Pregnancy Outcomes in Women Screened for Tuberculosis Infection in Swedish Antenatal Care.

BACKGROUND: Tuberculosis (TB) disease has been associated with pregnancy complications. However, the potential impact of TB infection (TBI) on pregnancy outcome is unknown. To investigate this, we conducted a register-based study in immigrant women screened with QuantiFERON assays for TBI in antenatal care in Sweden. METHODS: Women with history of immigration from TB-endemic countries were eligible for inclusion if national identification numbers and available QuantiFERON results obtained during pregnancy from 2014 to 2018 were available. QuantiFERON results were linked to data on maternal characteristics and pregnancy outcomes from the national Pregnancy and Patient Registers. TBI was defined as nil-corrected QuantiFERON result ≥0.35 IU/mL, in the absence of TB disease. Pregnancies in women with TB disease or human immunodeficiency virus were excluded, as were multiplex pregnancies, pregnancies resulting in miscarriage, and pregnancies occurring >10 years after immigration. Odds of defined adverse pregnancy outcomes were compared by maternal TBI status using mixed effects logistic regression with adjustment for maternal age and region of origin. RESULTS: In total, 7408 women with 12 443 pregnancies were included. In multivariable analysis, stillbirth (adjusted odds ratio [AOR], 1.90; 95% confidence interval [CI], 1.13-3.21; P = .016), severe preeclampsia (AOR, 1.62; 95% CI, 1.03-2.56; P = .036), low birthweight (<2500 g; AOR, 1.38; 95% CI, 1.01-1.88; P = .041), and emergency cesarean section (AOR, 1.28; 95% CI, 1.02-1.63; P = .033) were significantly associated with TBI. CONCLUSIONS: Among immigrant women seeking antenatal care in Sweden, TBI was independently associated with adverse pregnancy outcomes. Further studies are needed to corroborate these findings and to explore mechanisms involved.

Tuberculosis Infection and Disease Among Pregnant People Living in Sweden With Origin in Tuberculosis-Endemic Countries.

Background: Pregnancy has been associated with elevated incidence of tuberculosis (TB) disease. Since 2014, people living in Sweden with origin in TB-endemic countries have been offered screening for TB infection in antenatal care (ANC) using Quantiferon-TB assays. We assessed factors associated with TB infection in this population and determined the incidence of TB disease during pregnancy and postpartum periods with regard to ANC Quantiferon-TB results. Methods: Quantiferon-TB results obtained during ANC in Sweden, 2014-2018, were linked to data from national registers (Pregnancy Register, Patient Register and Tuberculosis Register). Factors associated with TB infection (defined as Quantiferon-TB ≥0.35 IU/mL) were identified using logistic regression analysis. Incidence of TB disease was determined with regard to pregnancy, postpartum and subsequent periods, and ANC Quantiferon-TB results. Results: Among 7638 screened individuals, 1424 (18.6%) had TB infection. Tuberculosis infection was independently associated with higher age at immigration (adjusted odds ratio, 1.04 [95% confidence interval, 1.03-1.05]; P < .001), and was more common among people originating from Africa compared to other world regions (845/3088 [27.4%] vs 579/4550 [12.7%]; P < .001). In total, 16 participants were diagnosed with TB disease (10 during pregnancy, 4 at <6 months after delivery, 2 at >6 months after delivery); among these, all diagnosed during pregnancy/postpartum had positive ANC Quantiferon-TB results (constituting 14/1424 [1%] of people with TB infection). Conclusions: Among pregnant people screened in Swedish ANC, TB infection was associated with higher age and African origin. All cases of TB disease reported in persons with TB infection at ANC screening occurred during pregnancy or postpartum.

High variability in tuberculosis treatment outcomes across 15 health facilities in a semi-urban area in central Ethiopia.

Background: Despite reported tuberculosis (TB) treatment success rate of 86%, TB remains a leading cause of death in Ethiopia. We investigated patient and provider-specific factors associated with unfavorable treatment outcomes in Ethiopian health facilities providing TB care. Methods: Data on characteristics and treatment outcomes of patients registered for TB treatment at 15 public health facilities (4 hospitals and 11 health centres) were collected from clinic registers. Proportions of unfavorable outcomes (defined as deaths, loss-to-follow-up [LTFU] and treatment failure), were compared across facilities using multivariable logistic regression, with separate analyses for death and LTFU. Results: Among 3359 patients (53.5 % male, median age 28 years, 19.6 % HIV-positive), 296 (8.8 %) had unfavorable treatment outcome. Proportions of unfavorable outcomes across facilities ranged from 2.0 % to 21.1 % (median 8.3 %). Median proportions of death and LTFU among facilities were 3.3 % (range 0-10.9 %) and 2.6 % (range 0.6 %-19.2 %), respectively. Three facilities had significantly higher rates of LTFU, whereas two facilities had higher rates of death. The two facilities with full-time TB-nurses had higher proportions of successful outcomes (95.2 % vs 90.1 %, adjusted odds ratio 2.27, p < 0.0001). Conclusion: Substantial variability of TB treatment outcomes was observed across the assessed health facilities providing TB care, independently of age and HIV co-infection, reflecting possible differences in service structure and related quality of care.

Intrauterine HIV exposure is associated with linear growth restriction among Ethiopian children in the first 18 months of life.

OBJECTIVE: The role of HIV exposure in determining growth among HIV-uninfected children is debated. We determined whether intrauterine HIV exposure influences linear growth in a cohort of Ethiopian children followed up to 18 months of age in public health facilities in Adama city, Ethiopia. METHODS: Participants were offspring of pregnant women enrolled in a prospective cohort study that included screening for HIV infection during antenatal care. Growth patterns of HIV-exposed and uninfected (HEU) and HIV-unexposed (HU) children were compared up to 18 months of age, with length-for-age z-score (LAZ) and proportion with stunting as primary outcomes. Multivariable linear and logistic regression models were constructed to investigate the associations between HIV exposure and linear growth, controlling for socio-demographic factors and breastfeeding status. RESULTS: Of 1705 included infants (164 HEU), 1276 remained in follow-up at 18 months. Among HIV-positive mothers, 132 (80.5%) were receiving antiretroviral therapy at enrolment. At the 18-month visit, mean LAZ was -1.08 among HEU children and -0.74 among HU children (p = 0.052). Proportions of HEU and HU children with stunting at the 18-month visit were 27.8% and 18.7%, respectively (p = 0.010). In multivariable models, HIV exposure was associated with lower LAZ at all follow-up visits, and with stunting at the 18-month visit (adjusted odds ratio 2.29, 95% confidence interval 1.40-3.71). HIV exposure was not associated with weight-related growth outcomes. CONCLUSIONS: HEU children in Ethiopia had inferior linear growth compared with HU children, implying that intrauterine HIV exposure impacts early childhood growth in this setting.

Dynamics of Mycobacterium tuberculosis-Specific and Nonspecific Immune Responses in Women with Tuberculosis Infection during Pregnancy.

The immune control of tuberculosis (TB) infection could be influenced by pregnancy. To elucidate this, we longitudinally characterized Mycobacterium tuberculosis (Mtb)-specific and nonspecific immune responses in women during pregnancy and postpartum. HIV-uninfected women without past or current active TB, and with blood samples available from the 1st/2nd trimester, 3rd trimester, and 9 months postpartum, were identified at Ethiopian antenatal care clinics. Twenty-two TB+ women and 10 TB- women, defined according to Mtb-stimulated interferon-γ levels (≥0.35 and <0.20 IU/mL, respectively, in the Quantiferon-TB Gold-Plus assay), were included in the study. Longitudinal dynamics of six cytokines (IL-1ra, IL-2, IP-10, MCP-2, MCP-3, and TGF-ß1) were analyzed in supernatants from Mtb-stimulated and unstimulated whole blood. In TB+ women, Mtb-specific expression of IL-2 and IP-10 was higher at 3rd compared to 1st/2nd trimester (median 139 pg/mL versus 62 pg/mL, P = 0.006; 4,999 pg/mL versus 2,310 pg/mL, P = 0.031, respectively), whereas level of Mtb-triggered TGF-ß1 was lower at 3rd compared to 1st/2nd trimester (-6.8 ng/mL versus 2.3 ng/mL, P = 0.020). Unstimulated IL-2, IP-10, and MCP-2 levels were increased postpartum, compared with those noted during pregnancy, in TB+ women. Additionally, postpartum levels of proinflammatory cytokines in unstimulated blood were higher in TB+ women, than in TB- women. None of the women developed active TB during follow-up. Taken together, dynamic changes of Mtb-specific cytokine expression revealed during the 3rd trimester in TB+ women indicate increased Mtb-antigen stimulation at later stages of pregnancy. This could reflect elevated bacterial activity, albeit without transition to active TB, during pregnancy. IMPORTANCE Tuberculosis (TB) is globally one of the most common causes of death, and a quarter of the world's population is estimated to have TB infection. The risk of active TB is increased in connection to pregnancy, a phenomenon that could be due to physiological immune changes. Here, we studied the effect of pregnancy on immune responses triggered in HIV-uninfected women with TB infection, by analyzing blood samples obtained longitudinally during pregnancy and after childbirth. We found that the dynamics of Mtb-specific and nonspecific immune responses changed during pregnancy, especially in later stages of pregnancy, although none of the women followed in this study developed active TB. This suggests that incipient TB, with elevated bacterial activity, occurs during pregnancy, but progression of infection appears to be counteracted by Mtb-specific immune responses. Thus, this study sheds light on immune control of TB during pregnancy, which could be of importance for future intervention strategies.

Ambient and indoor air pollution exposure and adverse birth outcomes in Adama, Ethiopia.

Air pollution poses a threat to human health, with pregnant women and their developing fetuses being particularly vulnerable. A high dual burden of ambient and indoor air pollution exposure has been identified in Ethiopia, but studies investigating their effects on adverse birth outcomes are currently lacking. This study explores the association between ambient air pollution (NOX and NO2) and indoor air pollution (cooking fuel type) and fetal and neonatal death in Adama, Ethiopia. A prospective cohort of mothers and their babies was used, into which pregnant women were recruited at their first antenatal visit (n = 2085) from November 2015 to February 2018. Previously developed land-use regression models were utilized to assess ambient concentrations of NOX and NO2 at the residential address, whereas data on cooking fuel type was derived from questionnaires. Birth outcome data was obtained from self-reported questionnaire responses during the participant's postnatal visit or by phone if an in-person meeting was not possible. Binary logistic regression was employed to assess associations within the final study population (n = 1616) using both univariate and multivariate models; the latter of which adjusted for age, education, parity, and HIV status. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) were reported. Within the cohort, 69 instances of fetal death (n = 16 miscarriages; n = 53 stillbirths) and 16 cases of neonatal death were identified. The findings suggest a tendency towards an association between ambient NOX and NO2 exposure during pregnancy and an increased risk of fetal death overall as well as stillbirth, specifically. However, statistical significance was not observed. Results for indoor air pollution and neonatal death were inconclusive. As limited evidence on the effects of exposure to ambient air pollution on adverse birth outcomes exists in Sub-Saharan Africa and Ethiopia, additional studies with larger study populations should be conducted.

Tuberculosis infection and stillbirth in Ethiopia-A prospective cohort study.

BACKGROUND: Tuberculosis is among the leading causes of death among infectious diseases. Regions with a high incidence of tuberculosis, such as sub-Saharan Africa, are disproportionately burdened by stillbirth and other pregnancy complications. Active tuberculosis increases the risk of pregnancy complications, but the association between latent tuberculosis infection (LTBI) and pregnancy outcomes is unknown. We explored the effect of latent tuberculosis infection on the risk of stillbirth in women attending antenatal care clinics in Ethiopia, a country with >170 000 annual cases of active tuberculosis. METHOD: Pregnant women were enrolled from antenatal care at three health facilities in Adama, Ethiopia, during 2015-2018, with assessment for previous and current active tuberculosis and testing for LTBI using QuantiFERON-TB-GOLD-PLUS. Proportions of stillbirth (≥ 20 weeks of gestation) and neonatal death (< 29 days of birth) were compared with respect to categories of maternal tuberculosis infection (tuberculosis-uninfected, LTBI, previous-, and current active tuberculosis). Multivariable logistic regression was performed for stillbirth. RESULTS: Among 1463 participants enrolled, the median age was 25 years, 10.2% were HIV-positive, 34.6% were primigravidae, and the median gestational age at inclusion was 18 weeks. Four (0.3%) were diagnosed with active tuberculosis during pregnancy, 68 (4.6%) reported previous treatment for active tuberculosis, 470 (32.1%) had LTBI, and 921 (63.0%) were tuberculosis-uninfected. Stillbirth was more frequent in participants with LTBI compared to tuberculosis-uninfected participants, although not reaching statistical significance (19/470, 4.0% vs 25/921, 2.7%, adjusted [for age, gravidity and HIV serostatus] odds ratio 1.38, 95% confidence interval 0.73-2.57, p = 0.30). Rates of neonatal death (5/470, 1.1% vs 10/921, 1.1%) were similar between these categories. CONCLUSION: Latent tuberculosis infection was not significantly associated with stillbirth or neonatal death in this cohort. Studies based on larger cohorts and with details on causes of stillbirth, as well as other pregnancy outcomes, are needed to further investigate this issue.

Cardiovascular effects of intrauterine exposure to maternal HIV and antiretroviral therapy in Ethiopian infants followed from fetal life.

OBJECTIVE: To assess cardiovascular effects of in-utero HIV and antiretroviral treatment (ART) exposure on offspring of HIV-positive mothers in Ethiopia. DESIGN: HIV-positive and HIV-negative pregnancies were identified from a prospective cohort of women recruited at their first antenatal care visit in Ethiopia, using a nested case-control design. METHODS: Fetal standard ultrasound and echocardiography were performed at 2237 weeks of pregnancy to assess fetal biometry and cardiac structure. Postnatal cardiovascular evaluation, including echocardiography and vascular assessment, was performed at 6 months of age. Cardiovascular data were correlated to HIV serostatus, antiretroviral drug exposure and HIV-unrelated maternal characteristics. RESULTS: Fetuses from 29 HIV-positive and 67 HIV-negative women paired by gestational age at scan were included. Among HIV-positive women, 25 were on ART before conception, and 4 initiated ART during pregnancy. Estimated fetal weight was similar in both groups [mean 1873 g (standard deviation; SD 569) vs. 1839 g (SD 579) P = 0.79, respectively]. Fetal cardiac morphometry was similar with regard to maternal HIV serostatus: cardiothoracic ratio mean 0.26 (SD 0.05) vs. 0.25 (SD 0.06), P = 0.48; and septal wall thickness mean 4.03 mm (SD 0.58) vs. 3.98 mm (SD 0.70), P = 0.94. No significant cardiovascular differences were detected postnatally according to maternal HIV serostatus: septal wall thickness mean 5.46 mm (SD 0.65) vs. 5.49 (SD 0.89); P = 0.896; isovolumic relaxation time 55.08 ms (SD 6.57) vs. 56.56 (SD 6.74); P = 0.359. CONCLUSION: In offspring of Ethiopian women, intrauterine exposure to HIV and ART were not associated with cardiovascular changes from fetal life up to infanthood.

Longitudinal Mycobacterium tuberculosis-Specific Interferon Gamma Responses in Ethiopian HIV-Negative Women during Pregnancy and Postpartum.

Pregnancy may influence cellular immune responses to Mycobacterium tuberculosis. We investigated M. tuberculosis-specific interferon-γ responses in women followed longitudinally during pregnancy and postpartum. Interferon-γ levels (stimulated by M. tuberculosis antigens [TB1 and TB2] and mitogen included in the QuantiFERON-TB Gold Plus assay) were measured in blood from pregnant HIV-negative women identified from a prospective cohort at Ethiopian antenatal care clinics. Longitudinal comparisons included women without active tuberculosis (TB) with M. tuberculosis-triggered interferon-γ responses of ≥ 0.20 IU/ml, sampled on two and/or three occasions (1st/2nd trimester, 3rd trimester, and 9 months postpartum). Among 2,093 women in the source cohort, 363 met inclusion criteria for longitudinal comparisons of M. tuberculosis-stimulated interferon-γ responses. Median M. tuberculosis-triggered interferon-γ concentrations were higher at 3rd than those at the 1st/2nd trimester (in 38 women with samples available from these time points; TB1: 2.8 versus 1.6 IU/ml, P = 0.005; TB2: 3.3 versus 2.8 IU/ml, P = 0.03) and postpartum (in 49 women with samples available from these time points; TB1: 3.1 versus 2.2 IU/ml, P = 0.01; TB2: 3.1 versus 2.3 IU/ml, P = 0.03). In contrast, mitogen-stimulated interferon-γ levels were lower at 3rd than those at 1st/2nd trimester (in 32 women with samples available from these time points: 21.0 versus 34.9 IU/ml, P = 0.02). Results were similar in 22 women sampled on all 3 occasions. In HIV-negative women, M. tuberculosis-stimulated interferon-γ responses were higher during the 3rd trimester than those at earlier stages of pregnancy and postpartum, despite decreased mitogen-triggered responses. These findings suggest increased M. tuberculosis-specific cellular responses due to dynamic changes of latent TB infection during pregnancy.

Tuberculosis Infection in Women of Reproductive Age: A Cross-sectional Study at Antenatal Care Clinics in an Ethiopian City.

BACKGROUND: Knowledge on tuberculosis (TB) infection epidemiology in women of reproductive age living in TB-endemic areas is limited. We used a composite definition of TB infection in a cohort of pregnant women recruited in an Ethiopian city as a model for TB exposure patterns, and to identify factors associated with TB infection. METHODS: Women seeking antenatal care at public health facilities underwent structured interviews, physical examination, and QuantiFERON-TB Gold-Plus (QFT) testing. Women with symptoms compatible with TB disease, and all human immunodeficiency virus (HIV)-positive women, were investigated for active TB by sputum bacteriological testing. TB infection (TB+) was defined as either positive QFT (≥ 0.35 IU/mL), self-reported previous active TB, or current active TB. Associations between TB infection and clinical, demographic, and socioeconomic characteristics were tested in multiple logistic regression analysis. RESULTS: Among 1834 participants, 679 (37.0%) met criteria for TB+ (80 [4.4%] previous active TB, 5 [0.3%] current active TB, and 594 [32.4%] QFT-positive without previous or current active TB). Age (annual adjusted odds ratio [AOR], 1.069 [95% confidence interval {CI}, 1.045-1.093]) and HIV infection (AOR, 1.43 [95% CI, 1.033-1.988]) were independently associated with TB+. The relationship with increasing age was only observed in HIV-negative women, and translated to an estimated annual risk of TB infection of 2.1% in HIV-negative women. CONCLUSIONS: TB infection in women of reproductive age in Ethiopia was independently associated with HIV infection and increasing age, suggesting exposure to contagious TB and continuous acquisition of TB infection in this population.

Alternative biomarkers for classification of latent tuberculosis infection status in pregnant women with borderline Quantiferon plus results.

Borderline interferon-gamma (IFN-γ) results (near the cut-off level 0.35 IU/ml) occur in QuantiFERON (QFT) assays. We investigated the performance of alternative biomarkers for classification of latent tuberculosis infection (LTBI) status in pregnant women with borderline QFT IFN-γ responses. Pregnant women (n = 96) were identified from a cohort study in Ethiopia, based on QFT-Plus IFN-γ results (QFT-low: <0.20 IU/ml, n = 33; QFT-borderline: 0.20-0.70 IU/ml, n = 31; QFT-high: >0.70 IU/ml, n = 32), including 12 HIV-positive individuals in each group and with 20 HIV-negative non-pregnant women from the same cohort with QFT IFN-γ <0.20 IU/ml as controls. Concentrations of 8 markers (IL-1ra, IL-6, IL-8, IP-10, MCP-1, MCP-2, osteopontin and resistin) were measured in whole blood QFT supernatants, stimulated separately with TB1 and TB2 antigens. K-nearest neighbor analysis (KNN) was used to classify participants with regard to likelihood of LTBI. Concentrations of MCP-2, IP-10 and IL-1ra were higher in QFT-borderline compared to QFT-low participants in both antigen stimulations (p < 0.001). KNN classification indicated high likelihood of LTBI in 13/31 (42%) women with QFT-borderline IFN-γ results. MCP-2, IP-10 and IL-1ra expressed in whole blood after TB antigen stimulation may be considered as alternative biomarkers for classification of LTBI status in pregnant women with borderline QFT IFN-γ results.

Performance of QuantiFERON-TB Gold Plus for detection of latent tuberculosis infection in pregnant women living in a tuberculosis- and HIV-endemic setting.

We evaluated the performance of QuantiFERON-TB Gold Plus (QFT-Plus), which includes two Mycobacterium tuberculosis antigen formulations (TB1 and TB2), for detection of latent tuberculosis infection during pregnancy. Eight-hundred-twenty-nine Ethiopian pregnant women (5.9% HIV-positive) were tested with QFT-Plus, with bacteriological sputum analysis performed for women with clinically suspected tuberculosis and HIV-positive women irrespective of clinical presentation. QFT-Plus read-out was categorized according to the conventional cut-off (0.35 IU/ml) for both antigen formulations. In addition, we analysed the distribution of QFT-Plus results within a borderline zone (0.20-0.70 IU/ml), and interferon-γ response in relation to HIV infection and gestational age. Two-hundred-seventy-seven women (33%) were QFT-Plus-positive (HIV-positive 16/49 [33%]; HIV-negative 261/780 [33%]). There was a strong agreement between the two antigen formulations (κ = 0.92), with discordant results in 29 cases (3.5%). Whereas discordant QFT-Plus results were rare in pregnancy, several results with both TB1 and TB2 within the borderline range were observed (11/49 [22%] vs. 43/780 [5.5%] in HIV-positive and HIV-negative women, respectively; p<0.0001). HIV-positive women had lower absolute interferon-γ levels (TB1: 0.47 vs. 2.16 IU/ml; p<0.001, TB2: 0.49 vs. 2.24 IU/ml, p<0.001, considering results ≥0.20 IU/ml) compared to HIV-negative women. QFT-Plus-positive women who submitted samples at later stages of pregnancy had lower mitogen- (p<0.001) but higher TB-antigen-specific (p = 0.031 for TB1, p = 0.061 for TB2) interferon-γ response. Considering their lower capacity to produce TB-specific interferon-γ, a lower cut-off level for defining QFT-Plus-positivity may be considered in HIV-positive pregnant women.

Growth pattern in Ethiopian infants - the impact of exposure to maternal HIV infection in relation to socio-economic factors.

BACKGROUND: Infants exposed to maternal HIV infection who remain HIV-uninfected (HIV-exposed/uninfected; HIV-EU) may be at increased risk of growth retardation, which could be due both to directly HIV-related effects and to socio-economic factors overrepresented among HIV-positive women. OBJECTIVE: To investigate growth development at 9-12 months of age in HIV-EU infants participating in prevention of mother-to-child transmission (PMTCT) care compared to HIV unexposed (HIV-U) infants in relation to socio-economic conditions. METHODS: Anthropometric and socio-economic data were collected retrospectively from PMTCT registers (for HIV-EU infants), with HIV-U controls recruited at measles vaccination at public health facilities in Ethiopia. Growth was compared with regard to HIV exposure and socio-economic variables in multivariate regression analysis. RESULTS: The following growth measurements were found for 302 HIV-EU and 358 HIV-U infants at 9-12 months of age, respectively: mean weight-for-age z-score (WAZ) 0.04 and -0.21, p < 0.001 (proportion underweight 5.7% and 6.7%, p = 0.60); median length-for-age z-score (LAZ) -0.92 and -0.91, p = 0.53 (proportion stunted 25.1% and 20.5%, p = 0.17). In multivariate analysis, lower WAZ was associated with male sex (p = 0.021), lower maternal education (p < 0.001), presence of siblings (p < 0.01) and HIV-U (p < 0.01). Underweight was associated with male sex (p = 0.017) and absence of maternal education (p = 0.019). Lower LAZ was associated with male sex (p < 0.001), presence of siblings (p < 0.001) and poor maternal education (p < 0.01), while stunting was associated with male sex (p < 0.001), presence of siblings (p < 0.001), few rooms in the home (p < 0.01), access to running water (p = 0.026) and low level of maternal education (p = 0.014). CONCLUSIONS: At 9-12 months of age, HIV-EU infants had non-inferior growth and higher mean WAZ than HIV-U controls. Poor growth development was associated with socio-economic factors. This suggests health benefits from PMTCT participation for infant growth. Similar interventions could be considered for Ethiopian infants, irrespective of HIV exposure, with a particular focus on children with poor socio-economic status.