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Abstract
Objectives This study aimed to clarify the relationship between white blood cell (WBC) and adverse pregnancy outcomes.
Design A total of 25 270 pregnant women underwent peripheral blood white blood cell count tests in the first, second and third trimesters. Adverse pregnancy outcomes were gestational hypertension, pre-eclampsia, gestational diabetes mellitus, preterm birth, low birth weight, caesarean delivery, macrosomia and fetal distress. Due to acute infectious disease or other diseases, 1127 were excluded.
Setting Minhang Hospital, China.
Participants A total of 24 143 pregnant women were included in this study.
Primary and secondary outcome measures The primary outcome was the adverse pregnancy outcomes.
Results For the 24 143 participants, we calculated adjusted ORs for adverse pregnancy outcomes associated with an increased WBC count. For gestational hypertension, the ORs were 1.18 (95% CI, 1.05 to 1.24) in the first trimester and 1.10 (1.06 to 1.13) in the second trimester; for pre-eclampsia, ORs were 1.14 (95% CI, 1.47 to 1.64) in the first trimester and 1.10 (1.05 to 1.16) in the second trimester; for gestational diabetes mellitus, ORs were 1.06 (95% CI, 1.00 to 1.13) in the first trimester and 1.10 (1.04 to 1.16) in the second trimester; for preterm birth, ORs were 1.12 (95% CI, 1.06 to 1.18) in the first trimester, 1.10 (1.06 to 1.13) in the second trimester and 1.12 (1.09 to 1.15) in the third trimester; for low birth weight, ORs were 1.09 (95% CI, 1.02 to 1.17) in the first trimester, 1.03 (0.99 to 1.08) in the second trimester and 1.12 (1.08 to 1.16) in the third trimester. Significant associations were not observed obviously for caesarean delivery, macrosomia and fetal distress.
Conclusions Our results indicate strong, continuous associations of maternal WBC count with increased risks of adverse pregnancy outcomes.
- Maternal medicine
- Fetal medicine
- Other metabolic, e.g. iron, porphyria
Data availability statement
Data are available upon reasonable request. The datasets generated during and/or analysed during the current study are available upon reasonable request through the corresponding author.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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Strengths and limitations of this study
The study was one of the largest retrospective cohort studies to examine the associations between peripheral blood white blood cell (WBC) count and adverse pregnancy outcomes.
The study was focused on multiple pregnancy outcome endpoints rather than a single one.
The peripheral blood WBC count during the whole pregnancy phase from the first to the third trimester was consistently associated with adverse pregnancy outcomes.
Limitation of the study was the retrospective design so that the data on the nutritional status and gestational weight gain of the participants were not obtained.
Background
In 1936, Carey reported physiologically increased peripheral blood white blood cell (WBC) counts in pregnant women.1 In 1962, a study showed that some peripheral blood WBC (in particular myelocytes and metamyelocytes) counts in pregnant women physiologically increased in the third trimester.2 In 1979, Pitkin reported that maternal peripheral blood WBC counts during pregnancy were significantly higher than those at 6 weeks postpartum,3 further indicating changes in the WBC count during pregnancy. WBCs are acute phase reactants and are elevated in stress situations. During pregnancy, the normal range of WBCs is elevated and defined as 5.6–13.8×109/L.4 Physiologically, pregnancy is a normal stress process, and peripheral blood WBC counts are considerably higher in pregnant women than in non-pregnant women. Therefore, elevated WBC counts are a normal response to physiological stress. However, it is unclear whether abnormally elevated WBC counts during pregnancy are associated with adverse pregnancy outcomes. In 2004, Diabetes Care published a prospective cohort study on the association between WBC counts in the first trimester and gestational diabetes mellitus (GDM), which showed that increased peripheral blood WBC counts during the first trimester were associated with the occurrence of GDM.5 In 2020, Diabetes published a study on the association between peripheral blood WBC count in the first trimester and GDM, which suggested an association between elevated neutrophil count (rather than WBC count) and GDM.6 In addition, some studies using small sample sizes showed an association between the neutrophil/lymphocyte ratio (rather than WBC) in the first trimester and birth weight and pre-eclampsia.7–10
However, previous studies on the association between WBC and pregnancy or pregnancy outcomes used small sample sizes, or the end points observed for pregnancy outcomes were relatively unitary. Furthermore, observations on the relationship between WBC and pregnancy outcome focused on the first trimester and lacked data for the second and third trimesters. Therefore, more comprehensive studies are required to assess the relationship between the WBC count and pregnancy outcomes. We conducted a large-sample retrospective cohort study and measured peripheral blood WBC counts during the first, second and third trimesters to examine the association between peripheral blood WBC count and overall adverse pregnancy outcomes.
Methods
Study population
We established a database of antenatal examination and delivery registration data at Minhang Hospital according to the requirements of the national policy on the management of pregnant women in China. The database contained information on patients’ demographics, clinical characteristics, physical examination, laboratory data and delivery outcome follow-up data.
We retrospectively assessed 25 270 pregnant women at Minhang Hospital, Fudan University, China, from January 2013 to June 2020. Clinically pregnant women were required to register their demographical information via a questionnaire at their first obstetric outpatient visit. Routine clinical care was conducted until delivery. All data from the first antenatal visit till delivery were recorded and checked by qualified obstetric professionals.
We abstracted antenatal and inpatient records data from the hospital’s medical record system on maternal demographics, clinical examination and obstetric records for all women. Demographics included age; ethnicity; education; prepregnant weight and height; clinical examination data, including blood analysis, biochemistry measurements and antenatal routine ultrasound measurements; and obstetric records, including complete maternal and infant information such as gravidity and parity history, type of delivery, gestational age, comorbidity and infant characteristics (sex, birth weight, height and Apgar score). The exclusion criteria were (1) any infectious disease 2 weeks prior to blood cell analysis; (2) abnormal liver or renal function; (3) presence of viral infection or positive carrier status (hepatitis B virus, syphilis and HIV); (4) pre-existing diabetes mellitus; (5) chronic hypertension; and (6) multiple gestation. Of these, 1127 were excluded due to acute infectious disease or other diseases. A final total of 24 143 women were included in the analysis. Ethical approval was granted by the Ethics Committee of Shanghai Minhang Hospital.
Data collection and laboratory assessments during pregnancy
At the first visit, gestational age was calculated based on the date of last menstruation or first-trimester ultrasonography. Blood samples were collected after a 12-hour overnight fast to measure blood cell count (Automatic Blood cell analyzer, Sysmex XN9000, Japan) and biochemical parameters (Automatic biochemical analyzer, Roche Cobas 8000, Switzerland). Blood pressure and anthropometrical parameters were measured, and a questionnaire was completed. Information about date of last menstruation, method of conception, parity, obstetric history and prepregnancy weight was included in the patient questionnaire. Prepregnancy body mass index (BMI) was calculated as prepregnancy weight in kilograms divided by height in metres squared. Peripheral blood was collected at 6–8 weeks (first trimester), 14–18 weeks (second trimester) and 28–32 weeks (third trimester). After delivery, details about gestational age at delivery, mode of delivery, newborn weight and newborn sex were recorded by the medical staff.
Outcomes
The following eight maternal and infant outcomes during pregnancy were examined: gestational hypertension, pre-eclampsia, GDM, preterm birth (<37 weeks of gestation), low birth weight (birth weight <2500 g), caesarean delivery, macrosomia (birth weight ≥4000 g) and fetal distress. Hypertension disorders during pregnancy that occurred after 20 weeks of gestation were categorised according to the International Society for the Study of Hypertension guidelines.11 Pre-eclampsia was defined as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on two or more occasions at least 6 hours apart and proteinuria ≥1+ using a dipstick test or urine protein levels ≥300 mg over a 24-hour period. Hypertension was classified as gestational hypertension when the criteria for elevated blood pressure were met but those for proteinuria were not met. GDM was diagnosed as fasting plasma glucose ≥5.1 mmol/L or 1-hour plasma glucose levels ≥10.0 mmol/L or 2-hour plasma glucose ≥8.5 mmol/L after a 75 g oral glucose load in the second trimester (24–28 weeks).
Statistical analysis
Continuous variables were reported as mean (SD) or median (IQR) and compared using Student’s t-test or Wilcoxon rank-sum test. Categorical variables were reported as frequency (percentage) and compared using Pearson’s χ2 test or Fisher’s exact test.
For associations between WBC count and pregnancy outcomes, WBC measurements at each phase were considered as both categorical and continuous variables in multiple logistic regression analyses. For categorical analyses, each WBC measurement was divided into six categories such that the WBC measurements in the second and third trimesters reflected data for approximately the same number of women in each category as that in the first-trimester WBC measurement. Categories for the WBC count in the first trimester were originally prespecified as 12.5×109/L or more, 10.5–12.49×109/L, 8.5–10.49×109/L, 6.5–8.49×109/L, 4.5–6.49×109/L and less than 4.5×109/L. The highest and second-highest categories for each WBC measurement, accounting for 2% and 8% of participants, respectively, were specifically selected to determine whether there were threshold effects. For continuous variable analyses, ORs were calculated for a 1 SD increase in first-trimester, second-trimester and third-trimester WBC levels.
Logistic regression was used to assess correlations between maternal WBC count and pregnancy events, including adjustment for multiple potential prespecified confounders such as age, education, prepregnancy BMI, smoking status, alcohol use, sex of the infant, gravidity and parity. Pregnancy outcomes (including gestational hypertension, pre-eclampsia, GDM, preterm birth, low birth weight, caesarean section, macrosomia and fetal distress) with p values of <0.05 in the crude ORs were further analysed.
Finally, the average WBC count was used as a parameter to further verify the association between adverse pregnancy outcomes and peripheral blood WBC count. The average WBC (AVE WBC) counts in the first and second trimesters were calculated for three pregnancy outcomes, including gestational hypertension, pre-eclampsia and GDM. The AVE WBC counts in the first, second and third trimesters were calculated for five pregnancy outcomes, including preterm birth, low birth weight, caesarean section, macrosomia and fetal distress. The association between the AVE WBC count and adverse pregnancy outcomes was further verified using logistic regression according to the statistical analysis of each phase WBC count.
All data were analysed using SPSS 26.0 (IBM SPSS Inc, Chicago, IL, USA). Two-tailed p values of <0.05 were considered to indicate statistical significance.
Patient and public involvement
It was not appropriate or possible to involve patients or the public in the design, or conduct, or reporting, or dissemination plans of our research since its retrospective cohort study.
Results
Participants
A total of 25 270 deliveries were recorded at the Minhang Hospital affiliated to Fudan University, Shanghai, China, during the study period. Of these, 1127 were excluded due to acute infectious disease or other diseases or missing data. Data for the remaining 24 143 patients were available for the analysis. The mean age of the participants was 29.1 years, and the mean WBC counts in the first, second and third trimesters were 8.1×109/L, 8.9×109/L and 9.2×109 /L, respectively. The correlations among the three WBC measurements were 0.61 for the WBC count in the first and second trimesters, 0.52 for the WBC count in the first and third trimesters and 0.63 for the WBC count in the second and third trimesters (p<0.001 for all three comparisons). The incidence of adverse pregnancy outcomes was as follows: 4.8% for gestational hypertension, 1.8% for pre-eclampsia, 5.6% for GDM, 5.0% for preterm birth, 3.1% for low birth weight, 45.0% for caesarean delivery, 7.4% for macrosomia and 8.5% for fetal distress. There were 69 cases of major malformation in newborns and 64 perinatal deaths (53 fetal and 11 neonatal or infant; incidence, 2.7 per 1000) among 24 143 deliveries (table 1).
Characteristics of the study participants and their newborns and frequency of outcomes*
WBC and pregnancy outcomes
Categorical analyses
The frequency of the five pregnancy outcomes across the six WBC categories is shown in figure 1. The frequency of each outcome increased with increasing maternal WBC count. For the first-trimester WBC count, the frequencies in the lowest and highest categories (<4.5×109/L and ≥12.5 ×109/L) were 1.0% and 12.3% for gestational hypertension, 1.0% and 4.7% for pre-eclampsia, 3.1% and 15.8% for GDM, 2.1% and 8.8% for preterm birth and 1% and 5.3% for low birth weight, respectively.
Frequency of adverse pregnancy outcomes across the six WBC categories. (A)Gestational hypertension; (B) pre-eclampsia; (C) gestational diabetes mellitus; (D) preterm birth; (E) low birth weight. WBC-1, WBC-2 and WBC-3 mean white blood cell (WBC) count in the first, second and third trimesters. Average WBC (AVE WBC) means the average WBC count with each phase trimester WBC for the adverse pregnancy outcomes. WBC categories are defined as follows: WBC count in the first trimester (WBC-1) category 1, less than 4.5×109/L; category 2, 4.5×109/L to 6.49×109/L; category 3, 6.5×109/L to 8.49×109/L; category 4, 8.5×109/L to 10.49×109/L; category 5, 10.5×109/L to 12.49×109/L; and category 6, 12.5×109/L or more; WBC count in the second trimester (WBC-2) category 1, less than 5.13×109/L; category 2, 5.13×109/L to 7.12×109/L; category 3, 7.13×109/L to 9.33×109/L; category 4, 9.34×109/L to 11.59×109/L; category 5, 11.60×109/L to 13.62×109/L; and category 6, 13.63×109/L or more; WBC count in the third trimester (WBC-3) category 1, less than 5.32×109/L; category 2, 5.32×109/L to 7.33×109/L; category 3, 7.34×109/L to 9.58×109/L; category 4, 9.59×109/L to 11.96×109/L; category 5, 11.97×109/L to 14.27×109/L; and category 6, 14.28×109/L or more.
Online supplemental table 1 shows the associations between maternal WBC count as a categorical variable and five outcomes, including ORs and 95% CI for each category compared with the lowest category, with adjustment for confounders. The OR for gestational hypertension increasing across the categories of maternal WBC was 3.35 in the highest category of WBC in the second trimester. The OR in the highest category of WBC in the first trimester did not differ significantly from 1.00. The adjusted ORs for pre-eclampsia and GDM were substantially attenuated, and none of the ORs for the highest WBC categories were significantly different from 1.00, except for the OR for GDM in the highest category of WBC in the second trimester (OR=3.74; 95% CI, 1.01 to 13.88). After adjustment for confounders, there was an association between preterm delivery and maternal WBC, with the association increasing with increasing WBC category (OR, 3.01; 95% CI, 1.57 to 5.78) for the highest category of WBC in the third trimester. The OR of low birth weight was 3.00 for the highest category of third-trimester WBC. A post hoc analysis was used to examine interactions between the average WBC count and the eight outcomes shown in models I and II (18 tests in total). The results showed that the associations between average WBC and pregnancy outcomes were consistent with those between the WBC count in each trimester and each pregnancy outcome (online supplemental table 1). In the categorical analysis, the OR for gestational hypertension increased across the categories of maternal WBC count and was 3.32 in the highest category of average WBC count in the first and second trimesters. There was an association between preterm delivery and average WBC count, and the association increased with increasing WBC category (OR, 2.01; 95% CI, 1.04 to 4.00) for the highest category of average WBC for each trimester. The OR for low birth weight was 3.03 in the highest category of average WBC count for each trimester.
Supplemental material
Continuous analyses
The results of the analyses of WBC as a continuous variable with model II adjustment for eight outcomes are shown in table 2. Among the first five outcomes, the ORs for an increase in WBC by 1 SD were significant for gestational hypertension (range, 1.10–1.18), pre-eclampsia (range, 1.10–1.14), GDM (range, 1.06–1.10), preterm birth (range, 1.10–1.12) and low birth weight (range, 1.09–1.12), and only the association of low birth weight with the second-trimester WBC count was not significant.
Relationship between maternal WBC/neutrophil and pregnancy outcomes*
Six of the nine analyses of the last three outcomes showed non-significant associations with maternal WBC after adjustment for confounders (table 2). Fetal distress was not related to total maternal WBC during any trimester. Only caesarean section was associated with WBC count in the first and second trimesters, and macrosomia was associated with WBC count in the second trimester, although the OR values were approximately 1 (range, 1.02–1.04). We also tested the relationship between WBC and stillbirth but found no significant correlation attributing to an extremely low incidence of stillbirth which was consistent with the previous studies.7–10
In the continuous analyses, the ORs for the increase in average WBC by 1 SD were significant for gestational hypertension, pre-eclampsia, GDM, preterm birth and low birth weight. However, there were no statistically significant associations between maternal average WBC count and caesarean section, macrosomia and fetal distress.
Discussion
The associations between WBC count and pregnancy and pregnancy outcomes have been studied over the past 10 decades. Our study is one of the largest retrospective cohort studies until now to examine the associations between peripheral blood WBC count and adverse pregnancy outcomes, including associations between changes in WBC count in the first, second and third trimesters and multiple maternal and fetal adverse pregnancy outcomes. Our data showed associations between increased WBC counts in the first and second trimesters and gestational hypertension, pre-eclampsia and GDM. The study also found the relationship between increased WBC count in the first, second and third trimesters and preterm birth and low birth weight, with weaker associations between WBC count and caesarean delivery, macrosomia and fetal distress.
Approximately 10% of pregnant women experience hypertension, with gestational hypertension without proteinuria developing in 5%–6% and pre-eclampsia developing in 2%.12 Gestational hypertension and pre-eclampsia prior to 34 weeks are associated with an increased risk of perinatal and maternal complications.13–15
Evidence suggests that vascular endothelial multisystem disorder, which leads to microvascular thrombosis induced by inflammation, increases capillary permeability, increases vascular tone and hypertension and contributes to the pathogenesis of gestational hypertension and pre-eclampsia.16 Altered immune response, excessive maternal inflammation and immune maladaptation are also among the proposed etiological factors.17 Jeon et al reported that neutrophils may be a predicting marker of pre-eclampsia from gestational hypertension.18 These findings prompted us to examine whether the initiation of pre-eclampsia could be predicted by assessing WBC count, which is a marker of systemic inflammatory during the first trimester of pregnancy.
Our results showed that the risk of gestational hypertension in the highest category of peripheral blood WBC count was still 3.35-fold greater in the second trimester than that of the lowest category even after adjustment for traditional risk factors for gestational hypertension, including age, prepregnancy BMI, height, smoking, alcohol use, sex of the baby, gravidity and parity, and history of gestational hypertension. Furthermore, the risk of gestational hypertension increased by 18% with a 1 SD increase in peripheral blood WBC count in the first trimester. We obtained similar results for the pregnancy outcome of pre-eclampsia. Thus, increased peripheral blood WBC count in the early phase may be an independent predictor of the occurrence of gestational hypertension and pre-eclampsia in the future.
GDM, which is one of the most common complications of pregnancy, is associated with an increased risk of stillbirth and neonatal death as well as various severe conditions in both mothers and babies.19 Universal gestational diabetes screening is recommended at 24–28 weeks of gestation20 because data from randomised, controlled trials have shown that the treatment of patients with GDM improves maternal and perinatal outcomes.21 22
Several traditional factors, including family or personal history of diabetes, previous adverse pregnancy outcome, glycosuria and obesity, are associated with GDM, although the exact pathophysiology of GDM remains unclear. Previous studies have shown that low-grade chronic inflammation plays a crucial role in the pathophysiology of GDM and type 2 diabetes mellitus.23–25
Our results showed that the risk of GDM was still 3.74-fold greater in the highest category of peripheral blood WBC count in the second trimester than the lowest category and the risk of GDM still increased by 10% with a 1 SD increase in peripheral blood WBC count even after adjustment for traditional risk factors for GDM, including age, prepregnancy BMI, smoking, alcohol use, baby sex, gravidity and parity, triglycerides and GDM history. These results suggested that peripheral blood WBC count was an independent predictor of GDM in both first and second trimesters of pregnancy, whereas previous studies were limited to the first trimester.6
Preterm birth is a leading cause of death worldwide in infants and children aged <5 years26 and is associated with short-term and long-term maternal and fetal sequelae.27 28 Preterm birth is believed to be a syndrome initiated by multiple mechanisms, including infection or inflammation, uteroplacental ischaemia or haemorrhage, uterine overdistension, stress and other immunologically mediated processes.29 In most cases, the precise mechanisms are not established; therefore, factors associated with preterm birth, but not the causal pathway, have been investigated to explain preterm birth.
Our study showed a significant correlation between peripheral blood WBC count and preterm birth. The risk of preterm birth was still 3.01-fold greater in the highest category of peripheral blood WBC count in the third trimester than in the lowest category, and the risk of preterm birth still increased by 12% with a 1 SD increase in peripheral blood WBC count after adjustment for risk factors for preterm birth, including age, prepregnancy BMI, height, smoking, alcohol use, newborn sex, gravidity, parity, GDM, gestational hypertension and pre-eclampsia. These results suggested that peripheral blood WBC count in the first, second and third trimesters could be an independent predictor of preterm birth.
Low birth weight is a leading determinant of neonatal mortality worldwide that particularly affects those in developing countries.30 Infants with low birth weight who are born preterm, small for their gestational age or both constitute approximately 15% of all neonates worldwide and account for 70% of all neonatal deaths.31 Our study showed a significant correlation between peripheral blood WBC count and low birth weight. The risk of low birth weight was still threefold greater in the highest category of peripheral blood WBC count in the third trimester than that in the lowest category, and the risk of low birth weight increased by 12% with a 1 SD increase peripheral blood WBC count even after adjustment for risk factors for low birth weight, including age, prepregnancy BMI, height, smoking, alcohol use, newborn sex, gravidity, parity, GDM, gestational hypertension and pre-eclampsia. These results suggested that peripheral blood WBC count in the first and third trimesters was an independent predictor of low birth weight.
Some small-sample studies6 showed that increased peripheral blood WBC count was correlated with macrosomia and may be related to chronic low-grade inflammation and insulin resistance. But our study, which included a large sample, found that the peripheral blood WBC in the first and third trimesters and AVE WBC were not related to the occurrence of macrosomia. These results suggested that the increase in peripheral blood WBC was more likely to predict an increase in the occurrence of preterm birth and low birth weight, whereas the effect on the occurrence of macrosomia caused by chronic low-grade inflammation was minimal.
Although increased WBC counts in the first and second trimesters were associated with a slight increase in the rate of caesarean section, there was no significant association between WBC count in the third trimester or AVE WBC count and occurrence of caesarean section. Over the past decade, the indication for caesarean section in China has not been strictly controlled.32 Caesarean section is affected by various factors, including subjective (patients’ wishes, fear, pain and physician judgement) and objective (uterine condition and pelvic condition) factors.33 Therefore, the association between peripheral blood WBC count and caesarean section is unclear. Likewise, peripheral blood WBC count is not significantly associated with fetal distress.
Some studies have reported that the neutrophil count is related to some adverse pregnancy outcomes.6 18 In the present study, the associations between peripheral blood neutrophil counts in the first, second and third trimesters and each adverse pregnancy outcome showed similar results to the association between peripheral blood WBC and pregnancy outcomes. But we did not find the association between the other populations of WBC such as lymphocyte or monocyte and the adverse pregnancy outcomes. It may be concluded that the association with adverse pregnancy outcomes is mainly caused by neutrophils, a population of WBCs, while other populations have no impact on pregnancy outcomes.
Our study had some limitations. First, we were unable to obtain data on the nutritional status and gestational weight gain of the participants, which could have affected fetal growth and other perinatal outcomes. Second, confounders, such as family history of GDM or hypertension, may have influenced clinical decisions such as the choice of delivery route. Furthermore, because of the observational design of our study, we cannot conclude that maternal WBC is causally related to the adverse outcomes observed; however, such a relationship is plausible.
Our results suggested that the peripheral blood WBC count during pregnancy is independently related to overall adverse pregnancy outcomes. It should be noted that the peripheral blood WBC count during the whole pregnancy phase from the first to the third trimester is consistently associated with adverse pregnancy outcomes.
In summary, peripheral blood WBC count during pregnancy is a good predictor of overall adverse pregnancy outcomes. Whenever in the first, second or third trimesters, elevated WBC count can indicate both maternal and infant adverse outcomes, suggesting a possible predictive role for this simple, low-cost and readily available biomarker, which may have great implications in clinical practice.
Data availability statement
Data are available upon reasonable request. The datasets generated during and/or analysed during the current study are available upon reasonable request through the corresponding author.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
YZ, YQ and CL contributed equally.
Contributors YZ wrote the manuscript and researched data. YQ, CL and JY contributed to discussion and reviewed and edited manuscript. XF, YF and XL contributed to data collection. YS and ZH contributed to data collection and database establishment. YZ and JY reviewed and edited the manuscript. YQ researched data. JY is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We thanked all patient advisers involved in this study.
Funding National Natural Science Foundation of China (No. 82070889, 81900788).
Competing interests We declare no conflict of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval statement Ethical approval was granted by the Ethics Committee of Shanghai Minhang Hospital (ID 2021-060-01K).
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.