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Antenatal care and its effect on risk of pregnancy induced hypertension in Lao PDR: A case-control study [version 1; peer review: 1 approved, 1 approved with reservations]

Background: Pregnancy induced hypertension (PIH) is a global public health concern as a leading cause of maternal mortality. Lao PDR has a high prevalence of PIH, but little is known about its risk factors. This study aimed to identify risk factors of PIH relating to antenatal care (ANC) in Lao PDR. Methods: This hospital-based age-matched case control study was carried out between July and December 2017 in tertiary and secondary hospitals in Lao PDR. A total of 258 pregnant women (86 hypertensive and 172 normotensive pregnant women) were recruited to join the study based specific inclusion criteria. For each case, two consecutive controls were included in the study with matched maternal age. Data was collected using a structured questionnaire interview to identify the risk factors of PIH relating to ANC. The association between the independent variables and PIH was assessed through bivariable and conditional multiple logistic regression analyses. Results: Mothers with PIH had inadequate ANC (defined as <4 times) (adj. OR= 10.23 , 95%CI: 3.67 – 28.49, p<0.001), excessive maternal weight gain during pregnancy (>13kg) ( adj. OR=7.35, 95%CI: 3.06 17.69, p<0.001), had a history of abortion (adj. OR=3.54, 95%CI: 1.309.59, p=0.013), and had received inadequate information about PIH (adj OR= 2.58 , 95%CI: 1.03 – 6.46 , p=0.043). Conclusion: Inadequate ANC and maternal factors were major risk factors of PIH in Lao PR. National PIH guidelines for effective counseling, ANC and treatment should be promptly developed and implemented at all levels in order to improve pregnancy outcomes. Open Peer Review


Introduction
Pregnancy induced hypertension (PIH) is a major reproductive health concern, complicating 2-3% of pregnancies 1 and has an incidence of 6-8% for all pregnancies 2 . PIH, including preeclampsia and eclampsia, was the second leading cause of maternal mortality and morbidity, especially in developing countries 3 . Globally, PIH was responsible for 16% of maternal deaths 4 .
The complications of PIH are severe in developing countries 5,6 . Compared to postpartum hemorrhage and sepsis, PIH is quite difficult to prevent due to late presentation of symptoms 7-9 . The causes of PIH are still unknown and the mechanism is yet to be elucidated 10 . Maternal mortality in Lao PDR still remains the highest in Southeast Asia. The direct causes of maternal mortality in Lao PDR were postpartum hemorrhage, PIH, obstructed labor and sepsis, of which PIH was the second leading cause of maternal mortality 11 .
Antenatal care (ANC) is a care of women during pregnancy by skilled health care providers. The components of ANC include: early high risk screening, prevention and care of pregnancy-related complications, including PIH, and provision of health education and health promotion 12 . PIH can be detected by routine screening of blood pressure and presence of proteinuria during ANC 12,13 . Adequacy of ANC is very useful in the early detection of PIH screening. Focussed ANC is recommended by the World Health Organization, who show using evidence-based intervention that there are 4 critical times for ANC during pregnancy 14 . Therefore, in the present study ≥4 times of ANC was defined as adequate or good ANC. Current PIH risk factors and preventive strategies are still questionable. The prevention and management of PIH are unclear due to insufficient knowledge concerning influencing factors, screening methods and preventive strategies. There is limited research on PIH in Lao PDR. Consequently, this study was conducted to identify risk factors of PIH in Lao PDR as relating to ANC.

Participants
Postpartum women who had delivered a baby between July and December 2017 in eight hospitals in Vientiane capital were included in this study. Four tertiary hospitals: The Mother and Child, Mahosot, Mitaphab and Sethathirath hospitals. Four provincial secondary care hospitals: Oudomxay, Xiengkhouang, Luangnamtha and Sekong hospitals.

Sample size
Primigravida was considered as an exposure of PIH, however, there was no exact data available in Lao PDR for the proportions of primigravida among the subjects in this study. Therefore, the sample size was computed by using proportions of primigravida among cases and controls obtained by similar study in Thailand 15 . With 95% confidence level and 80% power of the study, the required minimum sample size was calculated to be 86 for cases and 172 for controls (case: control ratio of 1:2), 258 subjects in total.

Inclusion criteria
The subjects were selected based on specific inclusion criteria. Cases were screened for eligibility from medical record by physicians. Single pregnant women were eligible subjects. Cases were women with PIH diagnosed by physicians. PIH was defined as a pregnant women with systolic blood pressure of ≥140 mmHg and diastolic blood pressure of ≥90 mmHg measured on two occasions 6 hours apart, accompanied by proteinuria of ≥300 mg per 24 hours, or ≥1+ on dipstick testing after 20 weeks. Controls were selected based on age-matching with cases in the same hospital. Controls were normotensive pregnant women who had delivered a baby within 3 days in the same hospitals and matched ± 2 years to maternal cases. Pregnancy with abnormal fetus and hydrop fetalis were excluded.

Data collection
A structured questionnaire (Supplementary File 1) was used as a data collection tool for both cases and controls. The questionnaire consisted of four parts including: General information, socio-demographic characteristics, previous pregnancy history and present pregnancy history. The content of this questionnaire was reviewed by five experts for validity. From the total of five experts, four were obstetricians from central hospitals in Vientiane Lao PDR and members of the Laos Association of Obstetrics, and one was a public health specialist who had experience research reproductive health reseach and worked at the University of Health Sciences, Lao PDR, for fifteen years.
In total, 30 test subjects tested the reliability of the questionnaire at the Military Hospital in Vientiane Capital. The Cronbach's alpha coefficient of the questionnaire was 0.87.
All cases and controls were interviewed during their hospital admission by physicians from other hospitals who were blinded to the subjects' PIH status. Data were collected between July and December 2017.
This study is a case control study which is retrospective in nature; therefore it is subjected to information bias, including recall and investigator bias. To circumvent recall bias we limited the recruitment of the cases to mothers who recently gave birth within one week. To limit investigator bias as a result of awareness of PIH conditions, the investigators were blinded to PIH in cases or controls. Therefore the questions the investigators posed would be asked in the same way for both cases and controls.

Statistical analysis
Data analysis were done using STATA version 10.0 16 . Descriptive statistic was used to describe the characteristics of cases and controls presenting frequencies, percentage, means, and standard deviations, minimum and maximum. Simple logistic regression was used to identify the association between each independent variable and PIH. The independent variables with p-value <0.25 were selected to proceed to the multivariable analysis. Since this is a matched case control design, the conditional logistic regression was administered to identify the risk factors of PIH presenting adjusted odd ratio (OR) with 95% Confidence Interval (95% CI) and p-value 17 .

Ethical statement
The research proposal, questionnaire and reliability test of the questionnaire were submitted and approved by the Research Ethical Committee of Khon Kaen University, Thailand (Reference No: HE 602069) and University of Health Sciences, Vientiane, Lao PDR (Reference No: 012/17). Ethical approval from both institutions was obtained prior to the validity test and the study data collection. Patient information (demographic, socioeconomic, reproductive health and pregnancy history, ANC) and written informed consent for participation was obtained from all women, including those who took part in the validity test.

Results
A total sample of 258 postpartum women comprising 86 cases and 172 controls were included in the analysis. There was no significant differences between cases and controls regarding ethnicity, religion, educational attainment, occupation, type of health insurance, family size, number of pregnancies and number of deliveries (Table 1).
Excessive maternal weight gain (>13 kg) was higher among cases (65.1%) when comparing with controls (25.8%). History of abortion was higher in controls (35.5%) compared to cases (22.1%). Cases receiving adequate information about PIH

Discussion
This is first hospital-based matched case control study aiming at identifying risk factors of PIH in Lao PDR. We found that inadequate ANC had a strong association with PIH. It was found that 93.6% of controls received ≥4 times of ANC whereas only half of cases had ≥4 times ANC. This is also supported by other associated factors, including excessive weigh gain, which were found among 65.1% of cases but only 23.4% of controls, and only 18.6% of cases received adequate information about PIH whereas almost half of the controls did. Quality ANC should include physical checkup, treatment, health education, and counselling and improving health behaviors. With adequate ANC (≥ 4 times), pregnant women would be monitored and have better pregnancy outcomes and a reduction in complications. This finding supports the results of other similar studies 18-20 . In addition, a study in Ethiopia also identified a lack awareness on the risk of hypertension as one of a risk factors of PIH 21 .
We also found that a history of abortion is a protection factor for PIH, which was similar to a study in Iran and Norway, as indicated that pregnant women who had history of abortion had lower incidence of PIH 22,23 . In addition, some studies in the US and Norway reported that a history of abortion was a protective factor for PIH 24,25 .
Other factors that could have been risk factors for PIH such as gravida, pre-pregnancy body mass index and other socioeconomic factors did not show any association with PIH in this study.
There were some limitations of this study since it is a case control study. However, we have minimized information bias from investigators during interview by blinding the investigators to the PIH status of the cases and controls. Therefore, the investigators asked the questions to both case and control groups similarly.

Conclusion
Inadequate ANC is a major risk factor of PIH in Lao PDR, leading to poor access to information related to PIH. These put pregnant women at risks of other risk factors such as excessive maternal weight gain. Promotion of attending of ANC at least 4 times during pregnancy and developing national guidelines for PIH, including proactive strategies of antenatal screening, early detection, counseling, provision of health education, ANC and treatment, should help improve pregnancy outcomes In Lao PDR.

Data availability
F1000Research

Results:
In total, 5170 patients were interviewed and 252 had experienced pre-eclampsia. The number of previous spontaneous abortions was found to be associated with pre-eclampsia, and a higher number of previous spontaneous abortions was associated with increased odds of patients having experienced pre-eclampsia (adjusted odds ratio 1.28, 95% confidence interval 1.03-1.59; P=0.025).

Conclusion:
A history of spontaneous abortion was associated with increased odds of pre-eclampsia during a subsequent pregnancy.Both studies showed that the history of abortion increased odds ratio of PIH. In the discussion part should add some explanations in each factor The inadequate ANC numbers -how to explain for the increase PIH such as an early ANC can give some medication for prophylaxis (calcium supplementation in high risk pregnant women), etc.