Materials and Methods
This study was conducted following the Declaration of Helsinki. The study protocol was also approved by the Institutional Review Board (IRB) of Dalin Tzu Chi Hospital of Buddhist Tzu Chi Medical Foundation (approval number, B10402022). The IRB absolved the requirement for written informed consent due to no direct contact with individual patients from this de-identified database.
We used the Taiwan National Health Insurance Research Database (NHIRD) to analyze the incidence rate of stroke in women with pre-eclampsia/eclampsia and compared it to those without pre-eclampsia/eclampsia. Taiwan NHIRD contains all the records of diagnosis and treatment of approximately 99% of people from inpatient, outpatient, and emergency departments22. The data collection of pregnant women from the Taiwan NHIRD ranged from 2000 to 2017, and it was included in this study for statistical analysis. The data included were evaluated by the National Health Insurance Administration (NHIA) quarterly expert reviews on every 50 to 100 ambulatory and inpatient claims filed by each medical institution23. False diagnostic reports are subject to severe penalties from the NHIA24.
Records of pregnant women in this database were collected and categorized into two groups women, those with and without pre-eclampsia/eclampsia. Based on the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes for pregnant women, the codes were 650, 651, 652, and 653, while those for pregnant women with pre-eclampsia/eclampsia were 642.4, 642.5, 642.6, and 642.7. The primary outcomes included: codes for hemorrhagic stroke being 430, 431, 432, and codes for ischemic stroke being 433, 434, 435, 436, and 437.
Between 2001 and 2017, 1,384,427 pregnant women with delivery were registered in the Taiwan NHIRD. We included all pregnant women in Taiwan with different socioeconomic statuses, living areas (such as metropolises to rural), and hospital levels. The sample size exceeded million people. Figure 1 shows our study’s flow diagram. We excluded 38,707 cases with missing confounders and 566 cases with stroke history. In addition, we only included women with the delivery age between 18 to 45 years. Finally, we enrolled 1,338,334 cases in this study, divided into groups of normal delivery with (N=8,077) and without (N=1,316,550) pre-eclampsia/eclampsia.
In this study, we used exact matching method to control covariates, that is, these two cohorts had the same age, same distribution for comorbidities, and socioeconomic status (all p= 1.000). After 1:4 exact matching, 6,053 cases were selected in the pre-eclampsia/eclampsia group and 24,212 in the non-pre-eclampsia/eclampsia group. The follow-up time in this study was from 2000 to 2017. We divided the 17 years follow up into short (0-1, 1-3, 3-5 years), intermediate (5-10), and long (10-15 years), to further differentiate the risks at different intervals.
Covariates included were age, season, cesarean section or normal spontaneous delivery, multiple gestations, hospital levels, and comorbidities. The hospital level was included in the analysis, account for different care qualities during pregnancy at different hospital levels. The comorbidities included hypertension, gestational diabetes mellitus (GDM), anemia, and delivery conditions such as antepartum hemorrhage (APH) and postpartum hemorrhage (PPH). These young women, age 18 to 45, had no comorbidities, such as chronic kidney disease, heart failure, hypercholesterolemia, peripheral vascular disease, heart valve disorders, after matching. Socioeconomic variables, including geographic region, urbanization level, and monthly income-based insurance premiums were analyzed to reduce bias resulting from lifestyle.