Study participants
A nested case–control study involving 2,558 study participants (1,132 RPL cases and 1,426 non-RPL controls) was conducted with data from the prospective PWC study between June 2017 and June 2019 in the Gansu province of China, which was implemented to explore the pregnant women's weight management and other factors that affect pregnancy outcomes. Ethics approval for this study was obtained from the Gansu Provincial Maternity and Child-care hospital’s Ethics Committee.
Women diagnosed with a miscarriage (a pregnancy loss) before they underwent treatment were enrolled from the Reproductive Medicine Center at Gansu Provincial Maternity and Child-Care hospital in the city of Lanzhou, which is located in the province of Gansu, China. A pregnancy loss (miscarriage) is defined as the spontaneous demise of a pregnancy before 24 weeks of gestation[2]. Information on RPL outcomes was obtained from the participants’ medical records within the subsequent two years. Women who experienced the losses of two or more pregnancies were defined as RPL cases. The non-RPL controls were randomly screened out and matched by maternal age. Potential cases and controls were excluded if the woman chose to induce abortion, faced infertility problems, suffered from chronic diseases or had a history of psychiatric disorders or addiction and was not available for analysis. 1:1 matched case control, re-checked and eliminated those who did not meet the admission criteria and lost follow-up, a total of 1,132 cases (RPL group) and 1,426 controls (non-RPL group) were included in this study.
Data collection
An in-person structured interview was undertaken with the participants after their first miscarriage by a specially trained nurse at the hospital. Information collected during the interview included socioeconomic characteristics (e.g., maternal age, ethnicity, education, occupation, family monthly income, time limit of past pregnancy loss and foetal abnormalities) and lifestyle habits before miscarriage (e.g., active or passive smoking status, alcohol consumption, sleep quality and level of physical exercise). Maternal menstrual and reproductive history (e.g., menstrual cycle, self-reported last menstrual period, gravidity and parity, multivitamin supplement use during pregnancy, gestational age and information on the birth outcomes) were obtained from the participants’ medical records. Follow-up data about the subsequent pregnancy outcomes (e.g., RPL, no pregnancy, or ≥24 gestational weeks) were obtained through outpatient department visits and telephone interviews until 30 June 2019. The follow-up rate was 88.2%.
Measurements
We used the Self-Rating Anxiety Scale (SAS)[12] and the Self-Rating Depression Scale (SDS)[13], respectively (Chinese version) to ascertain the women’s true situations regarding depression and anxiety during the first few days after their first miscarriage. The SDS and the SAS both contain 20 items; they use a point score from the baseline of one. The point scores indicate the following: 1=‘none or a little of the time’; 2=‘some of the time’; 3= ‘a good part of the time’; and 4 = ‘most or all of the time’. The original total scores of the SDS and SAS all ranged from 20 to 80. The SDS Index and SAS Index were obtained by multiplying the total score on each questionnaire by 1.25 and converting to a 100-point scale. According to the primary screening diagnostic criteria of Chinese anxiety and depression norms: SAS ≥ 50 and SDS ≥ 53 were defined, respectively, as anxiety and depression diagnoses[14].
Statistical analysis
We converted the quantitative variables (e.g., maternal age, SAS score, SDS score) to qualitative variables. The category ranges were age(≤25, 26~, 30~, ≥35); family monthly income(<2000, 2000~, 4000~, ≥6000); anxiety: mild (score 50–59), moderate (score 60–69) and severe (score ≥70); depression: mild (score 53–62), moderate (score 63–72) and severe (score ≥72)[15]. A chi-square test was used to evaluate the statistically significant differences between the RPL group and the control group.
We performed multiple logistic regression analysis to analyse the relationship between anxiety/depression symptoms from miscarriage and the incidence of subsequent RPL. The data entering the regression equation were derived from the statistically significant variables and clinically relevant reported data. Maternal age, ethnicity, family monthly income, education, times of miscarriage at baseline, whether they had a child, time limit of past pregnancy loss and foetal abnormalities were analysed as the potential confounding factors.
We further analysed the effects of anxiety interaction with depression of different levels(no/mild/moderate/severe) on RPL by using addition or multiplication interaction statistical analysis models, which were taken from Andersson T’s literature report[16]. We used the odds ratios (ORA*B) and 95% confidence intervals (CIA*B) to analyse the multiplication interaction effect. Moreover, the relative excess risk of interaction (RERI, RERI = ORAB - ORA - ORB + 1) value with 95%CI and attributable proportion (AP) was used to reflect the additive interaction effect, which was more likely to evaluate the biological interaction between risk factors and the disease. The results suggest a synergistic effect of anxiety or depression on the incidence of RPL when the RERI>0 and the lower limit of 95%CI>0.
The SPSS software (SPSS Inc., Chicago, IL, USA, version 19.0) and the Excel software from Andersson T. were used to perform the statistical analyses. A P value less than 0.05 was identified as being significant.