Investigating and modelling risk factors for primary postpartum haemorrhage among childbearing Women in the Northern Province of Rwanda: A Case Control Study

Background : The vast majority of maternal deaths occur in Low- and Middle-Income Countries. Postpartum haemorrhage (PPH) remains a major global burden contributing to high maternal mortality and morbidity rates. Assessment of PPH risk factors should be undertaken during antenatal, intrapartum and postpartum periods for timely prevention of maternal morbidity and mortality associated with PPH. The aim of this study is to investigate and model risk factors for primary PPH in Rwanda. Methods: We conducted an observational case-control study of 430 (108 cases: 322 controls) pregnant women with gestational age of 32 weeks and above who gave birth in five selected health facilities of Rwanda between January and June 2020. Poisson regression, a generalized linear model with a log link and a Poisson distribution was used to estimate the risk ratio of factors associated with PPH. The research protocol was approved by the University of Rwanda, College of Medicine and Health Sciences Institutional Ethics Review Board. Results: The overall prevalence of primary PPH was 25.2%. The following risk factors were identified: antepartum haemorrhage (RR=3.36; 95% CI 1.80- 6.26, P <0.001); intrauterine fetal death (RR=1.93; 95% CI 0.93- 4.03, P <0.077); multiple pregnancy (RR=1.83; 95% CI 1.11- 3.01, P =0.016); haemoglobin level <11 gr/dL (RR=1.51; 95% CI 1.00- 2.30, P =0.050), and premature rupture of membranes (RR=0.58; 95% CI 0.32- 1.05, P <0.077). During the intrapartum and immediate postpartum period, the main causes of primary PPH were: uterine atony (RR=6.70; 95% CI 4.78- 9.38, P <0.001), retained tissues (RR= 4.32; 95% CI 2.87- 6.51, P <0.001); and lacerations of genital organs after birth (RR= 2.14; 95% CI 1.49- 3.09, P <0.001). Coagulopathy was not prevalent in primary PPH. Conclusion : Based on our findings, uterine atony remain the foremost cause of primary PPH. As well as other established risk factors for PPH, antepartum haemorrhage and intra uterine fetal death should be included as risk factors in the development and validation of prediction models for PPH. Large scale studies are needed to investigate further potential PPH risk factors.


Background
Maternal mortality remains unacceptably high worldwide [1]. According to the World Health Organization (WHO), approximately 295 000 women died during pregnancy or after childbirth in 2017. The vast majority of these deaths (94%) occurred in low-resource settings, and most could have been prevented [1]. The maternal mortality ratio (MMR) in Rwanda is reported to be 203/100,000 live births [2]. Reduction of maternal mortality has long been a global health priority, and a target in the United Nations (UN) 2030 agenda for Sustainable Development Goals is to reduce the global MMR to less than 70 per 100,000 live births [3].
Most maternal complications develop during pregnancy and many are preventable or treatable.
Complications, such as maternal obesity, curettage in previous pregnancy, hypertensive diseases, haemoglobin (Hb) level less than or equal to 10 g/dL [4] may exist before pregnancy and may pose problems during pregnancy leading to PPH, especially if not managed as part of the woman's care [1]. Primary postpartum haemorrhage (PPH), clinically defined as a blood loss of 500 ml or more following a normal vaginal delivery (NVD) or 1000 ml or more following a caesarean section within 24 hours after birth [5,6], is a major cause of maternal mortality and severe morbidity, particularly in developing countries [7]. WHO [5] indicates that most maternal deaths resulting from PPH occur within the first 24 hours postpartum and are preventable and manageable if appropriate and effective resources are readily available. In a nationwide facility-based retrospective cohort study of a maternal death audit conducted in Rwanda [8]; 70 % of reported maternal deaths were due to direct causes, of which PPH was the leading one (22.7% of all reported cases). These figures demonstrate that the rate of dying due to PPH in Rwanda, remains high compared to average rates of dying due to PPH in developed countries (8%). WHO works to contribute to the reduction of maternal mortality by increasing research evidence, providing evidence-based clinical and programmatic guidance [1]. Consequently, PPH has received increasing attention as a quality indicator for obstetric care [9]. Recent studies have shown an increasing trend in PPH, but the causes for this increase are still uncertain [10].
PPH is the consequence of several different factors that can occur in isolation or combination, such as: uterine atony, retained placental tissue, genital tract trauma and coagulation dysfunction (the '4Ts' mnemonic: tone, tissue, trauma, and thrombin) [5,11]. Most cases of PPH are caused by uterine atony [11,12] where the loss of myometrial tone allows maternal blood flow to the placental bed and the bleeding continues unchecked. Conversely, studies conducted in Nigeria and Ethiopia [13][14][15] demonstrated that the commonest causes of PPH were genital trauma and retained placenta.
A number of studies have also attempted to examine other predictors of PPH: delivery by Caesarean section [18,30], gestational age of 40 weeks of amenorrhoea and above [7,22], curettage in prior pregnancy, nulliparous or receiving pethidine in labour [22], gestational diabetes mellitus, body mass index (BMI) of 25 or above before pregnancy [21] and chorioamnionitis [31]. HIV positive status was found to be associated with PPH in a prospective cohort study conducted by Ononge et al., [18] in Uganda.
Severe morbidities associated with PPH include anaemia and need for blood transfusion, disseminated intravascular coagulation, hysterectomy, and renal or liver failure [32]. Women who develop PPH may also suffer from complications including: hepatic failure, acute respiratory distress syndrome, need for open surgery, need for intensive care, disseminated intravascular coagulation, hysterectomy and cardiac arrest [33,34]. In moderate complications, PPH can lead to minor anaemia, fatigue, depression and separation anxiety [33,35].
Interest in PPH has predominantly focused on the evaluation of its risk factors, prevention, and treatment [32]. Other studies have attempted to understand the reasons for substandard care in PPH [32,36], accurate diagnosis [37][38][39] and identification of potentially severe cases [19]. To date, little is known about risk factors of primary PPH investigated through a case control study in a Rwandan setting. Therefore, the purpose of this study is to investigate and model the risk factors of primary PPH among women admitted in postpartum units of selected health facilities. The key contribution of this work is the solution it provides for a proactive prevention of primary PPH.

Study design
The present study is part of a larger exploratory sequential mixed-methods study. This is the third phase of the larger study: an observational case control study [40,41] to investigate and model the risk factors for PPH. This study was preceded by a scoping review [4] which described the research output on factors affecting the prevention of PPH in low and middle income countries and a qualitative descriptive study [42] to explore influencing factors for prevention of PPH and early detection of women at risk in Northern Province of Rwanda as perceived by beneficiaries and health workers. These two studies led to developing a content validated risk assessment tool for the prediction and prevention of PPH (RATP) [43]. The findings from one phase of the larger exploratory sequential mixed-methods study informed the subsequent phases. Therefore, this case control study used the PPH risk assessment tool (RATP) developed during the preceding phase.

Population and setting
The target population was women aged 18 years or above, admitted to the postpartum ward after a live birth at ≥32 weeks' gestation at the health facilities of the Northern Province of Rwanda during the period January 1 st 2020 to June 30 th 2020. We sent invitations to participate to six health facilities: 5 hospitals and one medicalised health centre. Four district hospitals and one medicalised health centre provided permission to conduct the study. Therefore, five health facilities were included in this study while one district hospital was excluded. A medicalised health centre is a new level in the health system of Rwanda deployed with capable staff (medical doctor, nurses and midwives, paramedics, anaesthesia, etc…). It is the level in between district hospital and health centre, which is equipped to attend to patients with acute life threatening conditions especially obstetric conditions [44]. The selection criteria of health facilities included their level of performance in maternal and newborn health (a significant number of births per month compared to others health facilities in the same locality), location (rural versus urban), and the geographical accessibility of the health facilities to clients. Considering that the northern province is characterised by a hilly terrain, some inhabitants have difficulties to reach the health facilities as indicated by participants in a recent study [42] .The study sites were selected by the principal investigator and validated by the research committee. The Northern Province of Rwanda was purposively chosen for being in a rural area where some health centres are hard to access, and for its low uptake of antenatal and postnatal services among childbearing women [45].

Participants and data collection procedures
From the target population, the source population for the present case control study was selected to identify the outcome of interest as suggested by Song and Chung [41]. Hence, women in the postpartum period were our source population. A PPH case in our study is defined as blood loss of 500 ml or above within the first hour which is visually estimated by health care providers observing women who change the blood-soaked vaginal pads 2 times or more within the first hour after birth [5,46,47]. Primary PPH is also counted in case woman requires a blood transfusion for excessive bleeding after birth due to clinical symptoms and signs of anaemia or hemodynamic decompensation after birth [9] or with Hb level less than 11 gr/dL especially if symptomatic according the findings from Rwanda Demographic Health Survey 2019-20 [2]. Women who received a blood transfusion because of postpartum anaemia, without evidence of excessive blood loss after birth were excluded from this study. Women with secondary PPH which is characterised by vaginal blood loss (or lochia discharges) at least 24 hours after birth or six weeks after delivery [48], were also excluded from this study. The attending health care provider estimated the blood loss visually in all five health facilities. Controls were a random sample of all deliveries without primary PPH from the same source population and period of time as the cases of primary PPH. Based on the list in the birth registry, after identifying the case of PPH, the three following women who gave birth without primary PPH were selected as control cases. Hence inclusion criteria were being aged of 18 years and above, being admitted for postpartum monitoring at the health facility within the first 24 hours after birth.
After selecting eligible women for inclusion in the present study, we extracted the study participants [41], that included all cases confirmed to have primary PPH (n =108) and a random sample of controls without primary PPH (n =322) (Fig 1) to make a total sample size of 430 participants. Due to a limited study period, the number of study participants was slightly lower than the target sample size. A G*Power software for power analysis [49] indicated that we needed 118 cases and 354 controls considering three controls per case, with type I error of 5%, power of 80%, frequency of risk factors in control subjects of 0.2 %, and cases with potential risk factors to PPH being almost twice as likely to be exposed to PPH compared to controls (odds ratio (OR) = 1.8).

Figure 1: Selection of study subjects. PPH: Postpartum haemorrhage
One research assistant at each of the five health facilities was recruited by the principal investigator and selected in agreement with the health facilities' administration. The research assistants were all registered midwives with experience in PPH prevention and had two or more years of experience working full time in maternity. Prior to the period of data collection, the principal investigator organised a one-day training for the research assistants to have a common understanding on research aim, ethical principles, data collection tool and methods for data collection using the RATP [43]. To start data collection, research assistants verbally invited women in postpartum period who met inclusion criteria to take part in the study, told them about the study. Those who agreed to participate signed to indicate informed consent. Data was collected during the hospital stay of the woman to allow the research assistant to visit the client and cross check data. Accessing clients' charts facilitated the assessment of eligibility of study participants.
Therefore, registration of client data was based on information collected from clients' files, from maternity records completed on a regular basis on women in labour and birth, also documenting the birth outcomes, including cases that experienced blood loss during birth and immediately after birth. We also collected client data through structured interviews carried out by the research assistant with the women using the RATP to ensure the accuracy of data and to minimise missing data. After identifying a case of PPH, the research assistant was required to also identify three control participants who gave birth and who did not experience PPH within +/-24 hours in relation to the time the PPH happened.
The RATP was translated from English to French and Kinyarwanda by a professional translator to facilitate respondents' understanding of the tool by using their preferred language. The three languages are officially used in Rwanda. Back translation was done by an independent professional translator, to confirm that the meaning and content of the questions of the original copy had not been changed during the translation. Verification of the translated instrument was also done to ensure its validity.
As the research assistants were full-time staff working in maternity, they were able to identify cases who experienced PPH after birth during their working days. For some cases of PPH that happened during their days off, the research assistants could identify potential participants through maternity records (daily reports) and confirm whether the woman had primary PPH by asking the woman if she bled heavily and changed the blood-soaked vaginal pads two or more times during the first 24 hours after birth. The principal investigator made regular visits to the research sites during the data collection period to ensure that data collection was being conducted as planned.

Variables under study
The dependent variable in this study was primary PPH (presence or absence of primary PPH: Case Extensive discussion in the literature has reached a consensus that RR is preferred over the odds ratio for most prospective investigations for its scientific meaning [56,58]. Moreover, odds ratios are considered as more extreme than relative risks when the outcome is not rare [59,60] (prevalence above 10% in the study population [57,61]), and conversion of odds ratios into relative risks is known to produce biased estimates when adjusting for covariates [55,58].Therefore, Poisson regression, a generalized linear model with a log link and a Poisson distribution was used in this study to estimate the risk ratio because the prevalence of the outcome is not rare (prevalence of primary PPH = 25%) and the outcome variable itself is binary. When the outcome is binary, the exponentiated coefficients are risk ratios instead of incidence-rate ratios [55,62,63].The results are reported in the results section.

Results
Univariate analysis demonstrated that the mean maternal age was higher among PPH cases: 32 years (95% CI: 30.9-33.9) vs. 29 years (95% CI: 29.03-30.5) for the control group.  Results from bivariate analysis of selected demographic and clinical characteristics of women from the two groups are shown in Table 2 Table 2.
At this level of analysis, the causes of PPH that were found to be associated with primary PPH with a P-value of <0.001 were uterine atony, and retained tissues. Coagulopathy and lacerations of genital organs were also significantly correlated with PPH but their P-value of respectively 0.084 and 0.077 did not meet the 0.05 cut-off set for statistical significance. Level of Significance at 5% (*Significant; **very significant; *** highly significant) The risk factors found to be associated with primary PPH at bivariate analysis were further analyzed to control for possible confounders. This multivariate analysis indicated that the antepartum risk factors were: Hb level of <11 gr/dL on admission to labour, multiple pregnancy, intrauterine foetal death, antepartum haemorrhage and PROM (  Level of Significance at 5% (*Significant; **very significant; *** highly significant)

Discussion
PPH often occurs in the absence of known risk factors. In the present study, we investigated and modelled the potential risk factors of primary PPH among women admitted to postpartum units of five selected health facilities of the Northern Province of Rwanda.
The prevalence of PPH in our study participants was 25.1 %, which indicates that PPH was common in our study population as confirmed by other studies [56,57]. This result was likely due to the fact that majority of women included in this study gave birth in district hospital settings (76.2%) that receive referrals from health centres of the catchment area. The prevalence of PPH is also noted to be high in Yemen (29.1%) [64]. This variation in prevalence of PPH might be due to difference in study design, social stability, cultural difference and maternal health care services accessibility.
As highlighted by Main et al., [65], the risk assessment for PPH should be undertaken during antepartum care, at admission to labour and delivery, during labour and delivery and postpartum, as PPH risk factors can change or evolve throughout the perinatal period. Our assessment demonstrated that factors associated with primary PPH are found throughout the course of childbearing period; the antepartum, intrapartum and early postpartum periods including causes of PPH for the continuity of care in early detection and prevention of PPH.

Antepartum risk factors
Antepartum haemorrhage, multiple pregnancy, intrauterine foetal death, Hb level on admission to labour and PROM demonstrated an increased RR for developing PPH which was higher in women with these risks factors than in women without.
Antepartum haemorrhage (APH) was the strongest predictor among study participants and was associated with triple the risk for developing primary PPH. This finding concurs with the guideline released by the Royal College of Obsetricians and Gynecologists [66]in the UK, which states that PPH should be anticipated in women who have experienced APH [66]. A study in Brazil demonstrated that severe maternal outcome due to antepartum and intrapartum haemorrhage was highly prevalent [72]. APH might be associated with placental abruption or placenta praevia, placental anomalies and local genital tract disorders, such as cervicitis and neoplasms. No definitive cause is diagnosed in some patients [67]. In our study, insufficient data were available to classify APH, and participants were not sure about the kind of APH they experienced. A comprehensive documentation of client obstetrical history and antepartum complications could give light to birth preparedness and early detection of PPH.
Multiple pregnancy was one of the strongest predictors of primary PPH in this study, which is similar to previous studies [9,18,30,68]. The over distension induced by multiple pregnancy increases the risk of uterine atony with overstretching of uterine muscle. In addition, the large placental size in multiple pregnancy increases the insertion surface area which bleeds after childbirth. Multiple pregnancy contributes to an increased fundal height which is shown to be a predictor for PPH [22]. This finding calls for more vigilance on the part of practitioners attending labour and births to identify women at risk, to have adequate preparation and plan for early intervention to prevent PPH. The WHO encourages further research to determine the role of symphysis-fundal height measurement in detecting abnormal foetal growth and other risk factors for perinatal morbidity (multiple pregnancy, polyhydramnios, macrosomia) in settings where antenatal ultrasound is not available [69].
Intrauterine foetal death (IUFD) -also called stillbirth -was prevalent in participants of our study who experienced primary PPH, again supporting the existing evidence. PPH was observed in 10% of IUFD cases in a US study [70] and in 12% of patients in a study on aetiology and maternal complications of IUFD [75]. In case of stillbirth, PPH might be associated with retained placenta which was noted in a very high number of women (23%) in a retrospective chart review to evaluate stillbirth demographics, pregnancy and maternal risk factors, and complications of labour and birth [74].
Our study was conducted during the Covid-19 outbreak (study period: January -June 2020). Since pregnant women are potentially at risk of obstetric complications including PPH, regular consultation with a health professional is recommended throughout the course of pregnancy, because it is an optimal opportunity for healthcare providers to identify women who are at increased risk early on during pregnancy and to deliver necessary support and educate pregnant women on unexpected events [72].
Low Hb level (<11 gr/dL) on admission to labour is worth noting because it is an indication of anaemic pregnant women so that health care providers can be proactive in prevention of PPH. For participants included in this study the risk of PPH was 1.5 times higher for anaemic women than for non-anaemic women. Again, our findings are consistent with earlier research [27]. The key findings from Rwanda Demographic Health Survey 2019-20 demonstrated that among pregnant women, those in the lowest wealth quintile are more likely to be anaemic (Hb<11 gr/dL) than other women [2]. Our multivariate analysis also demonstrated PROM to be prevalent in women who developed primary PPH which was identified as potential risk factor in earlier case control study [9]. PROM is complicated with chorioamnionitis which was found to be associated with an increased risk of severe atonic PPH in previous studies [31,73].
In addition to prevalent risk factors, our analysis demonstrated significant association of some other risk factors with primary PPH with a P-value < 0.05. These included maternal age (being >35 was associated with higher risk), type of health facility where birth take place, BMI, holding medical insurance, grandmultiparity, previous PPH, anaemia during pregnancy and active management of third stage of labour. The significant antepartum risk factors for primary PPH observed in our study echoed previous evidence [18,22]. In contrast to previous studies [9,18,19,22], where these factors were found to be predictors of PPH, our multivariate analysis did not find these variables to be associated with increased risk of primary PPH. This dissimilarity might be associated with difference in sample size and in data collection period. A large scale case control study would investigate further all potential risk factors for improved PPH prevention.

Intrapartum risk factors and causes of PPH
For intrapartum and immediate postpartum factors analyzed in this study, with the exception of coagulopathy, the other causes of PPH demonstrated a strong association with primary PPH (uterine atony, trauma of genital organs and retained tissues). In this study, uterine atony was found to be the most prevalent cause of primary PPH, followed by retained tissues and genital trauma.
Our findings concur with previous studies highlighting that the main cause of primary PPH and the primary direct cause of maternal morbidity globally was uterine atony [5,6,17]. However, one other study concluded that genital tract laceration was the commonest cause of primary PPH followed by uterine atony [13]. The active management of the third stage of labour with uterotonics was found to reduce the risk of PPH especially due to atonic uterus, and injectable oxytocin is the treatment recommended by WHO [36].
Our study demonstrated that 88.6 % women who gave birth at the five health facilities in the  [75].

Strengths and limitations
The main strength of the present case-control study was the quality of the data source. The review of medical records combined with structured interviews with participants during the hospital stay allowed to collect accurate data and minimized missing data. Case control studies are useful to study multiple exposures in the same outcome [40]. Hence we were able to evaluate potential risk factors for primary PPH using a broad selection of demographic and clinical variables which may not be easily retrieved from registries and from other medical records. In addition, reading the medical records allowed us to record accurate information on the causes of PPH. Assessing risk factors in retrospect is a limitation in this study. In order to minimize selection bias, we selected all possible cases of primary PPH and a random sample of controls from the same source population. Blood loss was estimated visually by health care providers in the five health facilities included in our study, and the blood loss may have been under or overestimated, this might have led also to missing some PPH cases. To minimize this risk, we trained research assistants to identify cases of PPH based on clinical features and visual estimation of blood loss as recommended by Hancock et al., [39] that the diagnosis and early detection of PPH may rely on factors other than volume.

Conclusions
Primary PPH is a common occurrence in the Northern Province of Rwanda. Antepartum haemorrhage, intrauterine foetal death, multiple pregnancy and Hb Level <11 gr/dL on admission to labour and PROM were prevalent antepartum risk factors in primary PPH. During the intrapartum and immediate postpartum period, the main prevalent causes of PPH were uterine atony, retained tissues; and genital organ lacerations identified after birth. Since primary PPH is relatively common, all obstetric unit members should be prepared to manage mothers who experience it. Progress towards improvement of maternal health will require dedicated efforts to improve risk assessment, to encourage proper documentation of maternal information during the course of childbirth for an early detection of women at risk and prevention of PPH in Rwanda.
Improving the quality of proactive prevention should be a priority for policy makers, health managers and service providers to reduce the high risks of maternal mortality and morbidity associated with PPH. Large scale studies are needed to investigate further potential PPH risk factors.

Declarations Funding
Research for the Training, Support and Access Model for Maternal, Newborn and Child Health in Rwanda Project has been undertaken with financial support to the University of Western Ontario from the Government of Canada provided through Global Affairs Canada. The research team acted independently from the funders who had no role in the data collection, analysis, interpretation of data, writing of the report, or in the decision to submit the article for publication.

Availability of data and materials
The datasets used and analysed during the current study are available from the corresponding author on reasonable request. 16022021STROBEchecklistcasecontrol.pdf