The study was a prospective cohort study. Women with HDP and women with normotensive pregnancies who delivered in the participating hospitals were recruited from August 2017 to April 2018 and followed up over a subsequent period of one year. The last woman recruited exited the study on March 31, 2019 after one year of follow up.
The study was conducted at eight tertiary hospitals in the six geo-political zones of Nigeria. The hospitals were purposefully selected to reflect diversity in the country in terms of ethnic differences and socio-economic status. The following states (and hospitals) participated: Bauchi State (Abubakar Tafawa Balewa University Teaching Hospital, ATBUTH), Cross River State (University of Calabar Teaching Hospital, UCTH), Ebonyi State (Federal Teaching Hospital Abakaliki, FTHA), Kogi State (Federal Medical Center, FMC Lokoja), Kano State (Aminu Kano Teaching Hospital, AKTH), Ondo State (Mother and Child Hospital Akure and University of Medical Sciences Teaching Hospital, Ondo) and Sokoto State (Usmanu Danfodio University Teaching Hospital, UDUTH). The facilities were high-volume sites with well-functioning antepartum, intrapartum, and postpartum clinics, delivery rooms, and laboratory services with combined average annual deliveries of 38,400.
Receiving delivery care services at the facilities, being 18 years or above, and had a diagnosis of HDPs were the main eligibility criteria for inclusion in the study. The unmatched normotensive women were recruited from the same hospitals. HDP and normotensive women were recruited from similar population of women giving births in these facilities. Recruitment proceeded independently at all facilities. Case identification was carried out by specifically trained and experienced midwives using standard diagnostic criteria based on HDP definitions described above. Women with the following conditions (based on previously documented clinical history and diagnoses) were excluded: having multiple pregnancies, diabetes mellitus, sickle cell disease, heart disease, preexisting kidney disease and connective tissues disorders.
Normotensive women and women with HDPs were informed of the study either during antenatal care or after delivery. All recruitments were done in the postpartum period. Those willing to participate were individually counseled and signed or thumb-printed informed consent form obtained (consent rate over 95% among HDPs, 35% among normotensive). Enrollment forms, collecting information on socio-demographic and obstetrics variables such as age, body mass index (BMI), parity and booking status, were completed within 24 hours of delivery. After enrollment, the women underwent general and systemic clinical examination. In addition, laboratory investigations, including urine protein analysis and renal function tests, were performed on the participants before they were discharged from the hospitals. They were subsequently followed up undergoing the same clinical and laboratory investigations conducted at baseline, at nine weeks, six months and one year postpartum. To improve follow up rate, the research participants were requested to provide their contact information and spousal mobile telephone numbers. They were reminded of their follow up appointments through phone calls. Participants’ contact information was not linked to their clinical records while all clinical information was linked to unique identifiers.
The main exposures of interest were the presence of any of the HDP sub-type including chronic hypertension, gestational hypertension and pre-eclampsia as defined by the ISSHP1,2. Hypertension was defined as systolic blood pressure of ≥140mmHg and or diastolic blood pressure of ≥90mmHg measured on two consecutive periods 4-6 hours apart. Chronic hypertension in pregnancy was defined as any hypertension with onset before the index pregnancy or diagnosed within the first 20 weeks of the index pregnancy. Gestational hypertension was defined as any hypertension occurring after the first 20 weeks of pregnancy without significant proteinuria (<2++ of proteinuria on urine dipstick measurement) or any hematological or biochemical abnormality. Pre-eclampsia was defined as hypertension with onset after the first 20 weeks of pregnancy with significant proteinuria (≥2++ of proteinuria on urine dipstick measurement) or the presence of any hematological and biochemical abnormality1,2.
We assessed prevalence of CKD based on serum creatinine (Modified Jaffe Kinetic Method - Roche C311 and Abbott C4000) and estimated glomerular filtration rate (eGFR) by CKD-Epidemiology equation as recommended by the Kidney Disease Improving Global Outcomes for black women14:
- eGFR for creatinine ≤7mg/dl: 144 * (serum creatinine/0.7)-0.239 * 0.993Age *1.159]
- eGFR for creatinine >7mg/dl: 144 * (serum creatinine/0.7)-1.209* 0.993Age *1.159]
The CKD-epidemiology equation was used together with the GFR calculator of the National Kidney Foundation available at https://www.kidney.org/professionals/kdoqi/gfr_calculator. When the eGFR was < 60mL/min/1.73m2, it is considered decreased and when decreased eGFR persists for ≥ three months, it indicates presence of CKD6,16.
Data source/data collection
At baseline-within 24 hours of delivery, 9 weeks, 6 months and one year postpartum, laboratory tests were performed on the women. We collected blood samples for serum urea and creatinine measurement and estimated glomerular filtration rate. Clinical examination, blood and urine sample collection were performed by trained medical officers who served as research assistants for this study. Laboratory tests were performed using techniques as reported above. Both the medical officers and the laboratory scientists were not aware of clients’ categorization as either HDPs or normotensive.
Based on previous evidence that about 14% of women with pre-eclampsia had abnormal GFR, at least, four months after delivery17, we estimated that 185 women would be required to participate in the study, each for HDPs and normotensive (at 5% alpha level and power of 80%). Considering 10% potential loss to follow-up, 204 women were required to be recruited in each arm. However, we planned to enroll as many women as resources could accommodate given that the study was observational with minimal risks to the women. Because of the differential consenting rates between the two cohorts (95% and 38% for HDPs and normotensive respectively – due to low perception of risk and threat among the normotensive), we were able to recruit 410 and 78 women with HDPs and normotensive pregnancies respectively.
Data management and statistical analysis
The results of medical and laboratory investigations were entered into electronic data capturing platform (Open data kit - ODK) by trained research assistants. All women with HDPs and normotensive women who were recruited and successfully followed-up for each period were analyzed using SPSS IBM version 25.0. Frequencies, percentages, proportion and means (standard deviations) were used to describe participants’ baseline characteristics. For comparison of mean eGFR between normotensive women and women with HDP, independent t-tests was used in case of normally distributed data, otherwise the Mann–Whitney U test was applied. To compare mean differences in eGFR between HDP sub-types (gestational hypertension, pre-eclampsia and eclampsia), one-way analysis of variance (ANOVA) was performed. A Tukey post hoc test was used to determine where the difference lied between the HDP sub-types in their mean eGFR. Univariable and multivariable logistic regression analyses were performed to assess predictors of CKD at six months and one year postpartum. Confounders’ selection was theory-driven, and the following variables were included: age, BMI, parity, gestational age at delivery, early- and late-onset HDP, booking status and HDP sub-types.
Loss to follow up
Cases of loss to follow up were nearly similar between HDP and normotensive women and occurred when subjects failed to report for data collection for each period. Of the 410 women with HDPs enrolled, 147(36%), 178(43%) and 132(32%) were lost to follow up at nine weeks, six months and one year postpartum, respectively. The corresponding values for the normotensive women were 25(32%), 35(45%) and 19(24%) respectively. We assumed data were missing completely at random. Therefore, complete case analysis was performed such that for any data collection period only clients that have reported and provided complete information were analyzed.
The study was approved by the Population Council’s institutional review board in New York (protocol no. 810), National Health Research Ethics Committee (NHREC) at the Federal Ministry of Health of Nigeria and by the institutional review boards at all the participating hospitals.