Introduction
Preeclampsia (PE) is a complex and severe multisystem disorder in pregnancy, with a worldwide incidence of 3%–5%.1 Traditionally, it is diagnosed when maternal hypertension manifests after 20 weeks of gestation with proteinuria.2 PE is a leading cause of maternal and perinatal mortality and morbidity, especially in low- and middle-income countries.3,4 Severe PE is also associated with high rates of perinatal death, prematurity, and newborns that are small for gestational age.4,5 Furthermore, PE has been linked to maternal chronic hypertension, recurrent PE, and later-life cardiovascular diseases.6 Although the etiology of PE has not been elucidated, several clinical risk factors for this condition have been reported, including advanced maternal age, nulliparity, previous PE, multiple gestation, high body mass index (BMI), and pre-existing diseases such as antiphospholipid antibody syndrome, chronic hypertension, and renal disease.7–10
Identifying the most important risk factors for PE is vital for both clinical decisions and disease management, including identifying high-risk pregnant women, prioritizing intervention, and allocating resources. Routine screening for maternal risk factors of PE is strongly recommended by guidelines.11,12 According to previous clinical trials and meta-analyses, low-dose aspirin is recommended for women with moderate- or high-risk factors for PE prevention.12 Thus, focusing on pregnant women at high risk for PE can avoid over-treatment of healthy pregnant women, who will not benefit from aspirin prophylaxis.13 Moreover, it has been suggested that the risk factors for PE among Asian women are different from other ethnic groups.14,15 Therefore, it is crucial to identify the risk factors associated with PE in the Chinese population.
PE is recognized as a heterogeneous syndrome with different pathophysiological manifestations. It is graded as early-onset PE (EOPE) or late-onset PE (LOPE) based on the gestational age at the presentation of PE or at delivery.16 In particular, EOPE has a higher rate of severe maternal complications and fetal demise, and the only treatment is to deliver the baby prematurely.17 PE is also characterized into mild or severe PE based on the clinical presentation.2 If the risk factors are found to be similar, the etiology of the disease may be the same, while different risk factors may indicate different pathophysiological mechanisms. Thus, it is necessary to have an in-depth understanding of the relationship between known risk factors of PE and its clinical subtypes, which may help clarify the heterogeneous pathogenesis of PE. Moreover, characterizing risk factors can also reveal the factors related to PE severity, which may contribute to the prediction and management of PE. However, research is scarce regarding the risk factors associated with PE and its subtypes within the same population, and results have been inconsistent amongst different studies.15,18,19
Therefore, this study aimed to report the incidence of PE and its subgroups. Moreover, we aimed to examine the risk factors associated with PE, characterize risk factor patterns among different clinical subtypes of PE, and explore the relationship between the accumulated effect of risk factors and the overall risk for PE.
Methods
Data source and study population
This study was conducted as a secondary analysis from the Gestational diabetes mellitus Prevalence Survey (GPS), a multicentre retrospective cohort study investigating the prevalence and associated risk factors for pregnancy diseases. Detailed descriptions of the database have been published elsewhere.20 In brief, we selected 15 hospitals in Beijing as clusters using a systemic cluster sampling method according to the number of deliveries. A structured questionnaire was designed to collect the sociodemographic, obstetric, and medical history of 15,197 pregnant women, who delivered between June 20th and November 30th, 2013. This study was reviewed and approved by the institutional review board (reference number: 2013(572)), which waived the written consent. We included all pregnancies delivered at ≥28 gestational weeks, including live births and stillbirths. One hundred and ninety-four pregnancies had missing maternal and birth outcome information and were excluded from the study. In total, 15,003 pregnant women were included in the analysis to assess the prevalence and risk factors for PE and its subtypes.
Definitions
This study included pregnant women diagnosed with PE and its subtypes characterized as mild PE, severe PE, EOPE, and LOPE. In previously normotensive women, PE was diagnosed as the onset of hypertension (systolic blood pressure (sBP) ≥140 mmHg and/or diastolic blood pressure (dBP) ≥90 mmHg) after 20 weeks of gestation and with co-existence of one or more of the following new-onset conditions: proteinuria (urinary protein ≥300 mg in 24 hours, or urinary protein dip stick ≥1+ if no 24-hour collection is available) and other maternal organ dysfunction, including thrombocytopenia, impaired liver function, new development of renal insufficiency, neurological complications, and uteroplacental dysfunction.2 Chronic hypertension with superimposed PE was diagnosed as chronic hypertension in association with PE symptoms.2
PE was characterized into early-onset (<34 weeks) and late-onset (≥34 weeks) PE as both settings have been described to have different risk factors, clinical manifestations, and prognoses.16 Women were classified to have mild PE if they meet the criteria for elevated blood pressures (sBP ≥ 140 mmHg or/and dBP ≥ 90 mmHg) at least 4 hours apart after 20 weeks of gestation, had proteinuria (≥300 mg over 24 hours; ≥1+ on dipstick), and did not meet the criteria for severe PE. Women were classified to have severe PE if they meet the criteria for mild PE and at least one of the following complications: sBP ≥ 160 mmHg or/and dBP ≥ 110 mmHg, proteinuria ≥5 g per 24 hours or dipstick ≥3+, oliguria, thrombocytopenia, pulmonary edema, epigastric or right upper quadrant pain, impaired liver function, cerebral or visual disturbances, or fetal growth restriction.2
Study factors
Potential risk factors, including maternal age, pre-pregnancy BMI, parity, multiple gestations, chronic hypertension, pre-existing diabetes, and gestational diabetes mellitus were evaluated as determinants for PE and its subtypes. Maternal age was defined as the age at the time of delivery and was divided into three groups: <25 years, 25–34 years, and ≥35 years. Pre-pregnancy BMI was defined as pre-pregnancy weight (kg)/(eight (m)) and categorized into three groups: underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5–23.9 kg/m2), overweight (BMI: 24.0–27.9 kg/m2), and obesity (BMI: ≥28.0 kg/m2).21 Chronic hypertension was defined as hypertension diagnosed before 20 weeks of gestation. Parity status, multiple gestation, pre-existing diabetes, and gestational diabetes were also recorded.
Statistical analysis
Logistic regression analysis was used to determine potential risk factors. Crude odds ratios with 95% confidence intervals (CIs) were calculated to estimate the effects of the individual factors. A multivariable logistic regression was performed, including the aforementioned factors, to obtain adjusted odds ratios (aORs) and 95% CIs. Binary logistic regression analysis was applied to explore the association between the accumulated number of risk factors and the risk of PE. All statistical analyses were performed by SPSS version 22.0 (IBM, Armonk, NY, USA). A P-value < 0.05 was considered significant.
Results
The incidence rate of PE was 2.65% (397/15,003), and the gestational week-specific incidence of PE was higher in women who delivered prematurely (Fig. 1). Among the study population, 0.36% (54/15,003) developed EOPE and 2.29% (343/15,003) developed LOPE. Regarding the severity of PE, 0.91% (137/15,003) had mild PE and 1.73% (260/15,003) had severe PE. Moreover, severe PE was predominant in both EOPE and LOPE, occurring at an incidence of 83.33% (45/54) and 62.68% (215/343), respectively. The average maternal age in the 15,003 women assessed was 29.54 ± 4.30 years, and the average pre-pregnancy BMI was 21.64 ± 3.26 kg/m2. Among the 15,003 women, 70.71% (10,608/15,003) were nulliparous, 1.63% (245/15,003) had multiple gestation, 2.28% (342/15,003) had chronic hypertension, 0.87% (131/15,003) had pre-existing diabetes, and 18.46% (2770/15,003) had gestational diabetes.
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Figure 1: Gestational week-specific incidence of PE, Beijing, China, 2013. PE: Preeclampsia.
Table 1 displays the risk factors associated with PE. After using multivariable logistic regression, we found most of the previous reported risk factors were related to the increased risk of PE in the study. Our results revealed there was a dose-response effect of pre-pregnancy BMI on the risk for PE. Both overweight and obesity were associated with an increased risk for PE (aOR: 1.48, 95% CI: 1.06–2.05, P = 0.02 for overweight; and aOR: 2.15, 95% CI: 1.50–3.08, P < 0.001 for obesity). Nulliparity became a significant risk factor for PE in the adjusted analysis (aOR: 1.73, 95% CI: 1.32–2.25, P < 0.001). Multiple gestations (aOR: 4.58, 95% CI: 2.86–7.32, P < 0.001) and pre-existing chronic hypertension (aOR: 34.95, 95% CI: 26.60–45.93, P < 0.001) were associated with a significantly increased risk for PE. However, advanced maternal age, pre-existing diabetes, and gestational diabetes were not associated with PE and were not included in the final multivariable model.
Table 1 -
Maternal characteristics and clinical risk factors associated with preeclampsia.
| Variables |
Total cases (n = 15, 003) |
Preeclampsia (n = 397), n (%)∗
|
cOR (95% CI), P
|
aOR (95% CI)†, P
|
| Age (years) |
| <25 |
2182 |
38 (1.74) |
0.64 (0.46–0.90), P = 0.01 |
0.83 (0.58–1.20), P = 0.32 |
| 25–34 |
11,250 |
302 (2.68) |
Reference |
Reference |
| ≥35 |
1571 |
57 (3.63) |
1.37 (1.02–1.82), P = 0.03 |
1.20 (0.85–1.69), P = 0.30 |
| Pre-pregnancy BMI (kg/m2)‡
|
| <18.5 |
2104 |
30 (1.43) |
0.65 (0.44–0.96), P = 0.03 |
0.74 (0.50–1.10), P = 0.14 |
| 18.5–23.9 |
10,775 |
234 (2.17) |
Reference |
Reference |
| 24.0–27.9 |
1302 |
61 (4.69) |
2.21 (1.66–2.95), P < 0.001 |
1.48 (1.06–2.05), P = 0.02 |
| ≥28.0 |
683 |
67 (9.81) |
4.90 (3.69–6.51), P < 0.001 |
2.15 (1.50–3.08), P < 0.001 |
| Parity§
|
| 0 |
10,608 |
292 (2.75) |
1.16 (0.92–1.45), P = 0.21 |
1.73 (1.32–2.25), P < 0.001 |
| ≥1 |
4388 |
105 (2.39) |
Reference |
Reference |
| Multiple gestation |
| Yes |
245 |
32 (13.06) |
5.92 (4.03–8.71), P < 0.001 |
4.58 (2.86–7.32), P < 0.001 |
| No |
14,758 |
365 (2.47) |
Reference |
Reference |
| Chronic hypertension |
| Yes |
342 |
144 (42.11) |
41.42 (32.32–53.08), P < 0.001 |
34.95 (26.60–45.93), P < 0.001 |
| No |
14,661 |
253 (1.73) |
Reference |
Reference |
| Diabetes during pregnancy |
| Pre-existing diabetes |
131 |
13 (9.92) |
4.69 (2.61–8.41), P < 0.001 |
1.12 (0.52–2.42), P = 0.77 |
| Gestational diabetes |
2770 |
106 (3.83) |
1.69 (1.35–2.13), P < 0.001 |
1.13 (0.87–1.47), P = 0.35 |
| No |
12,102 |
278 (2.30) |
Reference |
Reference |
aOR: Adjusted odds risk; BMI: Body mass index; CI: Confidence interval; cOR: Crude odds risk.
∗n(%) presents the proportion of PE cases over total cases for each risk factor.
†aOR: adjusted with all variables in the table.
‡Missing data: 139 in total cases, including 5 in preeclampsia cases, due to missing values in the database.
§Missing data: 7 in total cases, 0 in preeclampsia cases, due to missing values in the database.
Table 2 displays the risk factors for mild (n = 137) and severe PE (n = 260). Women who developed mild PE alone were excluded from the analysis for severe PE, and women who developed severe PE alone were excluded from the analysis for mild PE. The pattern of risk factors amongst subjects with mild and severe PE was quite similar. Severe and mild PE shared risk factors, including obesity (aOR:1.80, 95% CI: 1.16–2.80, P = 0.01) vs. (aOR: 2.20, 95% CI: 1.28–3.76, P < 0.01), nulliparity (aOR: 1.48, 95% CI: 1.09–2.02, P = 0.01) vs. (aOR: 2.28, 95% CI: 1.44–3.60, P < 0.001), multiple gestations (aOR: 3.51, 95% CI: 1.93–6.41, P < 0.001) vs. (aOR: 5.50, 95% CI: 2.87–10.67, P < 0.001), and chronic hypertension (aOR: 35.03, 95% CI: 25.40–48.31, P < 0.001) vs. (aOR: 33.98, 95% CI: 22.20–52.01, P < 0.001). Advanced age and diabetic disorders had no relationship with mild or severe PE in the logistic regression analyses.
Table 2 -
Maternal characteristics and clinical risk factors associated with severe and mild PE.
| Variables |
Deliveries excluded mild PE (n = 14, 866) |
Severe PE (n = 260), n (%)∗
|
cOR (95% CI), P
|
aOR (95% CI)†, P
|
Deliveries excluded severe PE (n = 14,743) |
Mild PE (n = 137), n (%)∗
|
cOR (95% CI), P
|
aOR (95% CI)†, P
|
| Age (years) |
| <25 |
2167 |
23 (1.06) |
0.60 (0.39–0.93), P = 0.02 |
0.79 (0.50–1.24), P = 0.31 |
2159 |
15 (0.69) |
0.72 (0.42–1.23), P = 0.23 |
0.93 (0.52–1.64), P = 0.79 |
| 25–34 |
11,143 |
195 (1.75) |
Reference |
Reference |
11,055 |
107 (0.97) |
Reference |
Reference |
| ≥35 |
1556 |
42 (2.70) |
1.56 (1.11–2.18), P = 0.01 |
1.39 (0.94–2.05), P = 0.10 |
1529 |
15 (0.98) |
1.01 (0.59–1.75), P = 0.96 |
0.75 (0.41–1.37), P = 0.35 |
| Pre-pregnancy BMI (kg/m2)‡
|
| <18.5 |
2094 |
20 (0.95) |
0.65 (0.41–1.04), P = 0.07 |
0.73 (0.45–1.19), P = 0.21 |
2084 |
10 (0.48) |
0.65 (0.34–1.26), P = 0.20 |
0.74 (0.37–1.45), P = 0.38 |
| 18.5–23.9 |
10,697 |
156 (1.46) |
Reference |
Reference |
10,619 |
78 (0.73) |
Reference |
Reference |
| 24.0–27.9 |
1261 |
40 (3.17) |
2.18 (1.53–3.10), P < 0.001 |
1.39 (0.94–2.07), P = 0.10 |
1262 |
21 (1.66) |
2.29 (1.40–3.72), P = 0.001 |
1.41 (0.82–2.40), P = 0.21 |
| ≥28.0 |
655 |
39 (6.00) |
4.28 (2.98–6.13), P < 0.001 |
1.80 (1.16–2.80), P = 0.01 |
644 |
28 (4.35) |
6.81 (3.96–9.53), P < 0.001 |
2.20 (1.28–3.76), P < 0.01 |
| Parity§
|
| 0 |
10,500 |
184 (1.75) |
1.01 (0.77–1.32), P = 0.97 |
1.48 (1.09–2.02), P = 0.01 |
10,424 |
108 (1.04) |
1.55 (1.03–2.33), P = 0.04 |
2.28 (1.44–3.60), P < 0.001 |
| ≥1 |
4359 |
76 (1.74) |
Reference |
Reference |
4312 |
29 (0.67) |
Reference |
Reference |
| Multiple gestation |
| Yes |
230 |
17 (7.39) |
4.73 (2.84–7.87), P < 0.001 |
3.51 (1.93–6.41), P < 0.001 |
228 |
15 (6.58) |
8.31 (4.78–14.44), P < 0.001 |
5.50 (2.87–10.67), P < 0.001 |
| No |
14,636 |
243 (1.66) |
Reference |
Reference |
14,515 |
122 (0.84) |
Reference |
Reference |
| Chronic hypertension |
| Yes |
290 |
92 (31.72) |
39.85 (29.81–53.27), P < 0.001 |
35.03 (25.40–48.31), P < 0.001 |
250 |
52 (20.80) |
44.52 (30.67–64.61), P < 0.001 |
33.98 (22.20–52.01), P < 0.001 |
| No |
14,756 |
168 (1.14) |
Reference |
Reference |
14,493 |
85 (0.59) |
Reference |
Reference |
| Diabetes during pregnancy |
| Pre-existing diabetes |
124 |
6 (4.84) |
3.18 (1.38–7.32), P = 0.01 |
0.65 (0.24–1.75), P = 0.39 |
125 |
7 (5.60) |
7.88 (3.58–17.37), P < 0.001 |
2.01 (0.75–5.42), P = 0.17 |
| Gestational diabetes |
2729 |
65 (2.38) |
1.52 (1.15–2.03), P < 0.01 |
1.01 (0.73–1.40), P = 0.95 |
2705 |
41 (1.52) |
2.05 (1.41–2.97), P < 0.001 |
1.38 (0.92–2.08), P = 0.13 |
| No |
12,013 |
189 (1.57) |
Reference |
Reference |
11,913 |
89 (0.75) |
Reference |
Reference |
aOR: Adjusted odds risk; BMI: Body mass index; CI: Confidence interval; cOR: Crude odds risk; PE: Preeclampsia.
∗n(%) presents the proportion of severe PE cases over deliveries excluded mild PE cases or mild PE cases over deliveries excluded severe PE cases for each risk factor.
†aOR: adjusted with all variables in the table.
‡Missing data: 139 in severe PE analysis and 134 in mild PE analysis, due to missing values in the database.
§Missing data: 7 in severe PE analysis and 7 in mild PE analysis, due to missing values in the database.
The subgroup analysis for EOPE and LOPE is shown in Table 3. For EOPE, women who developed PE and delivered at or after 34 weeks of gestation were excluded: 54 women developed EOPE, and 236 women delivered before 34 weeks of gestation. For LOPE, women who delivered before 34 weeks of gestation were excluded: 343 women developed LOPE, and 14,676 women delivered after 34 weeks of gestation. A comparison of all the risk factors showed that chronic hypertension was the only shared risk factor between EOPE and LOPE (aOR: 13.75, 95% CI: 4.78–39.58, P < 0.001) vs. (aOR: 35.57, 95% CI: 26.66–47.47, P < 0.001). We found that higher pre-pregnancy BMI, overweight (aOR: 1.54, 95% CI: 1.09–2.18, P = 0.01) and obesity (aOR: 2.23, 95% CI: 1.53–3.27, P < 0.001), nulliparity (aOR: 2.00, 95% CI: 1.49–2.68, P < 0.001), and multiple pregnancies (aOR: 4.11, 95% CI: 2.40–7.05, P < 0.001) were significant risk factors for LOPE, but not EOPE. Advanced age and diabetic disorders were not significantly associated with either EOPE or LOPE in the logistic regression analyses.
Table 3 -
Maternal characteristics and clinical risk factors associated with early- and
late-onset preeclampsia.
| Variables |
Deliveries <34 weeks (n = 236) |
EOPE (n = 54), n (%)∗
|
cOR (95% CI), P
|
aOR (95% CI)†, P
|
Deliveries ≥34 weeks (n = 14,767) |
LOPE (n = 343), n (%)∗
|
cOR (95% CI), P
|
aOR (95% CI)†, P
|
| Age (years) |
| <25 |
39 |
4 (10.26) |
0.34 (0.11–1.01), P = 0.05 |
0.55 (0.17–1.81), P = 0.33 |
2143 |
34 (1.59) |
0.66 (0.46–0.95), P = 0.03 |
0.84 (0.57–1.23), P = 0.37 |
| 25–34 |
154 |
39 (25.32) |
Reference |
Reference |
11,096 |
263 (2.37) |
Reference |
Reference |
| ≥35 |
43 |
11 (25.58) |
1.01 (0.47–2.20), P = 0.97 |
1.31 (0.52–3.31), P = 1.31 |
1528 |
46 (3.01) |
1.28 (0.93–1.76), P = 0.13 |
1.13 (0.78–1.64), P = 0.52 |
| Pre-pregnancy BMI (kg/m2)‡
|
| <18.5 |
37 |
6 (16.22) |
0.77 (0.29–2.04), P = 0.60 |
0.78 (0.26–2.28), P = 0.65 |
2067 |
24 (1.16) |
0.60 (0.39–0.91), P = 0.02 |
0.69 (0.44–1.07), P = 0.09 |
| 18.5–23.9 |
140 |
28 (20.00) |
Reference |
Reference |
10,635 |
206 (1.94) |
Reference |
Reference |
| 24.0–27.9 |
23 |
5 (21.74) |
1.11 (0.38–3.25), P = 0.85 |
1.07 (0.31–3.74), P = 0.91 |
1279 |
56 (4.38) |
2.32 (1.72–3.13), P < 0.001 |
1.54 (1.09–2.18), P = 0.01 |
| ≥28.0 |
26 |
10 (38.46) |
2.50 (1.03–6.10), P = 0.04 |
0.77 (0.22–2.65), P = 0.68 |
657 |
57 (8.68) |
4.81 (3.55–6.52), P < 0.001 |
2.23 (1.53–3.27), P < 0.001 |
| Parity§
|
| 0 |
140 |
28 (20.00) |
0.67 (0.36–1.24), P = 0.21 |
1.04 (0.49–2.21), P = 0.92 |
10,468 |
264 (2.52) |
1.38 (1.07–1.78), P = 0.01 |
2.00 (1.49–2.68), P < 0.001 |
| ≥1 |
96 |
26 (27.08) |
Reference |
Reference |
4292 |
79 (1.84) |
Reference |
Reference |
| Multiple gestation |
| Yes |
40 |
8 (20.00) |
0.82 (0.35–1.89), P = 0.63 |
1.06 (0.42–2.71), P = 0.90 |
205 |
24 (11.71) |
5.92 (3.81–9.19), P < 0.001 |
4.11 (2.40–7.05), P < 0.001 |
| No |
196 |
46 (23.47) |
Reference |
Reference |
14,562 |
319 (2.19) |
Reference |
Reference |
| Chronic hypertension |
| Yes |
29 |
20 (68.97) |
11.31 (4.75–26.95), P < 0.001 |
13.75 (4.78–39.58), P < 0.001 |
313 |
124 (39.62) |
42.65 (32.79–55.47), P < 0.001 |
35.57 (26.66–47.47), P < 0.001 |
| No |
207 |
34 (16.43) |
Reference |
Reference |
14,454 |
219 (1.52) |
Reference |
Reference |
| Diabetes during pregnancy |
| Pre-existing diabetes |
5 |
2 (40.00) |
2.18 (0.35–13.45), P = 0.40 |
1.14 (0.12–11.03), P = 0.91 |
126 |
11 (8.73) |
4.74 (2.52–8.91), P < 0.001 |
1.12 (0.49–2.55), P = 0.79 |
| Gestational diabetes |
52 |
10 (19.23) |
0.78 (0.36–1.68), P = 0.52 |
0.84 (0.33–2.18), P = 0.73 |
2718 |
96 (3.53) |
1.81 (1.43–2.31), P < 0.001 |
1.17 (0.89–1.55), P = 0.26 |
| No |
179 |
42 (23.46) |
Reference |
Reference |
11,923 |
236 (1.98) |
Reference |
Reference |
aOR: Adjusted odds risk; BMI: Body mass index; CI: Confidence interval; cOR: Crude odds risk; EOPE: Early-onset preeclampsia; LOPE: Late-onset preeclampsia.
∗n(%) presents the proportion of EOPE cases over deliveries <34 weeks cases or LOPE cases over deliveries ≥34 weeks cases for each risk factor.
†aOR: adjusted with all variables in the table.
‡Missing data: 10 in EOPE analysis and 129 in LOPE analysis, due to missing values in the database.
§Missing data: 0 in EOPE analysis and 7 in LOPE analysis, due to missing values in the database.
Table 4 illustrates the relationship between the accumulated number of risk factors and the risk of PE by logistic regression analysis. We found that patients with an increasing number of risk factors showed a greater risk of developing PE than those without any identified risk factors. The risk of PE in women presenting only one risk factor was OR: 2.25 (95% CI: 1.52–3.33, P < 0.001), presenting two risk factors was OR: 12.13 (95% CI: 8.80–18.22, P < 0.001), and presenting three or more risk factors was OR: 71.64 (95% CI: 42.83–119.83, P < 0.001). We also estimated the risk of PE with specific key clinical risk factor combinations (Table S1, https://links.lww.com/MFM/A9).
Table 4 -
Logistic regression analyses for the accumulated number of risk factors and preeclampsia.
| Risk factors∗ (No.) |
Total deliveries (n = 15,003) |
Preeclampsia (n = 397), n (%) |
OR (95% CI) |
P
|
| 0 |
3477 |
29 (0.83) |
Reference |
|
| 1 |
9808 |
182 (1.86) |
2.25 (1.52–3.33) |
<0.001 |
| 2 |
1447 |
134 (9.26) |
12.13 (8.80–18.22) |
<0.001 |
| ≥3 |
125 |
47 (37.60) |
71.64 (42.83–119.83) |
<0.001 |
| Missing data |
146 |
5 (3.42) |
– |
– |
BMI: Body mass index; CI: Confidence interval; OR: Odds ratio; –: Not applicable.
∗Risk factors includes overweight (pre-pregnancy BMI = 24.0–27.9 kg/m2), obese (pre-pregnancy BMI ≥ 28.0 kg/m2), nulliparity, multiple pregnancies, and chronic hypertension.
Discussion
In this large retrospective population study, the incidence of PE was 2.65%, which corresponds to the commonly reported 2%–5% incidence rate of PE in the Chinese population.22 The results also showed that the gestational week-specific incidence of PE was higher in women who delivered prematurely. Our findings revealed that several factors, including high pre-pregnancy BMI, nulliparity, multiple pregnancies, and chronic hypertension were associated with an increased risk of PE. However, other factors, including advanced maternal age, diabetes mellitus, and gestational diabetes, were not associated with PE when controlled for confounders.
We found women with high pre-pregnancy BMI, in particular obesity, had an increased risk for PE. This is in accordance with previous findings based on both Western23,24 and Asian25–27 populations. The molecular mechanisms of obesity leading to PE may include dyslipidemia, insulin resistance, hyperinsulinemia, oxidative stress, inflammation, and impaired endothelium function.28 Previous studies have shown that being overweight/obese before pregnancy increases the risk of LOPE,29,30 mild PE,30 severe PE,31,32 but not EOPE.29–32 These same results were found in our study. Raymond et al.33 also pointed out that EOPE and LOPE were two different disease types, having different risk factors, clinical features, hemodynamic characteristics, and biochemical markers.
We found that the occurrence of PE was higher in primiparous women than in multiparous women, in agreement with the findings of previous studies.14,34,35 One possible explanation is that immune maladaptation due to primipara may be involved in the development of PE.36 Among PE subtypes, we found that nulliparous women had a two-fold increased risk for LOPE, but the risk for EOPE was not increased. Regarding the severity of PE, nulliparity was a stronger risk factor for mild PE than for severe PE.
Multiple gestations were also associated with increased risk for PE. This may be due to the larger placenta in multiple pregnancies, which leads to greater maternal exposure to paternal antigens or a significantly more impaired placental perfusion. There was a strong association between multiple gestation and LOPE but not for EOPE. Francisco et al.37 reported that the risk of PE <37 gestational weeks in twins is higher than in singletons. The result is kind of different from our study, which may be related to the different gestational week setting of PE and the limited number of observations in EOPE group in our study.
Women with chronic hypertension had the greatest risk for PE. More interestingly, chronic hypertension did not manifest into a particular clinical subtype of PE. We also found that the OR of chronic hypertension was higher for EOPE than LOPE. This finding is consistent with those of previous studies.18,32,38 The pathophysiology of PE in pregnant women with chronic hypertension is still unclear, and hemodynamic disorders may be involved in this. It is well known that impaired perfusion of the placenta is involved in the pathogenesis of PE. Studies reported that hypertensive pregnant women may have hemodynamic disorders, leading to the imbalance of systemic vascular endothelial factors, especially in the placenta.39,40
In this study, we found that advanced maternal age was not a risk factor for PE, which is in accordance with the findings of previous studies.10,32,41 However, maternal age has been associated with PE in other studies.7,42,43 It is known that older pregnant women are more likely to have a pre-existing medical disorder, such as hypertension or obesity.44 It is possible confounders exaggerated the effect of advanced maternal age in some other studies.45 Moreover, no association between diabetic disorders and PE was observed in the present study. Previous studies have reported pre-existing diabetes and gestational diabetes is associated with a pronounced increased risk for PE46,47; however, some studies did not note this association.18
To identify women at increased risk for PE, many clinical, biophysical, and biochemical studies have been conducted to develop prediction models.48,49 However, these studies involved some invasive or expensive tests or required special expertise. In addition, many of these tests demonstrated poor sensitivity and poor predictive value.50,51 Unlike prediction models that frequently use a combination of clinical factors and plasma markers or ultrasound, which may be expensive, the present study focused on the specific risk factors and their relationship with PE. We found that women with more risk factors had a higher risk for PE compared to pregnant women without any risk factors. In addition, we also listed a detailed combination of risk factors and their associations with PE, which may provide useful information to healthcare providers and pregnant women at high risk (Table S1, https://links.lww.com/MFM/A9).
Due to the retrospective nature of the study, there are a few limitations. We could not investigate some important risk factors for PE, such as previous PE history, family PE history, infertility treatment, and smoking information, because these factors were not collected in the GPS study. It has been reported that low-dose aspirin prophylaxis should be considered as an early intervention in patients at high risk for PE.52 Unfortunately, we did not investigate the use of aspirin in the enrolled population as the information were not collected in the GPS study, which could have provided additional information regarding the clinical manifestation of PE. Our study's strengths include its use of a large multicentre population from China and its investigation on the clinical risk factors for PE according to its subtypes. Consistent with prior findings, our findings may provide some evidence to guide the early prediction and prevention of PE.
Conclusions
In summary, our study identified risk factors for PE and its subtypes in Chinese pregnant women. We found there was an increased risk for PE as the number of risk factors increased. In addition, this study showed the relationship between a combination of risk factors and the risk of PE. Our logistic regression model's predictive performance can help monitor patients, ensure an earlier diagnosis, and predict women who are more likely to develop PE.
Acknowledgments
The authors acknowledge the GPS study group for providing medical records from the 15 hospitals in Beijing, China. The authors appreciate all the investigators’ efforts in data collection.
Funding
The study was supported by the National Natural Science Foundation of China (Grant No. 81490745 and No. 81701466), State Key Development Program for Basic Research of China (Grant No. 2015CB943304), Peking University First Hospital Research Seed Fund (Grant No. 2020SF05), and World Diabetes Foundation (Grant No. WDF14-908). These fundings only provided financial support and have no role in the study design, data analysis and manuscript preparing.
Author Contributions
Li Lin participated in the data collection and analysis, and prepared the manuscript. Li Lin and Huixia Yang contributed to the initial study conception and design. Jing Huai, Rina Su, Chen Wang and Boya Li were involved in the data collection and cleaning. All authors have read and approved the final manuscript.
Conflicts of Interest
None.
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