix":""},{"id":507693610,"identity":"0e93b29a-b343-4f1e-91fa-1de2d0c37dd9","order_by":1,"name":"Christine Sekaggya-Wiltshire","email":"","orcid":"","institution":"Infectious Diseases Institute, Makerere University College of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"","lastName":"Sekaggya-Wiltshire","suffix":""},{"id":507693611,"identity":"ef08c5d1-bc10-4393-94e5-7213f56b853f","order_by":2,"name":"Stella Zawedde-Muyanja","email":"","orcid":"","institution":"Infectious Diseases Institute, Makerere University College of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Stella","middleName":"","lastName":"Zawedde-Muyanja","suffix":""},{"id":507693614,"identity":"1e0ed69d-03a9-482a-9154-ce6735b4a98d","order_by":3,"name":"Proscovia M. Namuwenge","email":"","orcid":"","institution":"National Tuberculosis and Leprosy Program, Uganda Ministry of Health","correspondingAuthor":false,"prefix":"","firstName":"Proscovia","middleName":"M.","lastName":"Namuwenge","suffix":""},{"id":507693615,"identity":"af868ced-6e5e-4b97-8fea-5e10a9c9c4bc","order_by":4,"name":"M. Sanni Ali","email":"","orcid":"","institution":"London School of Hygiene \u0026 Tropical Medicine","correspondingAuthor":false,"prefix":"","firstName":"M.","middleName":"Sanni","lastName":"Ali","suffix":""},{"id":507693616,"identity":"6ce7d83d-4bdc-43a1-9d68-e471e373b4ac","order_by":5,"name":"Yukari C Manabe","email":"","orcid":"","institution":"Johns Hopkins University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yukari","middleName":"C","lastName":"Manabe","suffix":""},{"id":507693617,"identity":"7dbb9b97-1fce-4823-bb94-941a9cf0ab96","order_by":6,"name":"Barbara Castelnuovo","email":"","orcid":"","institution":"Infectious Diseases Institute, Makerere University College of Health Sciences","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Castelnuovo","suffix":""},{"id":507693618,"identity":"5c1284b6-98b5-44f6-99b6-6c572b1ded38","order_by":7,"name":"Nele Brusselaers","email":"","orcid":"","institution":"University of Antwerp","correspondingAuthor":false,"prefix":"","firstName":"Nele","middleName":"","lastName":"Brusselaers","suffix":""}],"badges":[],"createdAt":"2025-07-20 14:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7170241/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7170241/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90464375,"identity":"acbf03a9-385d-42a5-a93c-1335812eee0c","added_by":"auto","created_at":"2025-09-03 05:09:00","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":277555,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrevalence of adverse pregnancy outcomes by timing of TPT exposure\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7170241/v1/8bb5197dc6277edd89c04b7b.jpeg"},{"id":90464373,"identity":"8a01d52e-544f-44ee-a6ca-ce276293572e","added_by":"auto","created_at":"2025-09-03 05:09:00","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":211437,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup Analysis for the impact of TPT-exposure during pregnancy on pregnancy outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLegend:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroups for ART started after Sep 2018 (Yes) denotes participants initiated on ART after September 2018, which coincides with dolutegravir-based ART regimen roll-out in Uganda, whereas ART started after Sep 2018 (No) denotes those were initiated on ART before September 2018.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7170241/v1/1bfbb630414fa2f5bf8a03bf.jpeg"},{"id":93097315,"identity":"dffa0850-7177-4bbe-939f-134b992155ac","added_by":"auto","created_at":"2025-10-09 03:54:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1592100,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7170241/v1/65376ad1-0953-4737-89e7-a1c52d7f26ea.pdf"},{"id":90464376,"identity":"b98741d1-6b2c-4a40-9a2c-17035cfe42f3","added_by":"auto","created_at":"2025-09-03 05:09:00","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24718,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARY.docx","url":"https://assets-eu.researchsquare.com/files/rs-7170241/v1/15a7b21b86317aa0ffc5435b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of Tuberculosis Preventive Treatment on Adverse Pregnancy Outcomes in women living with HIV in Uganda: A Quasi-experimental study using routine care data","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe World Health Organization (WHO) recommends tuberculosis preventive treatment (TPT) for people living with HIV (PLHV) including pregnant women, to reduce the risk of developing active tuberculosis(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). However, some studies show that pregnancy is associated with increased risk of hepatoxicity in women living with HIV(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), with higher risk among those exposed to isoniazid preventive therapy (IPT) compared to those not exposed(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). For instance, the IMPAACT P1078 randomized controlled trial, conducted across 13 sites in 8 high TB-burden countries reported a higher risk of adverse pregnancy outcomes in a composite outcome that included stillbirth or spontaneous abortion, low birth weight, preterm delivery, and congenital anomalies among women who initiated IPT during pregnancy (24%) versus those who deferred initiation until postpartum (17%) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Conversely, a systematic review that included the IMPAACT P1078 trial reported mixed findings. Of the five studies reviewed, only the P1078 trial, a randomized controlled trial, identified a significantly increased risk of adverse pregnancy outcomes associated with IPT exposure during pregnancy, whereas the remaining observational studies found no such association (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). These divergent findings highlight ongoing uncertainty about the safety of IPT during pregnancy, particularly in real-world settings.\u003c/p\u003e\u003cp\u003eUganda bears a high burden of both TB and HIV. According to the 2023 joint United Nations programme on HIV/AIDS (UNAIDS), HIV prevalence among Ugandan women aged 15–49 years is 6.6%, nearly double that of men (3.6%) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The 2015 Uganda National TB Survey estimated TB incidence at 198 cases per 100,000 population (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). TB during pregnancy or the postpartum period has been associated with serious outcomes, including spontaneous abortion, low birth weight, preterm delivery (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), and perinatal mortality(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Following WHO recommendations, the Uganda Ministry of Health (MoH) adopted TPT for high-risk populations in 2021, including pregnant women living with HIV (WLHIV), based on the presumption that benefits outweigh potential risks (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). By 2023, TPT uptake and completion rates among PLHIV in Uganda had surpassed 90%, with higher completion observed among women than men (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), reflecting both strong program implementation and national commitment to TB control.\u003c/p\u003e\u003cp\u003eDespite these gains, data on TPT safety during pregnancy remain limited, especially from routine care settings in high-burden countries. While both clinical trials and observational studies have assessed safety (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), evidence from real-world programmatic data remains scarce. Although the P1078 trial demonstrated a modest increase in adverse outcomes with pregnancy-initiated IPT, WHO and Uganda-MoH recommends TPT for pregnant WLHIV especially residing in high TB burden settings, emphasizing that the benefits outweigh the risks.\u003c/p\u003e\u003cp\u003eThis study aimed to evaluate the association between the tuberculosis preventive therapy (IPT) use during pregnancy and adverse pregnancy outcomes including spontaneous abortion or miscarriage, stillbirth, low birth weight, congenital anomalies, and maternal or neonatal death among pregnant WLHIV. Using routinely collected programmatic data, we assessed both the prevalence of adverse outcomes and the potential impact of TPT exposure during pregnancy.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cb\u003eStudy design, population and setting\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy design and population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe conducted a quasi-experimental study using routinely collected clinical data from five public primary health care facilities in Kampala Capital City Authority, Uganda. The clinics provide free care and treatment for people living with HIV (PLHV) through the President's Emergency Plan for AIDS Relief (PEPFAR) program, including antiretroviral treatment, and prophylaxis for opportunistic infections and tuberculosis, and antenatal services. The clinics maintain registers for the TPT program, antenatal and post-partum visits; other individual clinical data is collected into the Uganda electronic medical record (EMR) system.\u003c/p\u003e\u003cp\u003eThe study population included pregnant women living with HIV (WLHIV), aged 15 years and older, who initiated antiretroviral therapy (ART) between January 2016 and December 2023, coinciding with the rollout of the HIV Test and Treat strategy and expanded TPT provision in Uganda(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe excluded women with missing ART initiation dates, those with a ≥ 12-month gap in HIV clinic attendance, and women who initiated TPT before starting ART to minimize confounding due to the absence of ART’s protective effect against TB at the time of TPT initiation.\u003c/p\u003e\u003cp\u003e The study sites were purposively selected due to the relative completeness and reliability of their clinical documentation compared to other facilities in the region. Kampala was selected as the study setting due to its high burden of both HIV and tuberculosis (TB) relative to other regions in Uganda.\u003c/p\u003e\u003cp\u003e\u003cb\u003eProgrammatic Implementation of TPT in Uganda\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn 2015, the Uganda-MoH adopted and expanded the WHO recommendation to provide TPT to all people at risk of developing active TB. This includes all PLHV including pregnant women without active TB, and household contacts of individuals with confirmed TB disease.\u003c/p\u003e\u003cp\u003eFrom 2015 until 2021, isoniazid monotherapy, taken daily for six months, was the only available TPT option recommended for asymptomatic PLHIV in Uganda(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). In 2021, the Uganda-MoH rolled out revised national TPT guidelines, incorporating rifamycin-based shorter-course regimens to improve uptake and adherence (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBetween 2018 and 2023, the Uganda-MoH intensified efforts to expand TPT coverage among PLHV through a series of strategic interventions. In July 2019, the Uganda-MoH launched a 100-day accelerated IPT scale-up campaign aimed at initiating 300,000 PLHV on TPT and achieve \u0026gt; 90% completion rate among those initiated(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). In 2021, the Uganda-MoH updated national guidelines that integrated TPT into the routine HIV care package for all PLHV without symptoms of TB (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). These guidelines endorsed the use of shorter-course, rifamycin-based TPT regimens alongside isoniazid monotherapy, to improve adherence and programmatic uptake. While earlier TPT guidelines in Uganda permitted isoniazid use at any stage of pregnancy, the 2021 revision introduced more restrictive criteria for TPT provision in pregnant WLHV. Under the new guidance, TPT during pregnancy was recommended only for those with CD4 counts \u0026lt; 200 cells/mm³, WHO stage III or IV HIV disease, or a history of contact with a person with bacteriologically confirmed pulmonary TB. For all other pregnant WLHIV, TPT initiation was advised to be deferred until three months postpartum (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eData extraction and collection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBetween July 2020 to March 2021, trained research assistants abstracted demographic, clinical, and pregnancy data from TPT, maternity and antenatal registers using a structured abstraction tool programmed in Open Data Kit (ODK)(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). To ensure data quality, built-in validation checks were applied within the ODK tool. Additional quality assurance measures included training research assistants in standardized data abstraction procedures and conducting daily reviews of the collected data.\u003c/p\u003e\u003cp\u003eAdditional data were obtained directly from the Uganda Electronic medical records (EMR) database system (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) using a pre-defined abstraction guide. Data from the different sources were linked using the patient's unique HIV clinic identifier number.\u003c/p\u003e\u003cp\u003eThe specific data variables extracted are described in section below. To select study participants, systematic random sampling was employed at each of the five health facilities. The sampling interval was calculated by dividing the total number of eligible patients at each facility by the number of participants allocated to that site.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome measure and covariates\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe primary outcome was a composite measure of adverse pregnancy outcomes, defined as the occurrence of any of the following: spontaneous abortion/miscarriage, stillbirth, low birth weight, congenital anomalies, neonatal death, or maternal death. Individual pregnancy outcomes were assessed as secondary outcomes. The denominator was all pregnant WLHIV included in the study. For participants with multiple pregnancy events, the most recent pregnancy was used for analysis. The pregnancy event date was estimated as the first clinic visit at which pregnancy was recorded. Preterm birth was excluded from the composite outcome due to a lack of documented data in the reviewed pregnancy records.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDefinitions of individual pregnancy outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSpontaneous Abortion (miscarriage)\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe loss of a fetus before 20 gestation weeks of pregnancy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eStillbirth\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe death of a fetus at or after 20 weeks of pregnancy.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eLow Birth Weight\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eBabies born weighing less than 2,500 grams (5 pounds, 8 ounces).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCongenital Anomalies in an Infant\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAlso known as birth defects, these are structural or functional abnormalities that occur during intrauterine life and can be identified prenatally, at birth, or later in life. Major anomalies to be defined according to the Metropolitan Atlanta Congenital Defects Program of the Centers for Disease Control and Prevention(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eNeonatal Mortality\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe death of a live-born baby within the first 28 days of life.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMaternal Mortality\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThe death of a woman during pregnancy, childbirth, or within 42 days of termination of pregnancy, from any cause related to or aggravated by the pregnancy or its management.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe primary exposure was tuberculosis preventive therapy (TPT) using 6-months isoniazid prophylaxis during pregnancy, which was the only regimen available during the study period. A secondary analysis further classified TPT exposure by trimester: no exposure, 1st trimester (\u0026lt; 13 weeks), 2nd trimester (13–28 weeks), and 3rd trimester (29–40 weeks), in accordance with national guidelines (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) and previous studies (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePotential covariates included both clinical and reproductive factors. Clinical variables comprised viral load (copies/mL), nadir CD4 count at ART start (cells/µL), ART regimen type at the time of pregnancy, ART duration in months, WHO HIV clinical stage (I/II vs III/IV), body mass index (BMI, kg/m²) and, ART initiation calendar year before and after September 2018 to coincides with dolutegravir-based ART regimen roll-out in Uganda. Viral load during pregnancy was defined as the closest measurement within 12 months before or 6 months after the pregnancy event date. Baseline CD4 count at ART start was defined as any test conducted within 6 months before or 3 months after ART start. Reproductive factors included maternal age (in years), gestational age (in weeks) at first antenatal care (ANC) visit, parity, gravidity, number of ANC visits, and anemia. Information on other maternal health conditions such as preeclampsia, hypertension, diabetes, and sexually transmitted infections (including syphilis) were limited or inconsistently recorded and therefore excluded from the analysis. Pre-pregnancy weight was defined as the most recent recorded weight within six months prior to the first documented pregnancy visit.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSample size and statistical power\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total sample size of 538 pregnant WLHIV (269 per group) was estimated to provide 80% power to detect a ≥ 10 percentage-point difference in adverse pregnancy outcomes between exposed and unexposed groups, assuming a baseline risk of 17% in the unexposed group (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), with a two-sided alpha of 0.05 and a Pearson Chi-square test.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics (frequencies, percentages, means with standard deviations, or medians with interquartile ranges) were used to summarize participant characteristics. For longitudinal variables such as weight, missing values were imputed using last observation carried forward (LOCF).\u003c/p\u003e\u003cp\u003eThe primary outcome; any adverse pregnancy outcome was compared between women exposed and unexposed to TPT during pregnancy using the Pearson Chi-square test. To address confounding, inverse probability of treatment weighting (IPTW) using stabilized propensity scores was applied, followed by weighted logistic regression models for effect estimation. Missing data were addressed using multiple imputation by chained equations (MICE) with five imputations via predictive mean matching for continuous and logistic model for binary variables. Details of the imputation models used for each covariate with missing values are provided in Supplementary Section, Table S1.\u003c/p\u003e\u003cp\u003eSubgroup analyses were conducted based on CD4 count (\u0026lt; 200 vs ≥ 200 cells/µL), viral load (\u0026lt; 200 vs ≥ 200 copies/mL), age (\u0026lt; 25 vs ≥ 25 years), ART initiation year (\u0026lt; 2018 vs ≥ 2018), and BMI (\u0026lt; 18.5, 18.5–\u0026lt;25, ≥ 25 kg/m²), selected based on clinical relevance and prior evidence. Pregnancy weight was defined as the most recent weight within six months prior to the first recorded pregnancy visit.\u003c/p\u003e\u003cp\u003eSensitivity analyses included unadjusted, covariate-adjusted, and Firth penalized logistic regression models, the latter used to address sparse outcomes. Firth regression was not used in the primary analysis due to incompatibility with imputed datasets. Statistical significance was set at 5% level.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eParticipants description\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 521 pregnant women living with HIV were included in this analysis (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Of these, 227 (44%) had used IPT for TPT during pregnancy, while 294 (56%) had not. Among those who used IPT, 139 (61%) started IPT in 1st trimester, 58 (26%) in the 2nd trimester, and 30 (13%) in the 3rd trimester. In the IPT unexposed group, 149 (51%) had completed IPT course before the onset of pregnancy, and 145 (49%) had never received IPT.\u003c/p\u003e\n\u003cp\u003eOverall, the median age at current pregnancy was 28 years (interquartile range [IQR] 24 to 31 years), 50.3% (238/473) had\u0026thinsp;\u0026ge;\u0026thinsp;2 prior live births, 0.6% were in HIV WHO stage 3 or 4, with median time on ART of 22 months (IQR: 0 to 53 months). At their first recorded antenatal visits, the median gestation age was 24 weeks (IQR: 18 to 30 weeks), implying that majority of the women had their first ANC visit in their 2nd trimester (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePregnant women living with HIV\u0026rsquo; characteristics at first antenatal visit by TPT exposure status during pregnancy*\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTotal\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTPT Unexposed group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTPT Exposed group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;521\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;294\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;227\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge in years, median (IQR) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (24, 31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (24, 32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (24, 31)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.403\u0026Dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParity\u0026thinsp;\u0026ge;\u0026thinsp;2 births\u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e238 (50.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125 (48.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e113 (52.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.374\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI in Kgs/m\u003csup\u003e2\u003c/sup\u003e, median (IQR) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.9 (22.3, 27.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.9 (22.2, 27.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24.9 (22.7, 27.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.750\u0026Dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWHO HIV stage 3/4, n (%) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (0.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 (0.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.469\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestation age at first ANC visit in weeks, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (18, 30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23 (18, 30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (20, 32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.013\u0026Dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCD4 count at ART start, in cells/mL, median (IQR) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e408 (243, 584)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e413 (215, 586)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e396 (268, 584)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.820\u0026Dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNadir CD4 count\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/mL, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73 (18.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (21.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28 (15.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.158\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eViral load at pregnancy \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;200 copies/mL, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e299 (89.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163 (88.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e136 (90.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.452\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;1000 copies/mL, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e308 (91.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e168 (90.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e140 (93.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.444\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eART start after 2018 \u0026dagger;\u0026yen;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e142 (32.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 (21.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92 (44.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eART duration in months, median (IQR) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (0, 53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (6, 56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (0, 46)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u0026Dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eART duration\u0026thinsp;\u0026ge;\u0026thinsp;2 years, n (%) \u0026dagger;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e245 (48.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e144 (52.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e101 (44.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.072\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eART regimen at pregnancy \u0026para;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDTG based\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (6.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (7.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (5.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"4\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.559\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEFV based\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e444 (89.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e240 (87.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e204 (91.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNVP based\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (2.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (2.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eATV/r or LPV/r\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (1.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e* Number of women exposed to TPT during pregnancy in: 1st trimester (n\u0026thinsp;=\u0026thinsp;139), 2nd trimester (n\u0026thinsp;=\u0026thinsp;58), and 3rd trimester (n\u0026thinsp;=\u0026thinsp;30). Among the unexposed group, n\u0026thinsp;=\u0026thinsp;149 had completed TPT before pregnancy onset, n\u0026thinsp;=\u0026thinsp;145 had never been exposed to TPT.\u003c/p\u003e\n\u003cp\u003e\u0026dagger; Missing values: age (n\u0026thinsp;=\u0026thinsp;3), parity (n\u0026thinsp;=\u0026thinsp;48), BMI (n\u0026thinsp;=\u0026thinsp;38), WHO stage (n\u0026thinsp;=\u0026thinsp;47), nadir CD4 (n\u0026thinsp;=\u0026thinsp;130, 25%), Viral load (n\u0026thinsp;=\u0026thinsp;186, 36%), ART duration (n\u0026thinsp;=\u0026thinsp;20, 4%), 5 of those with ART start date had no regimen specified.\u003c/p\u003e\n\u003cp\u003e\u0026Dagger; P-values derived using Man-Whitney Wilcoxon rank-sum test to comparing medians across groups, else P-values were derived using Pearson Chi-square test\u003c/p\u003e\n\u003cp\u003e\u0026yen; ART initiation calendar year before and after September 2018 to coincides with dolutegravir-based ART regimen roll-out in Uganda. This stratification helped to explore whether there\u0026rsquo;s interaction between TPT exposure before versus after DTG-based regimen DTG roll-out in Uganda.\u003c/p\u003e\n\u003cp\u003e\u0026para; ART regimen at pregnancy, 97% were on TDF based regimen on overall (96% in unexposed group, 98% in exposed group).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePregnancy outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 521 enrolled participants, pregnancy outcome data were available for 472 (90.6%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Among those with complete data, 47 women (10.0%) experienced at least one adverse pregnancy outcome.\u003c/p\u003e\n\u003cp\u003eThere was no statistically significant difference in the prevalence of adverse pregnancy outcomes between women exposed to TPT during pregnancy and those unexposed (22/213, 10.3% versus 25/259, 9.6% respectively, p-value\u0026thinsp;=\u0026thinsp;0.81). After adjusting for potential confounding using inverse probability of treatment weighting (IPTW), and completing missing values using multiple imputation, the pooled weighted estimates still showed no evidence for an increased risk of adverse pregnancy outcome due to TPT exposure during pregnancy (pooled weighted odds ratio [OR], 1.04; 95% confidence interval [CI], 0.69 to 1.58; p\u0026thinsp;=\u0026thinsp;0.84) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The distribution of composite adverse pregnancy outcomes across categories of covariates is detailed in Supplementary Section, Table S2.\u003c/p\u003e\n\u003cp\u003eSensitivity analyses yielded consistent results; re-running the analysis using Firth penalized logistic regression which accounts for sparse data bias, it further revealed no effect of TPT exposure during pregnancy on risk of adverse pregnancy outcome (adjusted OR, 1.08; 95% CI, 0.59 to 1.97). Similarly, conventional complete case analysis and covariate-adjusted logistic regression with multiply-imputed data showed no significant association (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eLow birth weight was the most frequent adverse outcome, occurring in 16 of 472 participants (3.4%), but was not significantly different between the TPT-exposed and TPT-unexposed (p-value\u0026thinsp;=\u0026thinsp;0.53). The overall median birth weight was 3200 g (IQR, 3000 to 3500 g). Additionally, there was no significant association between TPT exposure and other individual pregnancy outcomes; spontaneous abortion, stillbirth, neonatal or maternal deaths (all p-values were \u0026ge;\u0026thinsp;0.20) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAmong women who received TPT during pregnancy, the highest prevalence of adverse outcomes was observed in those who initiated TPT in the third trimester (6/29; 20.7%), compared with those who initiated in the first (12/130; 9.2%) or second trimester (4/54; 7.4%). However, this difference did not reach statistical significance (p-value\u0026thinsp;=\u0026thinsp;0.38) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, Supplementary Section Table S3). Stillbirth was the most frequently observed adverse event among those who initiated TPT in the third trimester (Supplementary Section, Table S4).\u003c/p\u003e\n\u003cp\u003eIn exploratory subgroup analyses (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), there was no significant interactions effect of being on TPT during pregnancy, and selected covariates which included; timing of ART initiation, HIV viral load at the first antenatal visit, or baseline CD4 count (all interaction p\u0026thinsp;\u0026gt;\u0026thinsp;0.10).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003ePregnancy outcomes by TPT-exposure status during pregnancy\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePregnancy outcomes\u0026para;\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTPT-exposed\u003c/p\u003e\n\u003cp\u003en (%)\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;213\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTPT-unexposed\u003c/p\u003e\n\u003cp\u003en (%)\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;259\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRisk difference (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP-value\u0026dagger;\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNon-adverse outcome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e191 (89.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e234 (90.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eN/A\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdverse outcome\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (10.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e25 (9.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.7 (-4.8,6.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eSpecific adverse outcomes\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLow birth weight (\u0026lt;\u0026thinsp;2500g)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e10 (3.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-1.0 (-4.3, 2.2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.53\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSpontaneous abortion or miscarriage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (1.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e6 (2.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.9 (-3.3, 1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStillbirth\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (2.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.0 (-0.4, 4.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeonatal death\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1 (0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.4 (-1.1, 0.4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.37\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMaternal death\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2 (0.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.8 (-1.8, 0.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther anomalies: Difficulty in breathing\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (3.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e4 (1.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.7 (-1.1, 4.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.21\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026para; Analysis performed on n\u0026thinsp;=\u0026thinsp;472 women who had pregnancy outcomes, 49/521 (9%) had missing pregnancy outcome.\u003c/p\u003e\n\u003cp\u003e\u0026dagger;Pearson Chi-square P-value comparing adverse pregnancy outcomes between women exposed to TPT during pregnancy versus those who were not. % denote column percentages\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eWeighted odds ratios and 95% confidence intervals for the impact of Isoniazid TPT monotherapy taken during pregnancy on adverse pregnancy outcomes\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOdds Ratio (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary analysis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIPTW weighted Logistic regression model\u0026yen;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.04 (0.69, 1.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.84\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analyses\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnadjusted Logistic regression model (complete case)\u0026para;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.08 (0.59, 1.97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnadjusted Logistic regression model (imputed)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.08 (0.60, 1.96)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.80\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCovariates-adjusted Logistic regression model\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.01(0.51, 12.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFirth penalized logistic regression model\u003csup\u003e\u0026Dagger;\u0026para;\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.08 (0.59, 1.97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.81\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eOR\u0026thinsp;=\u0026thinsp;odds ratio; IPTW\u0026thinsp;=\u0026thinsp;inverse probability of treatment weighting; TPT\u0026thinsp;=\u0026thinsp;tuberculosis preventive therapy.\u003c/p\u003e\n\u003cp\u003e\u0026yen; Pooled Odds Ratios and their 95% confidence intervals (95%CI) were estimated from Pooled Weighted Logistic Regression. Propensity scores used to generate Inverse Probability Treatment Weighted (IPTW) weights were calculated using a logistic regression model with covariates: maternal age, body mass index, anemia during antenatal care, ART duration, CD4\u0026thinsp;\u0026lt;\u0026thinsp;200, viral load\u0026thinsp;\u0026lt;\u0026thinsp;200, ART regimen timing (pre/post-September 2018), and parity\u0026thinsp;\u0026ge;\u0026thinsp;2. Missing data were completed using Multiple Imputation with chained equations using 5 imputations, via predictive mean matching for continuous and logistic model for binary variables. See Table S1 for details on specific imputation models used.\u003c/p\u003e\n\u003cp\u003e\u0026para; Complete case estimates analyzed on 472 participants (excluding 49 with missing pregnancy outcomes)\u003c/p\u003e\n\u003cp\u003e\u0026dagger;Covariate-adjusted logistic regression model included the same variables as the PS model.\u003c/p\u003e\n\u003cp\u003e\u0026Dagger;Firth penalized logistic regression model used to reduce sparse data bias.\u003c/p\u003e\n\u003cp\u003eAdverse pregnancy outcomes defined as proportion of composite outcome that includes any of the following: spontaneous abortion/miscarriage, stillbirth, preterm delivery, low birth weight, congenital anomalies, neonatal death, or maternal death.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study contributes to the body of knowledge about safety of TPT during pregnancy. Using routinely collected programmatic data from urban HIV clinics in Uganda, we evaluated the association between TPT exposure during pregnancy and adverse pregnancy outcomes. We found no statistically significant increase in the risk of composite or individual adverse outcomes that included; spontaneous abortion or miscarriage, stillbirth, low birth weight, congenital anomalies, maternal, or neonatal death among WLHIV on antiretroviral therapy (ART) who received IPT. These findings were consistent across causal inference models and sensitivity analyses, supporting their robustness.\u003c/p\u003e\u003cp\u003eWe did not observe evidence of effect modification by maternal viral load during pregnancy, baseline CD4 count, or timing of IPT initiation in relation to the rollout of dolutegravir-based ART in Uganda. However, the study may have been underpowered to detect interaction effects, limiting our ability to assess heterogeneity in IPT safety across subgroups.\u003c/p\u003e\u003cp\u003eLow birth weight emerged as the most common adverse outcome, consistent with findings from the IMPAACT P1078 trial, which attributed low birth weight to maternal factors such as poor nutrition and smoking(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Unfortunately, our dataset lacked information on these potential confounders, limiting exploration of their role in our cohort.\u003c/p\u003e\u003cp\u003eAlthough statistically non-significant, we observed slightly higher proportions of stillbirth and congenital anomalies of about 2 percentage points higher among IPT-exposed women. Notably, four of the six stillbirths occurred among those initiating IPT in the first trimester, a period critical to fetal development (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). These signals underscore the need for continued pharmacovigilance and larger studies to assess the safety of IPT during early pregnancy (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe also noted a higher frequency of adverse outcomes among women initiating IPT in the third trimester. Late IPT initiation may reflect delayed antenatal care, a known risk factor for poor outcomes such as stillbirth and preterm birth (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). These findings highlight the need to promote early antenatal attendance and ensure timely initiation of preventive therapies like IPT to improve pregnancy outcomes.\u003c/p\u003e\u003cp\u003eOur results align with observational studies from sub-Saharan Africa (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), and a systematic review by Hamada et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e), all suggesting no increased risk of adverse pregnancy outcomes with IPT. For instance, Taylor et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) found no association between IPT and adverse outcomes in Botswana, while Salazar-Austin et al. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) and Kalk et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) reported lower risks of adverse outcomes among IPT recipients in cohorts in South Africa. However, these studies are subject to residual confounding, as are ours, due to limited adjustment for key maternal risk factors.\u003c/p\u003e\u003cp\u003eIn contrast, Theron et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), using data from the IMPAACT P1078 randomized trial, reported significantly higher rates of composite adverse pregnancy outcomes among women initiating IPT during pregnancy versus postpartum. That study had strong internal validity, with a large sample size (925 mother\u0026ndash;infant pairs), conducted in 8 high TB countries, and rigorous adjustment for confounders. While our study used causal inference methods to minimize bias, unmeasured factors such as syphilis, hepatitis co-infection, multiple gestation, and other comorbidities were often undocumented and could still influence outcomes.\u003c/p\u003e\u003cp\u003eAbsence of increased risk of adverse pregnancy outcomes may reflect lower baseline risk in our cohort, as all women were already on ART at conception, and achieved viral suppression during pregnancy, factors known to protect against adverse outcomes and potentially mitigate adverse pregnancy outcomes.\u003c/p\u003e\u003cp\u003eA major strength of this study is its use of routine electronic medical record (EMR) data from multiple high-burden HIV/TB clinics in Uganda, enhancing generalizability in similar programmatic settings. Such data allow for practical evaluation of intervention safety within routine care, informing policy in contexts where randomized trials may not be feasible.\u003c/p\u003e\u003cp\u003eNonetheless, several limitations warrant consideration. First, misclassification and underreporting are possible, particularly for early pregnancy losses, preterm births, congenital anomalies, and maternal deaths, which may be inconsistently documented. Second, selection bias may have occurred, as most women initiated antenatal care in the second trimester, potentially excluding early losses. Third, key confounders such as syphilis, hepatitis, multiple gestation, nutritional status, and smoking were not available, limiting our ability to adjust for all relevant risk factors (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Finally, our modest sample size limited power to detect small or rare effects, though linked EMR data across several clinics enhances the external validity of our findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings show no evidence that 6-month isoniazid monotherapy TPT, delivered through routine HIV and antenatal care in Uganda, increases the risk of adverse pregnancy outcomes. However, interpretation should consider limitations such as limited statistical power and incomplete outcome documentation inherent to routine programmatic data. As TPT scale-up continues especially among pregnant women in high TB/HIV burden settings strengthening pharmacovigilance systems and ensuring systematic documentation of adverse events and relevant risk factors is essential. These efforts are critical to safeguarding maternal and neonatal health while supporting national and global goals for TB prevention among vulnerable populations, including women living with HIV.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWorld Health Organization\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHIV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAIDS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcquired Immune Deficiency Syndrome\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTB\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTuberculosis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTPT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTuberculosis Preventive Treatment\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIPT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIsoniazid Preventive Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eART\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntiretroviral Therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePLHV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePeople Living with HIV\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eWLHIV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eWomen Living with HIV\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eUganda\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMoH-Uganda Ministry of Health\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEMR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eElectronic Medical Record\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIPTW\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInverse Probability of Treatment Weighting\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003cp\u003e The AIDS Support Organization Research Ethics Committee (TASOREC), Kampala, Uganda (number: TASOREC/085/19-UG-REC-009) and the Uganda National Council for Science and Technology, Kampala, Uganda (UNCST number: HS729ES) granted ethical approval for the study. Due to the retrospective study design and that this was a public health surveillance, the need for patient informed consent was waived by the Ethic Committee.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eNot applicable\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe programme was supported by the President\u0026rsquo;s Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Centers for Disease Control (CDC) and Prevention (terms of Cooperative Agreement NU2GGH002022). Support for data collection was provided by the Fogarty International Center, National Institutes of Health (grant #2D43TW009771-06 \u0026lsquo;HIV and co-infections in Uganda\u0026rsquo;); and European \u0026amp; Developing Countries Clinical Trials Partnership (EDCTP) \u0026ndash; East Africa TB NODE (Grant number: EDCTP-RegNET2015-1104). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Research reported in this publication was supported by the Fogarty International Center of the National Institutes of Health under Award Number 2D43TW009771-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJM \u0026ndash; conceptualized the research idea and proposal, wrote the methodology, project administration, data collection supervision, data curation, data validation, formal analysis and writing the initial manuscript draft. JM, BC \u0026ndash; acquired the funding for data abstractionCS, BC, NB, MSA \u0026ndash; supervised project activitiesJM, CS, BC, NB, MSA, YCM, SZM, PMN \u0026ndash; Proposal and manuscript review \u0026amp; editing\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank various staff from the Infectious Diseases Institute (Kampala, Uganda) for their contributions: Dr Andrew KAmbugu, Dr Stephen Okoboi, J Nabbaale, A Nanvuma, G Banturaki, EJ Akumu, E Katunguka; D Kirumira, J Masika, C Kaidu, P Asiimwe, M Atugonza, NM Juma (research assistants); staff at the Kampala Capital City Authority (KCCA) Directorate of Public Health and Environment office in Uganda: D Okello, P Nazziwa; and staff and in-charges at the six KCCA healthcare facilities who assisted in retrieval of patients\u0026rsquo; records.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Global tuberculosis report 2023. Geneva; 2023.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOuyang DW, Shapiro DE, Lu M, Brogly SB, French AL, Leighty RM, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS. 2009;23(18):2425\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHamada Y, Figueroa C, Mart\u0026iacute;n-S\u0026aacute;nchez M, Falzon D, Kanchar A. The safety of isoniazid tuberculosis preventive treatment in pregnant and postpartum women: systematic review and meta-analysis. Eur Respir J. 2020;55(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta A, Montepiedra G, Aaron L, Theron G, McCarthy K, Bradford S, et al. Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women. N Engl J Med. 2019;381(14):1333\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHIV/AIDS JUNPo. UNAIDS Country Specific factsheets for Uganda 2023 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.unaids.org/en/regionscountries/countries/uganda\u003c/span\u003e\u003cspan address=\"https://www.unaids.org/en/regionscountries/countries/uganda\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. The Uganda National Tuberculosis Prevalence Survey, 2014\u0026ndash;2015. 2017 23 August 2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMathad JS, Gupta A. Tuberculosis in pregnant and postpartum women: epidemiology, management, and research gaps. Clin Infect diseases: official publication Infect Dis Soc Am. 2012;55(11):1532\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta A, Nayak U, Ram M, Bhosale R, Patil S, Basavraj A, et al. Postpartum Tuberculosis Incidence and Mortality among HIV-Infected Women and Their Infants in Pune, India, 2002\u0026ndash;2005. Clin Infect Dis. 2007;45(2):241\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. Guidelines for Programmatic Management of Latent TB Infection in Uganda; A Health Worker Guide. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Global tuberculosis report 2022. Geneva; 2022.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLukoye D, Gustavson G, Namuwenge PM, Muchuro S, Birabwa E, Dejene S, et al. Tuberculosis Preventive Therapy among Persons Living with HIV, Uganda, 2016\u0026ndash;2022. Emerg Infect Dis. 2023;29(3):609\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMusaazi J, Sekaggya-Wiltshire C, Okoboi S, Zawedde-Muyanja S, Senkoro M, Kalema N, et al. Increased uptake of tuberculosis preventive therapy (TPT) among people living with HIV following the 100-days accelerated campaign: A retrospective review of routinely collected data at six urban public health facilities in Uganda. PLoS ONE. 2023;18(2):e0268935.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKalk E, Heekes A, Mehta U, de Waal R, Jacob N, Cohen K, et al. Safety and Effectiveness of Isoniazid Preventive Therapy in Pregnant Women Living with Human Immunodeficiency Virus on Antiretroviral Therapy: An Observational Study Using Linked Population Data. Clin Infect diseases: official publication Infect Dis Soc Am. 2020;71(8):e351\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTheron G, Montepiedra G, Aaron L, McCarthy K, Chakhtoura N, Jean-Philippe P, et al. Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus. Clin Infect diseases: official publication Infect Dis Soc Am. 2021;72(11):e784\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. Consolidated guidelines for Prevention and Treatment of HIV in Uganda. 2016.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. Isoniazid Preventive Therapy in Uganda - A Health worker's guideline. 2014.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. 100-Day Accelerated Isoniazid Preventive Therapy Scale Up Plan. 2019.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKit OD. Open Data Kit documentation. [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://docs.opendatakit.org\u003c/span\u003e\u003cspan address=\"https://docs.opendatakit.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health METS. Uganda Electronic Medical Records (EMR) System User Manual [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://github.com/METS-Programme/ugandaemr-usermanual\u003c/span\u003e\u003cspan address=\"https://github.com/METS-Programme/ugandaemr-usermanual\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUganda Ministry of Health. Essential Maternal and Newborn Clinical Care Guidelines for Uganda. Kampala. 2022 May, 2022.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMoore K, Persaud V, Torchia M, Keith L, Moore TVN. Torchia: The Developing Human. Clinically Oriented Embryology. 11th edition. Elsevier, 20202020.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShafi J, Virk MK, Kalk E, Carlucci JG, Chepkemoi A, Bernard C, et al. Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment, and Findings from Low- and Middle-Income Countries: A Scoping Review. Drug Saf. 2024;47(10):957\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRaatikainen K, Heiskanen N, Heinonen S. Under-attending free antenatal care is associated with adverse pregnancy outcomes. BMC Public Health. 2007;7:268.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBater J, Lauer JM, Ghosh S, Webb P, Agaba E, Bashaasha B, et al. Predictors of low birth weight and preterm birth in rural Uganda: Findings from a birth cohort study. PLoS ONE. 2020;15(7):e0235626.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaylor AW, Mosimaneotsile B, Mathebula U, Mathoma A, Moathlodi R, Theebetsile I, et al. Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy. Infect Dis Obstet Gynecol. 2013;2013:195637.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSalazar-Austin N, Cohn S, Lala S, Waja Z, Dooley KE, Hoffmann CJ, et al. Isoniazid Preventive Therapy and Pregnancy Outcomes in Women Living With Human Immunodeficiency Virus in the Tshepiso Cohort. Clin Infect diseases: official publication Infect Dis Soc Am. 2020;71(6):1419\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCenters for Disease Control and Prevention (CDC). The Metropolitan Atlanta Congenital Defects Program (MACDP) 2024 [updated May 16, 2024. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/birth-defects/tracking/?CDC_AAref_Val=https://www.cdc.gov/ncbddd/birthdefects/macdp.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/birth-defects/tracking/?CDC_AAref_Val=https://www.cdc.gov/ncbddd/birthdefects/macdp.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tuberculosis Preventive Treatment (TPT), Pregnancy Outcomes, Women Living with HIV (WLHIV), Isoniazid Preventive Therapy (IPT), Sub-Saharan Africa, Routine Programmatic Data","lastPublishedDoi":"10.21203/rs.3.rs-7170241/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7170241/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eThe World Health Organization recommends tuberculosis preventive treatment (TPT) for people living with HIV, including pregnant women. However, data on the safety of TPT during pregnancy particularly from routine care settings in high tuberculosis (TB) burden countries remain limited. We evaluated the association between TPT exposure and adverse pregnancy outcomes among pregnant women living with HIV (WLHIV) in Uganda.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eWe conducted a quasi-experimental study using routinely collected data from five public urban primary health care facilities in Kampala, Uganda. We included pregnant WLHIV on antiretroviral therapy (ART) between 2016 and 2023. The primary outcome was a composite of adverse pregnancy outcomes: miscarriage, stillbirth, low birth weight, congenital anomalies, or maternal/neonatal death. The primary exposure was 6-months isoniazid TPT (IPT) during pregnancy. Analyses used inverse probability of treatment weighting (IPTW) using logistic regression model to adjust for confounding and multiple imputation for handling missing data.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eAnalysis included 521 pregnant WLHIV, 44% were exposed to IPT during pregnancy. Overall, 10.0% experienced an adverse pregnancy outcome, with no significant difference between IPT-exposed and unexposed groups (10.3% vs. 9.6%; p\u0026thinsp;=\u0026thinsp;0.81). Adjusted IPTW analysis showed no significant association between IPT exposure and adverse outcomes (pooled weighted odds ratio 1.04; 95% CI: 0.69\u0026ndash;1.58). Sensitivity and subgroup analyses yielded consistent results.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eWe found no evidence that 6-month isoniazid TPT increases the risk of adverse pregnancy outcomes. However, limitations in outcome and adverse event documentation from routine care may affect these findings. Strengthening pharmacovigilance and clinical reporting is essential to safeguard maternal and neonatal health as TPT coverage expands in high TB/HIV burden settings.\u003c/p\u003e","manuscriptTitle":"Impact of Tuberculosis Preventive Treatment on Adverse Pregnancy Outcomes in women living with HIV in Uganda: A Quasi-experimental study using routine care data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 05:08:23","doi":"10.21203/rs.3.rs-7170241/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a34595ef-5e60-41c6-b4c0-d0a92518c69e","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-09T03:53:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-03 05:08:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7170241","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7170241","identity":"rs-7170241","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}