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Does anemia risk for pre-eclampsia? A multi-center, Case control study in Amhara region, Ethiopia.

Objective This study aimed to identify determinants of preeclampsia among women visiting referral hospitals in Amhara region. A hospital-based unmatched case-control study was conducted from February 20, 2016 to May 18, 2016 among 871 women visiting West Amhara referral hospital for prenatal care. Result Advanced age (>35 years) [AOR (95%CI), 3.09(1.80-3.35), being primigravidae [AOR (95%CI), 2.32 (1.61–3.35) family history of hypertension [AOR (95%CI), 4.31 (2.37–7.85)], twin pregnancy [AOR 95%CI, 3.53(1.77–7.06)], and Anemia [AOR (95%CI) = 1.49 (1.06– 2.1)] were determinants of preeclampsia.


Introduction
Preeclampsia, a life threatening complication of pregnancy, is a condition that typically starts after 20 th week of pregnancy and is related to increased blood pressure (BP ≥140/90 mmHg) and protein in mother's urine (urinary albumin protein ≥ 300 mg/24 h) (1,2).Preeclampsia and eclampsia are major cause of maternal deaths in the world (3). Although the incidence varies from region to region, eclampsia accounts for up to 40% of maternal mortality (4). Eclampsia which is a complication of preeclampsia accounts for 50,000 maternal deaths a year (5).
Maternal near-miss cases were eight times more frequent in women with preeclampsia, and increased up to 60 times in women with eclampsia compared with women without these conditions (6).Preeclampsia increases risk of fetal morbidity and mortality. It is a major cause of stillbirths, neonatal deaths, small for gestational age, lower birth weight, perinatal death and responsible for 15% of all preterm births (7).
Preeclampsia/eclampsia is responsible for 16% of direct cause of maternal death in Ethiopia & there is an increasing trend. Despite this, health centers don't have necessary drugs for the management of preeclampsia. Women may be referred to hospital without getting anticonvulsants. In addition to this, laboratory test for protein & organ function tests are not available for the management & follow up of women with preeclampsia. Due to this reason, most women with preeclampsia & eclampsia are referred to hospitals for better investigation, management & follow up (8,9).Identifying the risk factors for preeclampsia is mandatory in order to prevent this high maternal mortality.
Although the exact etiology of preeclampsia is unidenti ed, many conditions are known as risk factors. Diabetes, renal disease, obesity, multiple pregnancy, primiparity, age above 30 years, personal or family history of preeclampsia and chronic hypertension are some of the risk factors identi ed for preeclampsia. In Ethiopia, there is no enough evidence on the risk factors of eclampsia and preeclampsia (10).Therefore, this study was done to identify determinants of preeclampsia in Amhara region, Northwestern Ethiopia.

Methods
Study setting Amhara regional state is one of the nine regional states in Ethiopia.Amhara Region is the second largest and populous regions in Ethiopia where close 20 million people are living. This region has a population of 21,134,988 of whom about 4,897,566 are women and the region have 55 hospitals, 839 health centers, and 3336 health posts; among these 5 are referrals hospitals,4 general and 42 primary hospitals . The hospitals have a total of 1023 skilled birth attendants. These hospitals have 646 beds and around 84,440 deliveries per year (11).The health center have a total of 3023 skilled birth attendants and 12900 deliveries per year. All these government health institution provides care for the pregnant mothers widely in ANC, intrapartum and postpartum period.

Source population
All women who get perinatal service at west Amhara referral hospitals.
Cases were women diagnosed with pre-eclampsia by skilled provider. Preeclampsia is de ned as high blood pressure (blood pressure of >140/90 mmHg)& excretion of 300mgor more protein in 24h urine sample after 20 weeks of pregnancy among previously normotensive pregnant women. This de nition is used to diagnose preeclampsia in Ethiopia. Controls were all women who came for perinatal service who didn't have high blood pressure or proteinuria above the level mentioned above. Controls were interviewed after the hospital team ruled out preeclampsia using the above de nition.

Study population
All women who get perinatal service at west Amhara referral hospitals during the study period Inclusion and exclusion criteria Exclusion criteria Women who were critically ill at the time of survey.

Study design and sample size determination
An institution based, unmatched case control study was conducted among women who visited west Amhara referral hospitals. Sample size was determined using Epi Info stat calc by taking 80% power, 95% con dence level and a case to control ratio of 1: 2. Based on the above assumption and adding 10% nonresponse rate, the nal sample size was 831(277 cases and 554 controls) women.

Sampling techniques and procedures
All cases in the study period were included in the study until the required sample size was obtained.
Proportion to size allocation was used to determine the number of cases to be recruited from each hospital. For each case, two controls were selected using systematic random sampling technique.

Data collection tools and procedures
A pre-tested and structured questionnaire and document review were used for data collection. The questionnaire had socio-economic and demographic variables, obstetric and medical variables which were used to identify determinants of pre-eclampsia.
Training was given for one day for data collectors and supervisors. Clarity was made on all content of the formats and areas of di culties. Besides, they were trained on overall procedures of data collection. Questionnaire was checked by data collectors & supervisors on daily base for completeness and consistency and fully completed with few missing items was coded.

Data processing and analysis
The collected data was checked for completeness and consistency. It was entered, cleaned, coded and analyzed using SPSS version 20.0. Pearson Chi-Square statistics was used to identify variation among cases and controls. Bivariable and multivariable logistic regression model were used to identify the association between explanatory and outcome variables with95% CI. Variables with p-value of less than or equal to 0.2 at 95% CI in the bivariable analysis were included to the multivariable model p value of < 0.05 was used to express the statistical signi cance of the variables.

Results
Socio-demographic characteristics of study participants A total of eight hundred thirty one women were enrolled in this study. The mean age of cases was 27 years with standard deviation (SD) of ±6.4 years. About 67.8% of the cases were in the age range of 20 and 34 years. The majority of controls (72.7%) were aged 20-34 years. Most of the cases (81.9%) and controls (91%) were married (Additional le 1: Table SD1).

Personal and family history of study participants
In this study 17(6.1%) of the cases and 12(2.1%) of the controls reported history of chronic hypertension. Similarly, 56(20%) of cases and 20(7.2%) controls reported family history of hypertension and 100(37.7%) of cases were anemic (Table 1).

Obstetric characteristic of the study participants
Almost half (49.4%) of the cases and 39% controls were primigravidae. Regarding type of pregnancy, 10% of cases and 3.1% controls had twin pregnancy (Table: 2).

Determinants of preeclampsia
In the bivariate analysis, maternal age, blood group, gravidity, type of pregnancy, history of diabetes mellitus, family history of hypertension and having new partner and being anemic were signi cant at <0.  (Table: 3).

Discussion
The study identi ed increased maternal age as determinant of preeclampsia. Pregnant women aged 35 or above were more likely to develop preeclampsia compared to women aged 20-34 years. This result was in line with the study done in Dessie town, Ethiopia(12). The nding was also similar with studies done in developed countries. A study based on nationwide data from the USA showed that the risk of preeclampsia increases by 30% per year after age 35(17). The reason for increased risk of preeclampsia among women with advanced age is that increasing age is associated with glucose intolerance due to a reduction in insulin sensitivity and abnormal lipid pro le with increased levels of triglycerides and cholesterol. This leads to increased villous reaction leading to preeclampsia in older women (18,19).
In this study, primigravidae women were more likely to develop preeclampsia compared with women of gravid 2-4. This may be due to exposure to chorionic villi for the rst time, which is fetal in origin and a consequence of maternal immune reaction against paternal antigens expressed in placenta (20). This result was in line with studies done in Uganda(13) and another study conducted in developed countries (14).
Women who had twin pregnancy were more likely to develop preeclampsia compared to those with singleton. This nding was supported by studies in India(15) and Cairo (16).Hyperplacentosis, a greater demand of blood and oxygen supply, and an increase in the maternal cardiac output have been proposed as underlying mechanisms to explain the increased incidence of preeclampsia among women with multiple pregnancies (24 -26).
This study identi ed that women with family history of hypertension were four times more likely to develop preeclampsia compared with those without family history of hypertension. This nding was in line with studies conducted in Dessie town, Ethiopia(12)and Brazil (17).This might be due to genetic factors that contribute to the physiologic predisposition of preeclampsia (13).Family history of hypertension is also a proxy measure for hereditary factors as well as common environmental or behavioral exposures that may underlie preeclampsia risk (28).
In this analysis, women with history of preeclampsia had higher risk of preeclampsia at current pregnancy.
This nding was in line with other studies. Women with preexisting renal disease were more likely to develop preeclampsia. This nding was inconsistent with a study done in India(15).Renal disease may alter the acid-base, electrolyte, and renal function which may be aggravated by pregnancy and lead to preeclampsia.
The main nding of this study has shown those women having anemia were more likely to have increased incidence of preeclampsia This nding is consistent with other studies (18).the study in Sudan showed that there is association between the degree of the anemia during pregnancy with increase risk of preeclampsia risk of preeclampsia(19).

Conclusions
Old maternal age, primigravidae, twin pregnancy, family history of hypertension, and anemia were determinant of preeclampsia. Avoiding pregnancy at an older age should be advocated to reduce preeclampsia. Prevention of renal disease can also help to reduce preeclampsia. Health care providers should give special attention when providing antenatal care for women who are aged, primigravidae, had twin pregnancy, family history of hypertension, and with the previous history of preeclampsia and renal disease to early diagnose and manage preeclampsia.

Limitations
The ndings of this study should be viewed in light of the following limitations. There might be introduced selection bias given that cases were selected consecutively as they appear for diagnosis additionally the study subjects were not followed after discharge from health institutions, Preeclampsia can be developed later on the postpartum period beside this there might be also introduced recall bias for some information acquired using the memory of participants.