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Introduction: Inflammation-induced remodelling of gestational tissues that underpins spontaneous preterm birth (sPTB, delivery < 37 weeks' gestation) may vary by race and context. To explore relationships between markers of these pathological processes, we (a) characterised the cervicovaginal fluid (CVF) cytokine profiles of pregnant South African women at risk of PTB; (b) determined CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these markers for sPTB. Method of study: The concentrations of 10 inflammatory cytokines and MMP-9 and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring women at high risk of PTB. We studied CVF sampled at three gestational time points (GTPs): GTP1 (20-22 weeks, n = 37), GTP2 (26-28 weeks, n = 40), and GTP3 (34-36 weeks, n = 29) and analysed for changes in protein concentrations and predictive capacities (area under the ROC curve (AUC) and 95% confidence interval (CI)) for sPTB. Results: There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term women with an average AUC = 0.73. At GTP2, IL-1β (18-fold, p < 0.0001), IL-8 (4-fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p = 0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm compared with term women with an average AUC = 0.80. By contrast, IL-10 was associated with term delivery with an AUC (95% CI) = 0.75 (0.55-0.90). At GTP3, IL-1β (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03), and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term women with an average AUC = 0.85. Elevated IL-1β was associated with delivery within 14 days of assessment with AUC = 0.85 (0.67-0.96). Overall, elevated MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1 at all GTPs (r = 0.61, p < 0.01) for women delivering at term was only observed at GTP1 for those who delivered preterm (r = 0.70, p < 0.03). Conclusions: In this cohort, sPTB is associated with gestation-dependent increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1β) and ECM remodelling proteins rise significantly in the final 2 weeks before the onset of labour when sPTB is imminent. The signalling mechanisms for these ECM remodelling observations remain to be elucidated. [ABSTRACT FROM AUTHOR]

Introduction: Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)‐based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG‐based ART on gestational weight gain (GWG) in sub‐Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes. Methods: We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri‐urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study‐measured at 24–28 (baseline) and 33–38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z‐scores were generated using the INTEGROWTH‐21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z‐score with adverse birth outcomes were assessed using multivariable linear or log‐binomial regression. Results: Among 292 participants (48% WHIV), median age was 29 years (IQR, 25–33), median pre‐pregnancy body mass index (BMI) was 31 kg/m2 (IQR, 26–36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12–0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG‐based ART 0.25 vs. efavirenz‐based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z‐score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01). Conclusions: Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub‐Saharan Africa are urgently needed. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral therapy (ART) use during pregnancy may be associated with adverse outcomes, but findings have been inconsistent, at least in part due to unreliably estimated gestational age.Objective: To quantify the association between HIV status, ART initiation timing and adverse birth outcomes, with reliably assessed gestational age at booking, in a public sector primary care facility in Cape Town, South Africa.Methods: Pregnant women, HIV-negative or living with HIV (WLHIV), were enrolled at first antenatal care visit and followed through delivery. Ultrasound-assessed gestational age was deemed the gold standard. Based on quantitative bias analysis for outcome misclassification, gestational age by non-ultrasound assessment was corrected using multiple overimputation, which deals with missing data and measurement error simultaneously. Using bias-corrected gestational age, birth outcomes were compared between WLHIV and HIV-negative women, and among WLHIV who initiated ART before versus during pregnancy, further divided into trimesters.Results: Of 3952 women enrolled, 37% were WLHIV (mostly using tenofovir + emtricitabine + efavirenz). Last menstrual period (LMP)-based gestational age was identified to be biased, and LMP measures were thus corrected using multiple overimputation. Comparing WLHIV and HIV-negative women, adjusted risk ratio (aRR) of overall pregnancy loss was 1.26 (95% confidence interval [CI] 0.98, 1.61); aRR of preterm delivery was 1.02 (95% CI 0.88, 1.20); aRR of small for gestational age infants was 1.43 (95% CI 1.14, 1.80). Among WLHIV, outcomes were similar by ART initiation timing.Conclusions: In this routine care cohort, risk of SGA, and possibly of pregnancy loss, was increased in WLHIV compared with HIV-negative women, with no evidence of increased risk of preterm delivery. Further research is needed to improve mechanistic understanding of the contribution of ART to adverse birth outcomes to optimize treatment for pregnant WLHIV and ensure optimal maternal and infant outcomes. [ABSTRACT FROM AUTHOR]

Dolutegravir is currently recommended by the WHO as the preferred first-line treatment for all people with HIV, including pregnant women. Estimates indicate that, by 2024, nearly 22 million adults in low- and middle-income countries will have transitioned to dolutegravir-based ART. It is therefore critical that there is a clear appreciation and understanding of the risks that may be associated with in utero exposure to dolutegravir. In this review we consolidate data from studies on dolutegravir and the placenta. The studies have largely focused on the pharmacokinetics and placental transfer of dolutegravir in pregnancy. These include studies on transplacental transfer of dolutegravir, ex vivo placenta perfusion models, physiologically based pharmacokinetic (PBPK) models and animal studies. The data available clearly demonstrate that placental transfer of dolutegravir occurs in moderate to high concentrations. Intracellular placental dolutegravir has been demonstrated in the placental villous tissue. There are limited data suggesting that pregnancy is associated with decreased maternal dolutegravir levels. In addition, PBPK models have great potential in predicting the passage of drugs through the placenta and further contributing towards the elucidation of fetal exposure. The animal studies available demonstrate that in utero dolutegravir exposure can be associated with neural tube defects. Taking into consideration that antiretroviral exposure may be associated with poor placental development or function and increased risk of adverse effects to the fetus, it is crucially important that these risks are evaluated, especially with the rapid scale up of dolutegravir-based ART into national treatment programmes. [ABSTRACT FROM AUTHOR]

Background: High blood pressure (BP) late in pregnancy is associated with preterm delivery (PTD); BP has also been associated with HIV and antiretroviral therapy (ART), but whether the relationship between BP assessed longitudinally over pregnancy and PTD and low birthweight (LBW) is modified by HIV/ART is unclear. We hypothesise the presence of distinctive BP trajectories and their association with adverse birth outcomes may be mediated by HIV/ART status.Methods: We recruited pregnant women at a large primary care facility in Cape Town. BP was measured throughout pregnancy using automated monitors. Group-based trajectory modelling in women with ≥3 BP measurements identified distinct joint systolic and diastolic BP trajectory groups. Multinomial regression assessed BP trajectory group associations with HIV/ART status, and Poisson regression with robust error variance was used to assess risk of PTD and LBW.Results: Of the 1583 women in this analysis, 37% were HIV-infected. Seven joint trajectory group combinations were identified, which were categorised as normal (50%), low normal (25%), high normal (20%), and abnormal (5%). A higher proportion of women in the low normal group were HIV-infected than HIV-uninfected (28% vs. 23%), however differences were not statistically significant (RR 1.27, 95% CI 0.98-1.63, reference category: normal). In multivariable analyses, low normal trajectory (aRR0.59, 0.41-0.85) was associated with decreased risk of PTD, while high normal (aRR1.48, 1.12-1.95) and abnormal trajectories (aRR3.18, 2.32-4.37) were associated with increased risk of PTD, and abnormal with increased risk of LBW (RR2.81, 1.90-4.15).Conclusions: While HIV/ART did not appear to mediate the BP trajectories and adverse birth outcomes association, they did provide more detailed insights into the relationship between BP, PTD and LBW for HIV-infected and uninfected women. [ABSTRACT FROM AUTHOR]