Risk factors for composite adverse outcomes of postpartum haemorrhage , Mpilo Central Hospital , Bulawayo , Zimbabwe

Background Globally, primary postpartum haemorrhage continues to cause considerable maternal morbidity and mortality. The aim of this study was to determine the risk factors for composite adverse outcomes of postpartum haemorrhage. The findings could potentially be used to anticipate and prevent composite adverse outcomes of postpartum haemorrhage. Methods This was a retrospective cross-sectional study carried out at Mpilo Central Hospital, a government tertiary referral centre, covering the period 1 July 2016 to 30 November 2019. Participants were included in the study if they had a diagnosis of postpartum haemorrhage. Those variables that had a p<0.2 from the univariate logistic regression analyses were considered for multivariable logistic regression. The association between independent variables and the dependent variable was assessed using odds ratio with 95% confidence intervals, to identify independent risk factors for composite adverse outcomes in PPH. A p< 0.05 was taken as statistically significant. Results The independent risk factors for composite adverse outcomes of postpartum haemorrhage were place of dwelling (AOR 4.57, 95% CI 1.87-11.12, p=0.01), prior Caesarean section (AOR 2.57, 95% CI 1.106.00, p=0.03), antepartum haemorrhage (AOR 5.45, 95% CI 2.23-13.27, p<0.0001), antenatal haemoglobin level (AOR 19.64, 95% CI 1.44268.50, p=0.03), and current delivery by Caesarean section (AOR 10.21, 95% CI 4.39-23.74, p<0.0001). Blood loss was also an independent risk factor for composite adverse Open Peer Review


Introduction
The definition of primary postpartum haemorrhage (PPH) is that of blood loss from the genital tract of ≥500 mL or more following a normal vaginal delivery or ≥1,000 mL or more following a cesarean section within 24 hours of delivery as evidenced by a rise in the pulse rate, and falling blood pressure [1][2][3] .
Every day in 2017, approximately 810 women died from all causes related to pregnancy and childbirth, and 94% of all maternal deaths occurred in low and lower middle-income countries 4 . Researchers have reported in a systematic analysis that low-and middle income countries accounted for 480 000 maternal deaths (32%) compared with 1200 (8%) in the developed regions 5 . PPH is the leading cause of maternal deaths in Sub-Saharan Africa 6 .
The multi-country Survey on Maternal and Newborn Health reported the prevalence of PPH to be 1.2%, with higher rates in developing countries than developed ones 7 . Other studies in Sub-Saharan Africa reported rates of 1.6% in Zimbabwe, 16.6% in Southern Ethiopia, 9% in Uganda and 23.6% in Cameroon 1,3,8,9 , respectively. Ford et al. reported increasing PPH rates from 6.1% in 2003 to 8.3% in 2011 (p<0.0001) in Australia due to better recording of PPH 10 .
Tort et al. found the following factors were significantly associated with PPH maternal mortality: age over 35 years, living in Mali, residing outside the region location of the hospital, pre-existing chronic disease before pregnancy, prepartum severe anemia, forceps or vacuum delivery, birth weight greater than 4000 grams, transfusion, transfer to another hospital. They also reported that there was a smaller risk of PPH maternal death in hospitals with gynecologist-obstetrician 13 .
Women suffering a PPH can face significant risks. Serious maternal morbidity include multiple blood transfusions, and their associated risks peripartum hysterectomy 16 , ultiple organ failure, maternal collapse, and maternal mortality.
PPH is an obstetric emergency. Prevention of PPH should be the aim with each delivery. The active management of the third stage of labour done routinely reduces the incidence of PPH, and the administration of oxytocin after delivery of the anterior shoulder being the most important and effective component of the active management practice 17 . The management of PPH include the use of additional oxytocic agents, multiple blood transfusions, uterine packing, ballon tamponade, B-Lynch sutures 18 , and peripartum hysterectomy 16 .
The aim of this research was to determine risk factors for poor composite adverse outcome of PPH. Poor composite adverse outcome was defined as maternal death or serious morbidity. This could help clinicians, study population, and policy makers to identify which women with PPH are at risk of composite adverse outcomes and increase further the clinical vigilance associated with the management of PPH thereby preventing deaths.

Study type, setting and participants
This was a retrospective cross-sectional study carried out at Mpilo Central Hospital, a government tertiary referral centre, covering the period 1 July 2016 to 30 November 2019. Mpilo Central Hospital is situated in the township of Mzilikazi in Bulawayo. Bulawayo, is the second largest city in Zimbabwe after the capital city Harare, with a population of 653, 337 as of the 2012 census 19 . Participants were included in the study if they had a diagnosis of postpartum haemorrhage within 24 hours of delivery at Mpilo Central Hospital. Mpilo Central Hospital delivers an average of 10 000 babies per year. It is has a 20 bedded, consultant-led labour ward. There are 150 midwives and 30 medical personnel that work in it. A single-centre study was chosen so that to exposure women to one standardized care so that risk factors could be determined without other confounding factors. Therefore, women that delivered outside the hospital were excluded from the study to control for confounding factors.

Independent variables
The independent variables included socio-demographic factors, mode of delivery, fetal characteristics, blood loss, laboratory tests, causes of PPH and the management of PPH.

Main outcome measure
The main outcome of interest for the study was the composite adverse outcome which included maternal death or serious morbidity (either of hypovolaemic shock or haemoglobin <4g/dL or massive blood transfusion >4 units or hysterectomy or admission to ICU or coagulopathy or major organ dysfunction), similar to the the Delphi consensus study on PPH 20 .

Data collection
Data was collected for the period 1 July 2016 to 30 November 2019, recording all the women that met the criteria during the study period. Data collection was done by using a paper data collection tool, that was used to collect secondary data from the labour ward delivery registers, and mortality

Amendments from Version 1
This new version is much clearer with more information added to most of the sections, but mostly on the introduction, methods, results, and discussion sections, which includes the addition of 6 new tables. There more clearer details on the conclusions. The explanations should help with the article understanding as this study focuses on risk factors for composite adverse outcomes of PPH rather than the usual risk factors for PPH. There are few studies of this nature so this is a unique study.
Any further responses from the reviewers can be found at the end of the article REVISED registers. Hospital case notes were retrieved the clinical data were extracted.

Data analysis
Data were cleaned, coded and entered into a Microsoft Excel spreadsheet, then exported to SPSS Version 20 (IBM, Armonk, NY, USA) for analysis. Descriptive statistical analyses were performed and presented as frequencies and percentages for categorical variables. Bivariate correlations of association between main independent variables and the outcome measures were performed using Pearson 2-tailed chi-square test. A p value of <0.05 was considered to be statistically significant, and these were considered for the univariate logistic regression. Those variables that had a p<0.2 from the univariate logistic regression analyses were considered for multivariable logistic regression. The association between independent variables and the dependent variable was assessed using odds ratio with 95% confidence intervals, to identify independent risk factors for composite adverse outcomes in PPH, holding other variables constant and adjusting for co-variates. The Hosmer-Lemeshow goodness-of-fit was used to check if the model fitted well. A p< 0.05 was taken as statistically significant.

Ethical approval
The Ethics Committee at Mpilo Central Hospital made a ruling for all retrospective studies to go ahead in the institution from 2016 onwards as long as the data remained anonymous. No individual patient consent was necessary as the study was retrospective and the data was anonymous. No ethical issues will arise during the study as all the data will remain anonymous with no identifying personal data. Minutes of the Committee's inaugural meeting held on the 13 th October 2016 set out the requirements of all the studies at the institution.

Results
Socio-demographic characteristics of participants A total of 386 cases of PPH were recorded during the period 1 July 2016 to 30 October 2019. The summary of maternal and fetal characteristics are shown Table 1-Table 5. The majority (27.7%) of women were aged 25-29 years. 60.1% of women were of gestational age of 37-40 weeks. 87.0% of women were from urban dwelling. More than threethirds (67.9%) had normal vaginal delivery. The commonest risk factory present for PPH was preeclampsia (25.1%). 71.7% of the babies weighed 2501-4000g. 73.6% of women lost 500-1000ml of blood. The commonest cause of PPH was uterine atony (78.8%). The maternal mortality rate was 2.8%, and the composite adverse outcome rate was 11.1%. Table 6 shows the bivariate correlations. De-identified results are available for each patient as Underlying data 21 .
Risk factors for composite adverse outcomes Table 7 and Table 8 show the results of the multivariable logistic regression. Rural women were 4.6 times more likely to be statistically significantly associated with composite adverse outcomes compared to women from urban areas (AOR 4.57, 95% CI 1.87-11.12, p=0.01). Only the post-delivery haemoglobin level was normally distributed with a mean of 9.6 g/dL (SD±2.4).
NB: Blood loss is estimated blood loss plus measured blood loss as protocol for the unit in all PPH cases.

History of Caesarean section
Women with a prior Caesarean section were statistically significantly associated with composite adverse outcomes of PPH.

Antenatal haemoglobin count
Antenatal haemoglobin count was also statistically significantly associated with composite adverse outcomes of PPH. Women with haemoglobin counts of 0-5.99 g/dL were 19.6 times more likely to be statistically significantly associated with composite adverse outcomes of PPH compared with women with haemoglobin counts of 11 g/dL and above (AOR 19.64, 95% CI 1.44-268.50, p=0.03).

Current delivery by Caesarean section
Current delivery by Caesarean section was statistically significantly associated with composite adverse outcomes of PPH. Women who had a Caesarean section were 10.2 times more likely to be statistically significantly associated with composite adverse outcomes of PPH compared to women who delivered vaginally (AOR 10.21, 95% CI 4.39-23.74, p<0.0001).

Blood loss
Blood loss was statistically significantly associated with composite adverse outcomes of PPH. The odds rose significantly higher as the amount of blood loss increased. Women who lost 1001-1500 ml of blood were 9.9 times more likely to be statistically significantly associated with composite adverse outcomes, compared to women that lost 500-1000 ml (AOR 9.94, 95% CI 3.68-26.88, p<0.0001). The odds rose to 41.3 times more like to be associated with composite adverse outcomes in those women who lost 1501-2000ml compared to those women who lost 500-1000 ml (AOR 41.27, 95% CI 11.32-150.54, p<0.0001). Whereas women who lost 2001 ml and above were 164.8 times more likely to be statistically significantly associated with composite adverse outcomes  Such women were 2.6 times more likely to be statistically significantly associated with composite adverse outcomes of PPH, compared to women without such history (AOR 2.57, 95% CI 1.10-6.00, p=0.03).

Antepartum haemorrhage
Antepartum haemorrhage (APH) was statistically significantly associated with composite adverse outcomes of PPH. Women who presented with APH were 5.5 times more likely to be statistically significantly associated with composite adverse outcomes of PPH compared to women who had no APH (AOR 5.45, 95% CI 2.23-13.27, p<0.0001).

Discussion
The strengths of this study include the fact that it used a large homogenous cohort of women with PPH that could make the findings generalizable to other places with similar populations in Sub-Saharan Africa, a region where PPH continues to contribute significantly to global mortality and morbidity. Secondly, using data from a single-centre meant that women received standardized care reducing confounding factors. Thirdly, this study is one of the few and unique ones in that it calculated risk factors for composite adverse outcomes of PPH unlike the previous ones that calculated risk factors for PPH. Therefore, the study adds new information on risk factors for composite adverse outcomes.
PPH rates have been reported to be rising in both low-income and high-income countries 11,22 . Hence PPH will remain an important global subject. There are few studies in the literature that specifically determined risk factors for composite adverse outcomes of primary PPH, rather there are many studies on risk factors for primary PPH.
Rural dwelling was associated with composite adverse outcomes. National governments need to made healthcare accessible to rural women so that the Sustainable Development Goals on Maternal Mortality to reduce global maternal mortality ratio to less than 70 per 100 000 live births by 2030 4 , could be achievable.
Women with a prior Caesarean section were associated with composite adverse outcomes of PPH. The means that women with a prior Caesarean section should receive extra clinical vigilance. Women who had a current Caesarean section were also associated with composite adverse outcomes of PPH. Women with a prior Caesarean sections, and those with current Caesarean sections should be closely monitored postoperatively to reduce the risks of adverse outcomes.
Antepartum haemorrhage was statistically significantly associated with composite adverse outcomes of PPH. Low haemoglobin levels were associated with composite adverse outcomes of PPH. Comparatively, a study in Senegal and Mali by Tort et al. found prepartum severe anemia was associated with maternal mortality in PPH 13 . This was similar to the findings of this study. Hence anaemia should be screened for antenatally and women should receive treatment so that they enter labour with normal haemoglobin counts. This will also cover up for possible complications like antepartum haemorrhage.
Massive blood loss was as expected associated with composite adverse outcomes of PPH. The amount of blood loss was found to be related to adverse maternal outcomes 23 . Prompt, effective prevention and management of PPH 22 , should be the aim to reduce the amount of blood loss and prevent the development of composite adverse outcomes.
The determination of risk factors for composite adverse outcomes of PPH is critical as it could help in reducing the risks of maternal mortality that women with PPH face.

Limitations
Its major limitation is that it was a retrospective, single-centre study that used secondary data. This could limit the generalizability of its findings to other centres of low-resourced settings who may not be using the same management standards or have fewer healthcare personnel.

Conclusions
The independent predictors for composite adverse outcomes of PPH were rural dwelling, a prior Caesarean section, antenatal haemoglobin level, and current delivery by Caesarean section. Blood loss was also an independent predictor for composite adverse outcomes of PPH. All these risk factors are easily identifiable and should be clearly noted by attending clinicians. Crucially, this new information should help in increasing clinical vigilance and preventing maternal deaths especially in low-and middle income countries were PPH  This project contains the following underlying data: PPH-Data-Share (XLSX). The raw de-identified data gathered from each patient examined in this study.

Is the study design appropriate and is the work technically sound? Partly
Are sufficient details of methods and analysis provided to allow replication by others?