Hypertensive disorders of pregnancy are a common complication of pregnancy that can lead to adverse maternal and fetal outcomes. Preeclampsia, especially severe preeclampsia, contributes the most to morbidity and mortality. Preeclampsia is a pregnancy-specific syndrome that can affect multiple target organs.1 The placenta, as one of the target organs, can also be affected, leading to fetal growth restriction (FGR).2,3 However, whether FGR is a severe feature of preeclampsia remains controversial. The guideline released by the American College of Obstetricians and Gynecologists (ACOG) in 2019 did not classify FGR as a severe feature.4
Our study aimed to assess the incidence of FGR in hypertensive pregnancies and its correlation with gestational age, previous FGR history, proteinuria and hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome in Chinese population.
Materials and methods
This is a retrospective cohort study. The clinical data of 4 451 women with hypertensive disorders of pregnancy were retrospectively collected from 11 tertiary hospitals in 10 provinces across China during January 2015 to December 2015. The mean maternal age was (31.0 ± 5.4) years old. The exclusion criteria includes: (1) renal disease including chronic nephritis, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, and so on; (2) presence of systemic lupus erythematosus; and (3) delivery before 20 gestational weeks. Hypertensive disorders were assessed by reviewing the medical records. The incidence of FGR and its correlation with gestational age, previous FGR history, 24-hour urinary protein excretion (24-hUPE), and HELLP syndrome were analyzed. Umbilical artery Doppler was investigated in all patients while middle cerebral artery Doppler and uterine artery Doppler was investigated in FGR patients. Neonatal outcomes including fetal/neonatal death, 5-minute Apgar score, and neonatal intensive care unit admission were investigated. Our study was approved by the Ethics Committee of Peking University First Hospital (Reference Number: 2013(572)). All women gave informed written consent according to the Declaration of Helsinki.
Hypertensive disorders of pregnancy consist of four categories: gestational hypertension (GH), preeclampsia (PE), and eclampsia (Ec), chronic hypertension (CH), and chronic hypertension with superimposed preeclampsia (CHPE). Preeclampsia and severe preeclampsia were diagnosed according to the criteria of Chinese guidelines.5 PE was defined as high blood pressure (BP) (≥140 mm Hg systolic BP or ≥90 mm Hg diastolic BP on two occasions at least 4 hours apart) that developed after 20 weeks of gestation with a previously normal BP, as well as proteinuria or target organ dysfunctions without proteinuria. Severe PE was diagnosed if one of the follows occurred: (1) systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg; (2) central nervous manifestations such as headache and visual disorder; (3) persistent upper abdominal pain, hepatic subcapsular hematoma and liver rupture; (4) elevated liver enzyme; (5) renal dysfunction, including proteinuria >2.0 g/24 h, oliguria (urine output <400 mL/24 h or <17 mL/h) and serum creatinine >106 μmol/L; (6) hypoalbuminemia with ascite, hydrothorax, or hydropericardium; (7) hematologic disorder, including continuous low platelet count <100 × 109/L and microangiopathic hemolysis (anemia, jaundice, and elevated lactate dehydrogenase); (8) heart failure; (9) pulmonary edema; (10) FGR, oligohydramnios, fetal death, and placental abruption.
FGR was defined as a birth weight below the 10th percentile for gestational age.6 Abnormal results of umbilical artery Doppler included elevated resistance (systolic/diastolic ratio or pulsatility index (PI) >95th percentile), absent end diastolic flow, and reversed end diastolic flow. Abnormal middle cerebral artery Doppler included low resistance (PI <5th percentile or reversed umbilical/middle cerebral ratio). Increased uterine artery resistance referred to elevated PI (>90th percentile).
Continuous data were presented as mean ± standard deviation and compared using the Student's t-test. Categorical data were presented as frequencies or percentages and compared using the Chi-square test. All statistical analyses were performed using the SPSS version 18.0 (SPSS Inc, Chicago, IL, USA). A P < 0.05 was considered statistically significant.
Our study included 4 451 women with hypertensive disorders of pregnancy, consisting of 2 721 women with PE, 29 women with Ec, 1 136 women with GH, 200 women with CH, and 365 women with CHPE. One thousand nine hundred and thirty-seven women had severe PE. The mean maternal age was (31.0 ± 5.4) years. The average gestational age of delivery was (36 ± 5) weeks. The average gravity was (2.3 ± 1.4). The average parity was (1.4 ± 0.7). The average neonatal birth weight was (2 597.2 ± 936.3) g. Table 1 shows the comparison between FGR and non-FGR group.
The overall incidence of FGR in our patients was 15.1% (670/4 451). The incidence of FGR was 18.9% (515/2 721), 17.2% (5/29), 6.1% (69/1 136), 6.5% (13/200), and 18.6% (68/365) in PE group, Ec group, GH group, CH group, and CHPE group, respectively. The incidence of FGR was 22.4% (433/1 937) in women with severe PE.
We then investigated the incidence of FGR in women with different gestational age at birth. The incidence of FGR was significantly higher in women who had preterm births than those who had term births (22.8% (432/1 898) vs. 9.3% (238/2 553), P < 0.001). FGR was also more prevalent in women delivered <37 gestational weeks than those delivered ≥34 gestational weeks (18.4% (189/1 025) vs. 14.0% (481/3 426), P = 0.001).
Among all women, 1 602 were multiparas, of whom six women had a previous FGR history. Women with a previous FGR history had a significantly higher incidence of FGR than those without FGR history (66.7% (4/6) vs. 15.7% (250/1 596), P = 0.007).
Women with HELLP syndrome in the FGR group were approximately twice that in the non-FGR group (6.9% (46/670) vs. 3.2% (122/3 781), P < 0.001) (Table 1). Women with FGR had significantly heavier 24-hUPE than those without FGR ((3.9 ± 3.7) g vs. (3.1 ± 4.2) g, P = 0.005). Significantly higher proportions of women with FGR had cesarean sections (82.5% vs. 70.2%, P < 0.001) and fetal/neonatal death (9.4% vs. 4.2%, P < 0.001) in comparison with those without FGR. The significantly higher proportion of cesarean section in FGR-women might also result in significantly less gestational weeks at birth ((35.3 ± 3.0) weeks vs. (36.4 ± 4.3) weeks, P < 0.001) and significantly lower birth weight ((1 731.0 ± 574.5) g vs. (2 753.9 ± 902.1) g, P < 0.001) in these patients compared to non-FGR women. Significantly higher proportions of FGR women had abnormal results of the umbilical artery Doppler (13.0% vs. 2.4%, P < 0.001) and the middle cerebral artery Doppler (3.3% vs. 0.4%, P < 0.001). The incidence of 5-minute Apgar score ≤7 was higher in FGR neonates (7.9% vs. 3.9%, P < 0.001). FGR neonates had higher rate of admission in intensive care unit (48.1% vs. 23.3%, P < 0.001).
Preeclampsia has been reported to affect 3%–5% of pregnancies in the United States.7 Our previous study revealed that the incidence of preeclampsia is 2.7% in the Beijing area of China.8 In Europe, the FGR incidence in newborns is 3%–7% of total pregnancies.9 The mean FGR prevalence is 23.8% in developing countries and 9.4% in China.10 Although FGR is a common complication of hypertensive disorders of pregnancy, especially preeclampsia, there are few studies that investigate the incidence of FGR complicating preeclampsia. In our study, the FGR incidence in women with hypertensive disorders of pregnancy was 15.1%. In women with severe preeclampsia, the FGR incidence was 22.4%, indicating that one-fourth to one-fifth of this population gives birth to a small-for-gestational-age baby. In women with preeclampsia superimposed on CH, the FGR incidence was 18.6%.
Research on the recurrence of FGR in hypertensive pregnancies is also lacking. Three decades ago, Patterson et al.11 followed up 9 596 women (not only hypertensive women) throughout two pregnancies and found the overall FGR incidence in the first pregnancy was 12.4%. If the previous birth was small for gestational age, the risk of FGR recurrence was increased by up to 20.1%. Our study showed that in the hypertensive population, the FGR risk in women with a previous FGR history was increased by four-fold (66.7% vs. 15.7%). This is consistent with previous findings that a previous small-for-gestational-age birth led to a four-fold increase in risk of FGR, while CH led to a two-fold increase, preeclampsia to a 5- to 12-fold increase depending on severity, and pregnancy-induced hypertension to a two-fold increase.12
Our study suggests that the FGR incidence differs with gestational age in hypertensive pregnant women. Preterm birth and early-onset preeclampsia are associated with a higher incidence of FGR. It is well understood that preterm birth or early-onset preeclampsia usually results in more severe symptoms than term birth or late-onset preeclampsia. Early-onset preeclampsia is more like an early placental ischemic disease than late-onset preeclampsia.13 Therefore, as our study shows, early-onset preeclampsia gives rise to a higher proportion of FGR. Preeclampsia and FGR are both feature of ischemic placental disease syndrome.14 FGR and preeclampsia are thought to have a shared mechanism of abnormal placentation, with FGR being the fetal manifestation and preeclampsia being the maternal manifestation. However, unexplained FGR may be a different entity entirely.15 Thus, it is inappropriate that the 2013 and 2019 ACOG guidelines do not include FGR as a severe feature because FGR is managed similarly in pregnant women either with or without preeclampsia.4,16
Our study also found that the incidence of HELLP syndrome in hypertensive pregnant women doubles when they are complicated with FGR. The amount of 24-hUPE in the FGR women was also elevated compared with the non-FGR women.
Neonatal outcomes of FGR patients were also worse than non-FGR patients. Besides significantly higher fetal/neonatal mortality, both asphyxia incidence at 5 minutes and rate of admission to neonatal intensive care unit doubled in FGR neonates.
These findings demonstrate that preeclampsia will be more severe once it is complicated with FGR. FGR should be recognized as a severe feature of preeclampsia syndrome. However, unlike the 2013 ACOG guidelines,16 the Williams obstetrics1 and 2015 Chinese guidelines5 both list FGR as an indication of severe preeclampsia.
Our study has limitations. All the clinical data were retrospectively collected and may contain certain bias. FGR was defined as a birth weight below the 10th percentile for gestational age rather than diagnosed using the fetal weight growth curve, thus some constitutionally small without being growth restricted babies were not excluded while those over 10th percentile but not meeting their growth potential were neglected.
Our multi-center study revealed the epidemiologic features of FGR complicated with hypertension across China, as well as its correlation with gestational age and previous FGR history. FGR is associated with an earlier onset of disease, heavier 24-hUPE, higher risk of HELLP syndrome, and worse neonatal outcomes in Chinese hypertensive gestations. We recommend that FGR should be classified as an indication of severe preeclampsia.
Our study was supported by grants from the National Natural Science Foundation of China (No. 81701466, 81490745), the National Major Scientific Research Program of China (No. 2015CB943304), and the National Science and Technology Support Program of China (No. 2015BAI13B06).
Li Lin, Xiao-Tian Li, Dun-Jin Chen, Xian-Lan Zhao, Shi-Hong Cui, Hong-Juan Ding, Gui-Feng Ding, Hai-Xia Meng, Hong-Wei Wei, Xiao-Tong Sun, and Hong Xin carried out the studies, participated in collecting data. Yu-Chun Zhu and Hui-Xia Yang drafted the manuscript. Yu-Chun Zhu performed the statistical analysis. Hui-Xia Yang, Yu-Chun Zhu, and Bo-Ya Li participated in its design. All authors read and approved the final manuscript.
Conflicts of Interest
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