Weight gain during pregnancy among women initiating dolutegravir in Botswana

Background: Recent data suggests clinically significant weight gain among non-pregnant HIV-positive adults after starting dolutegravir-based ART (DTG). Excess or insufficient weight gain in pregnancy could adversely impact pregnancy outcomes, but data for pregnant women receiving DTG are limited. Methods: The Tsepamo Study captured data at delivery sites in Botswana from 2014 to 2019. HIV testing, HIV treatment information, and weight measurements during antenatal care were abstracted from the maternity obstetric record at delivery. HIV-positive women initiating DTG or efavirenz-based ART (EFV) between conception and 17 weeks gestation and HIV-uninfected women first presenting for antenatal care before 17 weeks gestation were included. We evaluated weekly weight gain, total 18-week weight gain, excess weight gain (>0.59 kg/week), insufficient weight gain (<0.18 kg/week), and weight loss between 18±2 and 36±2 weeks gestation, adjusting for demographic and clinical variables. Findings: Baseline characteristics were similar by exposure group, including pre-pregnancy and early pregnancy weight. Compared with EFV, mean weekly weight gain between 18 and 36 weeks gestation was 0.05 (95% CI 0.03, 0.07) kg/week higher for women initiating DTG and 0.12 (0.10, 0.14) kg/week higher for HIV-uninfected women. Mean 18-week weight gain was 1.05 (95% CI 0.61, 1.49) kg higher for women initiating DTG and 2.31 (1.85, 2.77) kg higher for HIV-uninfected women, compared with EFV. Women initiating DTG were more likely to gain excess weight but less likely to gain insufficient weight or lose weight than women initiating EFV. Interpretation: Women initiating DTG compared with EFV during pregnancy gained more weight between 18 and 36 weeks gestation. Neither group gained as much weight as HIV-uninfected women. Initiating DTG compared with EFV during pregnancy could increase the risk of excess weight gain but decrease the risk of insufficient weight gain and weight loss, which could have positive and negative consequences in pregnancy. Our findings are consistent with prior studies in non-pregnant adults. Tsepamo is a birth outcomes surveillance study in Botswana [24]. Data are abstracted from the maternity obstetric record (a record of antenatal care) at the time of delivery from all women delivering at selected hospitals throughout the country. Tsepamo included 8 sites (~45% of all births in Botswana) from August 2014-July 2018 and expanded to include 18 sites (increasing coverage to ~72% of all births) from July 2018-March 2019. The maternity sites that were originally included were 2 tertiary referral hospitals, 5 district hospitals, and 1 primary-level hospital; 4 district and 6 primary-level hospitals were added in 2018. The surveillance study captures data on >99% of all births that take place at the included sites as almost all women bring their antenatal medical records (‘maternity card’) to delivery [6,24]. In Botswana, approximately 95% of women deliver at a hospital [25]. Information collected from the maternity obstetric record includes demographics, past medical history, diagnoses, hospitalizations and complications during pregnancy, medications prescribed during pregnancy, HIV history (including timing of diagnoses, ART regimens, CD4 count and viral loads), and clinical information including lab results, blood pressure, and weight measurements. All weight measurements ascertained and recorded by nurses or midwives from the time of the first antenatal care (ANC) visit to delivery are captured in the maternity obstetric record with associated dates. Self-reported pre-pregnancy weight is recorded when available. Height is measured but rarely recorded (approximately 1%) and upper arm circumference is not measured. Gestational age is documented by midwives at the time of delivery based on the estimated date of delivery (EDD). EDD is calculated at the first ANC visit using the reported last menstrual period and confirmed by ultrasound when available. If the last menstrual period date is unknown or suspected to be incorrect, fundal height measurements are used by the midwives to estimate gestational age. Before May 2016, Botswana recommended initiation of TDF/emtricitabine(FTC)/EFV for all ART naïve adults with CD4 <350 cells/mm3 and for all pregnant women, regardless of CD4 cell count. In May 2016, TDF/FTC/DTG replaced TDF/FTC/EFV as the first-line regimen for all adults and all pregnant women and CD4 restrictions were removed. In September 2018, Botswana began to transition from TDF/FTC/DTG to TDF/lamivudine (3TC)/DTG to decrease the pill burden from 2 pills per day (TDF/FTC plus DTG) to 1 pill per day (TDF/3TC/DTG combined formulation). Women with kidney dysfunction or intolerance/resistance to TDF/FTC could access abacavir/3TC or zidovudine/3TC. TAF is not yet available in Botswana's national HIV program. HIV-positive women who initiated ART for the first time between the estimated last menstrual period and 17 weeks gestation were included in our analysis. We excluded women who initiated an ART regimen other than a DTG-based or EFV-based regimen. We also included HIV-uninfected women within one standard deviation of the mean age of the HIV-positive women who attended an antenatal clinic between the estimated last menstrual period and 17 weeks gestation. Multiple pregnancies were included. Baseline was defined as the date of ART initiation for HIV-positive women and as the date of the first ANC visit for HIV-uninfected women. Our study population was restricted to women who gave birth from August 2014 to March 2019. We evaluated two primary outcomes. First, we calculated weekly weight gain from 18±2 to 36±2 weeks gestation as the difference in weight measured at 36±2 weeks and 18±2 weeks divided by the number of weeks between the measurements. Second, we calculated total 18-week weight gain from 18±2 to 36±2 weeks gestation as the difference in weight measured at 36±2 weeks and 18±2 weeks among women who had two weight measurements recorded 18 weeks apart. We required the 18±2 measurement to occur at or after baseline. We chose 18±2 and 36±2 weeks as the timeframes for the weight measurements to capture a weight measurement soon after baseline (ART initiation if HIV-positive) and to avoid the majority of the variation in gestational duration. Secondary outcomes included weekly weight gain greater than 0.59 kg/week from 18±2 to 36±2 weeks (‘excess weight gain’), weekly weight gain less than 0.18 kg/week from 18±2 to 36±2 weeks (‘insufficient weight gain’), and any weight loss from 18±2 to 36±2 weeks. These cut-points are based on the Institute of Medicine (IOM) 2009 guidelines on gestational weight gain (converted from pounds to kilograms), which recommend gaining no more than 0.59 kg/week and no less than 0.18 kg/week in the second and third trimesters, regardless of pre-pregnancy BMI category (IOM guidelines recommend women with BMI<18.5 gain the most weight of all BMI categories, up to 0.59 kg/week, and women with BMI≥30 gain the least week of all BMI categories, at least 0.18 kg/week; therefore, these values can be used to define excess and insufficient weight gain regardless of pre-pregnancy BMI) [13]. Follow-up ended at 36±2 weeks for the purpose of all of our analyses. We examined demographic information by exposure group using sample means and proportions. For weekly weight gain and total 18-week weight gain, we fit linear regression models to estimate mean differences and 95% confidence intervals comparing women initiating DTG to women initiating EFV, and comparing HIV-uninfected women to women initiating EFV. Our models included a 3-level exposure variable (with EFV as the referent) and were adjusted for several baseline covariates: age (<25, 25–30, ≥30 years), pre-ART CD4 in pregnancy (>200 cells/μl or HIV-uninfected, ≤200 cells/μl or missing), employment (salaried, other or unknown), education (secondary education or higher, other or unknown), parity (≥1, 0 or unknown), gravidity (≥2, 1 or unknown), marital status (yes, no or unknown), site (tertiary referral hospital, other), smoking during pregnancy (yes, no or unknown), alcohol use during pregnancy (yes, no or unknown), pre-pregnancy weight (<50 kg, 50–80 kg, ≥80 kg, unknown), baseline weight in pregnancy (<50 kg, 50–80 kg, ≥80 kg, unknown), gestational age at baseline (<12 weeks, ≥12 weeks), and any medical diagnosis prior to pregnancy other than HIV (yes, no or unknown). Examples of common diagnoses prior to pregnancy include sexually transmitted infections (STI), anemia, hypertension, and asthma. For weekly weight gain greater than 0.59 kg/week, weekly weight gain less than 0.18 kg/week, and weight loss from 18±2 to 36±2 weeks, we fit log-binomial regression models [26] to estimate risk ratios (an appropriate measure of association for non-rare outcomes) and 95% confidence intervals comparing women initiating DTG to women initiating EFV, and comparing HIV-uninfected women to women initiating EFV. Our models were adjusted for the same baseline covariates listed above. We conducted subgroup analyses to evaluate effect modification by baseline weight in pregnancy (<50 kg and ≥80 kg) and by gravidity (primigravid and non-primigravid). Women who did not have a weight measurement at 18±2 weeks and/or at 36±2 weeks had missing outcome data for weekly weight gain from 18±2 to 36±2 weeks gestation and women who did not have two weight measurements recorded 18 weeks apart had missing outcome data for total 18-week weight gain. If the factors associated with having a missing weight were also related to the weekly or total weight gain, restricting our analysis to only women who had the weight measurements of interest could induce selection bias. We attempted to adjust for this potential selection bias by estimating inverse probability of censoring weights in a sensitivity analysis [27]. To do so, we fit a logistic regression model for not having missing data on weekly weight gain conditional on the exposure group, the baseline covariates listed above, the number of ANC visits (<10, 10–14, >14), and any maternal diagnosis during pregnancy (yes, no or unknown). Our weights were stabilized [27] and used in the models evaluating weekly weight gain. A similar analysis was conducted for total 18-week weight gain. To further explore the sensitivity of our findings to missing outcome data, we performed additional sensitivity analyses where we restricted our analysis to individuals with baseline weight and where we evaluated weight at 36±2 weeks gestation as an outcome. To evaluate the potential for residual confounding by missing data for baseline weight in pregnancy, we also conducted a sensitivity analysis restricted to women with a known baseline weight. CD4 cell count was infrequently measured in Botswana after CD4 restrictions were removed from treatment initiation guidelines in 2016. [6,28] To account for unmeasured or residual confounding by CD4 cell count, we varied how we categorized CD4 cell count in several sensitivity analyses (e.g., including a missing indicator for CD4 cell count, dichotomizing CD4 cell count as <200 cells/μl versus ≥200 cells/μl or missing, and using cut-points of 350 cells/μl and 500 cells/μl). In a final sensitivity analysis, we restricted our analysis to singleton pregnancies. All analyses were conducted using SAS. The reporting of this study conforms to the STROBE statement. The funders had no role in study design, data collection and analysis, data interpretation, or preparation of the manuscript. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Ethics approval for this study was granted by the Health Research and Development Committee in Botswana and by the Office of Human Research Administration at the Harvard T.H. Chan School of Public Health. Maternal consent was waived as data were collected anonymously and via chart abstraction.