Study population
The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (the TMM BirThree Cohort Study)26,27 started in July 2013 collecting in utero and subsequent exposure and outcome information to establish personalized health care and medicine, and approximately 50 obstetric clinics and hospitals in the Miyagi Prefecture participated in the recruiting process. We recruited pregnant women and children, the children’s father, and grandparents between 2013 and 2017. A total of 22,493 pregnant women were included in the TMM BirThree Cohort Study. We excluded those who were not singletons (n = 328) or withdrew their consent (n = 335). A total of 12,744 pregnant women were missing the following data: diagnosis of PE (n = 827), dipstick test for proteinuria (n = 3,958), family history of PE (n = 6,350), and other predictor variables (n = 1,609), and were also excluded. Finally, 9,086 pregnant women were analyzed in our study. The present study was conducted in accordance with the Declaration of Helsinki. The Approval was obtained from the Ethics Committee of the Tohoku Medical Megabank Organization (2013-1-103-1), and all participants gave written informed consent for study inclusion.
Prediction model
There are many studies reporting prediction models for PE8, which differ not only in variables but also in terms of the statistical model used. Among them, the competing risks model has demonstrated successful performance in the prediction of PE20,28,29. In the competing risks model, all pregnant women are assumed to experience PE finally, but in most cases, delivery occurs before PE development and a survival time analysis, wherein delivery without PE is considered a censored observation, is conducted. One of the merits of this model is that we can easily calculate the risk of delivery with PE at any gestational age. This model has been well-validated in European countries20,28,29, and was therefore applied in our study population.
Predictor variables
We included variables that were verified as risk factors for PE30 and common in clinical practice. In addition, we referred to previous studies that used competing risks models for the prediction of PE20,28.
Maternal basic characteristics, including age30, systematic lupus erythematosus (SLE; present or absent)30, diabetes mellitus (DM) (present or absent)30, maternal family (mother or sisters), history of PE (present or absent) 30, method of conception (in vitro fertilization (IVF) or not)30, parity (nulliparous, parous with previous preeclampsia, or parous without previous preeclampsia)30, gestational age at last delivery20,28, and interval between present and last delivery20,28 were self-reported by the pregnant women.
It is standard practice in Japan for pregnant women to visit antenatal care clinics or hospitals once every 4 weeks until 23 weeks gestation, once every 2 weeks from 24–35 weeks gestation, and once a week after 36 weeks of gestation. Therefore, we obtained the results of the measured blood pressure and dipstick test for proteinuria (negative, ‘±’ or ‘≥1+’) at 10–13 weeks gestation, when most of our population underwent their first or second antenatal visit, from medical records in these clinics and hospitals. In this process, timing of We used only the first measurement of blood pressure in the visit because there were clinics and hospitals where blood pressure was measured only once. We then calculated the mean arterial pressure (MAP)30 ([systolic blood pressure + (2 X diastolic blood pressure)] / 3) and the log10 transformed multiple of the median (log MoM) value of MAP. In addition, we obtained the maternal pre-pregnancy weight and height from medical records and calculated the pre-pregnancy body mass index (BMI)30.
Outcome
We obtained the antenatal medical records to diagnose hypertensive disorders of pregnancy (HDP): chronic hypertension (CH), gestational hypertension (GH), and PE or PE superimposed on chronic hypertension (SP) on the basis of previous guidelines of the American College of Obstetricians and Gynecologists (ACOG)31, which was standard at the time of study recruitment.
We defined GH as a systolic blood pressure of 140 mmHg or more, or a diastolic blood pressure of 90 mmHg or more, on at least one visit after 20 weeks of gestation in a woman with a previously normal blood pressure, and PE as GH with proteinuria (≥‘2+’ on dipstick test) in at least one visit after 20 weeks of gestation. SP was diagnosed when women with CH developed proteinuria after 20 weeks gestation. These phenotypes were automatically diagnosed by computers according to an algorithm, and validated by one doctor.
Statistical analysis
Pregnant women’s blood pressure in early pregnancy and the dipstick test for proteinuria were compared between those with and without the onset of PE/SP using Welch's t-test for continuous variables and the chi-square test or Fisher's exact test for categorical variables.
We conducted parametric survival time analysis that considered delivery without PE/SP as a censored observation20. We assumed Gaussian distribution as a distribution of the survival curve. Maternal basic characteristics, MAP, and the dipstick test for proteinuria were included in our model as predictor variables. Before developing the prediction model, we examined the relationship between each continuous variable and the gestational age at delivery with PE/SP. Continuous variables were grouped, and we then plotted the effect of each group on gestational age at delivery with PE/SP. All continuous variables were centralized to their mean values before developing the model, and the gestational age at last delivery and the interval between present and last delivery were considered only among the parous women.
We compared two models: model 1 did not include the dipstick test for proteinuria, while model 2 did include the dipstick test for proteinuria as a predictor variable, considering delivery with PE/SP as the outcome. We applied five-fold cross-validation, and the area under the receiver operating characteristic curve (AUROC) was calculated. The mean of five AUROCs (mAUROC) was considered as the performance of the models. We used the bootstrap method to gain the distribution of each mAUROC and difference of mAUROCs between the models with and without the dipstick test for proteinuria, calculating the 95% confidence intervals (CI). In addition, we calculated the detection rates (DR) at false positive rates (FPR) of 5%, 10%, and 20%.
To investigate the effectiveness of our model in other classifications, such as hypertension after 20 weeks of gestation, we conducted a secondary analysis. We excluded pregnant women with CH or SP from our study population, and calculated the mAUROC and FPR considering only PE and GH/PE as the outcome. All statistical analyses were performed using R version 3.5.3 (https://www.R-project.org/.).