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neonatal outcomes in women with preeclampsia
Pregnancy Hypertension 19 (2020) 119–126
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Severe proteinuria as a parameter of worse perinatal/neonatal outcomes in women with preeclampsia
T
⁎
Mamoru Morikawa , Michinori Mayama, Yoshihiro Saito, Kinuko Nakagawa-Akabane, Takeshi Umazume, Kentaro Chiba, Satoshi Kawaguchi, Kazutoshi Cho, Hidemichi Watari Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Preeclampsia Proteinuria Pulmonary edema Central serous chorioretinopathy Preterm birth
Objectives: The present study aimed to determine the relationship between the severity of proteinuria and maternal/neonatal outcomes among women with preeclampsia. Study design: Proteinuria severity was measured at preeclampsia diagnosis and at delivery in 94 women with preeclampsia (among 2904 women with singleton pregnancies, who delivered after 22 gestational weeks). Preeclampsia was defined as hypertension with proteinuria. Main outcome measures: Protein:creatinine (P/C) ratio to worse the maternal outcome was 4.8 among women with preeclampsia. Results: The frequencies of HELLP syndrome and maternal pulmonary edema in women with a P/C ratio ≥5.0 (35.5% and 35.5%, respectively) were significantly higher than those in women with a P/C ratio < 5.0 (12.7%, P = 0.014 and 6.4%, P < 0.001, respectively). The best P/C ratio cutoff value to determine early-onset preeclampsia and early preterm birth (EPB) was 4.1 (P < 0.001 and P < 0.001, respectively). The best P/C ratio cutoff values to determine the interval between the preeclampsia diagnosis and delivery < 7 days and the need to undergo cesarean section were 1.8 and 1.5, respectively. The best P/C ratio cutoff value to determine maternal pulmonary edema and central serous chorioretinopathy (CSC) was 4.8 (P = 0.020 and P = 0.014, respectively). Finally, the best P/C ratio cutoff values to determine EPB and maternal CSC in women with preeclampsia were 4.1 (odds ratio, 10.9; 95% confidence interval; 4.08 to 29.2, P < 0.0001) and 4.8 (odds ratio, 17.6; 95% confidence interval; 0.898 to 344, P = 0.0008), respectively, according to the multivariate analysis. Conclusions: A higher P/C ratio at delivery in women with preeclampsia might cause EPB and CSC.
1. Introduction Over the past two decades, proteinuria during pregnancy has not been considered significant. Previous studies [1,2] have reported that severe proteinuria was associated with severe perinatal outcomes among women with preeclampsia. Conversely, other previous studies [3–5] have reported no relation between severe proteinuria and severe perinatal outcomes among women with preeclampsia. The American College of Obstetricians and Gynecologists (ACOG) defined proteinuria/24 h ≥5.0 g as severe proteinuria. In Japan, women with severe preeclampsia who develop severe proteinuria are recommended to consider undergoing induced delivery at ≥37 GW [6].
However, in 2013, the ACOG removed the severity criteria of proteinuria from the diagnostic criteria for preeclampsia [7]. Thus, in 2015, the Japan Society for the Study of Hypertension in Pregnancy recommended that the termination of pregnancy among women with conservatively managed preeclampsia is not necessary merely because they have severe proteinuria. In 2018, the International Society for the Study of Hypertension in Pregnancy (ISSHP) defined presence of proteinuria is not necessary to diagnose preeclampsia [8]. In the current Japanese criteria for “Hypertension disorders in pregnancy” since 2018, preeclampsia was defined as onset hypertension since 20 GW with one or more other maternal complication(s) following proteinuria, including liver dysfunction without underlying liver diseases, perinatal
Abbreviations: AUC, area under curve; AFLP, acute fatty liver of pregnancy; BP, blood pressure; CI, confidence interval; CSC, central serous chorioretinopathy; EPB, early preterm birth; FGR, fetal growth restriction; GW, gestational weeks; OR, odds ratio; P/C, protein:creatinine ratio; PPCM, peripartum cardiomyopathy; PRES, posterior reversible encephalopathy syndrome ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita-ku N15 W7, Sapporo 060-8638, Japan. E-mail address: [email protected] (M. Morikawa). https://doi.org/10.1016/j.preghy.2019.12.013 Received 2 August 2019; Received in revised form 12 December 2019; Accepted 23 December 2019 Available online 10 January 2020 2210-7789/ © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
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(AFLP), eclampsia, posterior reversible encephalopathy syndrome (PRES), pulmonary edema, peripartum cardiomyopathy (PPCM), abruptio placentae; and 4) non-reassuring fetal state on cardiotocography and biophysical profile score on ultrasonography. In addition, termination was discussed in the presence of severe proteinuria (P/C ratio ≥5.0) or kidney dysfunction (glomerular filtration rate < 50 mL/ min/1.73 m2) or maternal blood examination abnormalities (low platelet counts or antithrombin activity, high AST/ALT/LDH, etc.). 2.3. Statistical analyses Data are shown as the mean ± SD or frequencies. The statistical analyses were performed using the statistical software JMP Pro, version 14.0 (SAS Institute Inc., Cary, NC, USA). Tukey–Kramer HSD (honestly significant difference) tests or student ttests were used to compare means. Fisher’s exact test was used to compare categorical variables. Pearson’s product–moment correlation coefficient was used to measure linear correlations between two variables. A stepwise multiple logistic regression was used in the multivariate analysis to compare parameters with P < 0.1 in the univariate analysis. Receiver operating characteristic (ROC) curves were used to assess the ability of parameters to differentiate the onset of perinatal/ neonatal complications. In all analyses, P < 0.05 indicated statistical significance. Both a P value less than 0.05 and a correlation coefficient (r) greater than 0.25 or less than −0.25 were required to indicate statistical significance for linear correlations.
Fig. 1. Study flowchart of women with preeclampsia.
progressive kidney dysfunction, perinatal cerebral stroke or neuropathy, blood coagulation disorder, and uterus/placental dysfunction (fetal growth restriction; FGR, stillbirth without fetal chromosomal abnormality, or fetal anomalad/fetal anomalies) [9]. The present study aimed to determine the association between proteinuria severity and perinatal/neonatal outcomes. Thus, in the present study, preeclampsia was defined as hypertension with proteinuria, according to the previous criteria of the Japan Society of Obstetrics and Gynecology (JSOG) [10]. 2. Material and methods
2.4. Ethical approval
This retrospective hospital cohort study was conducted at the Hokkaido University Hospital between January 2009 and December 2017. TP levels and proteinuria were measured at the time of preeclampsia diagnosis and at delivery in the 94 women with preeclampsia (among 2904 singleton pregnancies) who delivered at ≥22 GWs (Fig. 1).
This study was conducted after receiving approval from the Institutional Review Board of Hokkaido University Hospital (No. 017405, No. 015-115). All women provided informed consent prior to participation in the study.
2.1. Diagnosis of preeclampsia
3.1. Characteristics of women with preeclampsia
Preeclampsia was diagnosed according to the classical criteria of JSOG [10]. Hypertension was defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg; gestational hypertension was defined as hypertension occurring on/after 20 GW in the absence of significant proteinuria defined as a spot-urine protein:creatinine (P/C) ratio > 0.27 or > 0.3 g/24 h urine collection. Preeclampsia was diagnosed in women who developed both hypertension and significant proteinuria on/after 20 GW. Women with superimposed preeclampsia (chronic hypertension or proteinuria as an underlying disease at < 20 GW) were excluded in the present study. A final diagnosis of preeclampsia required the absence of both hypertension and proteinuria at 12 weeks after delivery.
Proteinuria severity was measured in 94 women with preeclampsia (3.2%) at preeclampsia diagnosis and at delivery. Table 1 shows the characteristics of the women with preeclampsia. Fig. 2 shows the associations of the main parameters among all women with preeclampsia. There was a positive association between GW at preeclampsia diagnosis and GW at delivery (r = 0.980, P < 0.001, Fig. 2A) and between proteinuria at preeclampsia diagnosis and proteinuria at delivery (r = 0.758, P < 0.001, Fig. 2D). Proteinuria severity was negatively associated with GW at preeclampsia diagnosis (r = 0.280, P = 0.005, Fig. 2B) and at delivery (r = 0.439, P < 0.001, Fig. 2C). The interval between preeclampsia diagnosis and delivery was positively related to proteinuria at delivery (r = 0.326, P = 0.001, Fig. 2F); however, there was no relation to proteinuria at preeclampsia diagnosis (r = 0.000, P = 0.931, Fig. 2E). Furthermore, at delivery, proteinuria severity was positively associated with systolic (r = 0.267, P = 0.009) and diastolic (r = 0.333, P = 0.011) BP.
3. Results
2.2. Management and termination of pregnancy among women with preeclampsia All women with preeclampsia were admitted to the Hokkaido University Hospital for treatment, and preeclampsia management (proteinuria measurements and blood examinations once or twice per week) were performed according to the recommendations of the JSOG guidelines [6]. Pregnancy was terminated if maternal and fetal well-being deteriorated to the point where the pregnancy could not be continued [6]: 1) severe hypertension (systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg) without effective antihypertensive agents; 2) emergent hypertension (systolic BP ≥180 mmHg and/or diastolic BP ≥120 mmHg); 3) HELLP syndrome, acute fatty liver of pregnancy
3.2. Characteristics of women with P/C ratios of < 5.0 and ≥5.0 at delivery The 94 women were divided into those with a P/C ratio (or proteinuria/24 h) at delivery < 5.0 (< 5.0 group, n = 63) and those with a P/C ratio ≥5.0 (≥5.0 group, n = 31) (Table 1). The frequencies of early-onset preeclampsia (< 34 GW at preeclampsia diagnosis) and EPB (< 34GW at delivery) in ≥5.0 group (67.7% and 64.5%, respectively) were significantly higher than those in < 5.0 group (27.0% and 23.8%, P < 0.001, respectively). The frequencies of women with severe 120
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Table 1 Characteristics of the 94 women with preeclampsia (PE). Overall (n = 94)
P/C ratio at delivery < 5.0 (n = 63)
P/C ratio at delivery ≥5.0 (n = 31)
P-value
Age (years) Primipara (%) BMI before pregnancy
33.9 ± 5.3 66 (70.2%) 22.0 ± 4.4
34.4 ± 5.3 41 (65.1%) 22.6 ± 4.7
32.6 ± 5.1 25 (80.7%) 20.9 ± 3.5
0.112 0.153 0.061
At preeclampsia diagnosis GW (weeks) Early-onset preeclampsia (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg)
33.9 ± 5.1 38 (40.3%) 158.6 ± 14.1 96.9 ± 9.8 2.36 ± 2.68 1.19 ± 1.37
36.0 ± 4.1 17 (27.0%) 160.0 ± 14.3 96.3 ± 10.3 1.18 ± 1.16 1.10 ± 1.46
32.2 ± 4.7 21 (67.7%) 155.7 ± 13.5 98.1 ± 8.5 4.77 ± 3.26 1.34 ± 1.18
< 0.001 < 0.001 0.155 0.366 < 0.001 0.409
At delivery GW (weeks) Preterm birth (GW < 37) (%) Early preterm birth (GW < 34) (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg) Interval between preeclampsia diagnosis to delivery < 7 days (%)
34.7 ± 4.6 53 (56.4%) 35 (37.2%) 170.2 ± 16.8 100.9 ± 11.6 4.01 ± 4.28 1.19 ± 1.37 5.9 ± 7.7 63 (67.0%)
36.0 ± 4.1 27 (42.9%) 15 (23.8%) 168.4 ± 17.8 99.0 ± 12.2 1.66 ± 1.38 1.16 ± 1.87 4.7 ± 6.7 45 (71.4%)
32.2 ± 4.7 26 (83.9%) 20 (64.5%) 173.8 ± 14.1 104.8 ± 9.1 8.79 ± 4.19 2.88 ± 2.24 6.7 ± 9.0 18 (58.1%)
< 0.001 < 0.001 < 0.001 0.118 0.011 < 0.001 < 0.001 0.0495 0.245
Perinatal outcomes Cesarean section (%) HELLP syndrome or AFLP (%) Abruptio placentae (%) Eclampsia or PRES (%) Pulmonary edema (%) PPCM (%) CSC (%) Maternal death (%)
75 (79.8%) 19 (20.2%) 3 (3.2%) 5 (5.3%) 15 (16.0%) 3 (3.2%) 4 (4.3%) 0 (0.0%)
47 (74.6%) 8 (12.7%) 2 (3.2%) 2 (3.2%) 4 (6.4%) 1 (1.6%) 1 (1.6%) 0 (0.0%)
28 (90.3%) 11 (35.5%) 1 (3.2%) 3 (9.7%) 11 (35.5%) 2 (6.5%) 3 (9.7%) 0 (0.0%)
0.102 0.014 1.000 0.327 < 0.001 0.252 0.103 1.000
Neonatal outcomes Birthweight SD Light-for-date infant (%) Apgar score < 8 at 5 min (%) Stillbirth or END (%)
−1.16 ± 1.46 29 (30.9%) 13 (13.8%) 7 (7.5%)
−0.96 ± 1.53 17 (27.0%) 8 (12.7%) 3 (4.8%)
−1.55 ± 1.23 12 (38.7%) 5 (16.1%) 4 (12.9%)
0.049 0.342 0.753 0.213
Data are presented as the mean ± SD. PE, preeclampsia; GW, gestational weeks; BMI, body mass index; P/C, protein:creatinine; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; SD, standard division; END, early neonatal death. Early-onset preeclampsia, GW at preeclampsia diagnosis < 34 GW; Early preterm birth, GW at delivery < 34 GW.
hypertension and emergent severe hypertension at delivery in ≥5.0 group were similar to those in < 5.0 group (data not shown in Table 1). The frequencies of HELLP syndrome or AFLP and pulmonary edema in ≥5.0 group (35.5% and 35.5%, respectively) were significantly higher than those in < 5.0 group (12.7%, P = 0.014, and 6.4%, P < 0.001, respectively). However, the frequencies of abruptio placentae, eclampsia or PRES, PPCM, and maternal central serous chorioretinopathy (CSC) were similar in both groups. The birthweight SD in ≥5.0 group (−1.55 ± 1.23) was significantly lower than that in < 5.0 group (0.96 ± 1.53, P = 0.049). However, the frequencies of light-fordate infants (with newborn birthweight SD based on normative birthweight for Japanese newborns [11] ≤−1.5) were similar in both groups.
The cutoff to determine maternal pulmonary edema and CSC was 4.8 (Fig. 3E and F). Those AUCs were 0.736 and 0.838 (P = 0.020 and 0.014, respectively), and the ORs (95% CIs) were 11.8 (3.02–46.1) and 17.6 (0.898–344), respectively (Table 2). According to the multivariate analysis, EPB and CSC were the perinatal outcomes used to determine the cutoff values in preeclampsia (P < 0.001 and P < 0.001, respectively). In Table 1, the mean diastolic BP at delivery in women with a P/C ratio ≥5.0 was significantly higher than that in women with a P/C ratio < 5.0 (P = 0.011). Based on ROC curves, the diastolic BP cutoff values at delivery to determine early preterm birth (EPB) and central serous chorioretinopathy (CSC) were 97 mmHg and 105 mmHg, respectively. The cutoff values for EPB and CSC corresponded to areas under the curve (AUC) at 0.655 and 0.806 (P = 0.015 and P = 0.041, respectively) and ORs (95% CI) at 5.00 (1.81–13.8) and 15.3 (0.780–297), respectively. However, according to the multivariate analysis, the variable associated with EPB and CSC was the P/C ratio at delivery (P < 0.001 and P < 0.001, respectively), not the diastolic BP at delivery. Thus, the diastolic BP at delivery was not a confounding factor at delivery for maternal outcomes among women with preeclampsia.
3.3. The best P/C ratio cutoff in preeclampsia to determine perinatal/ neonatal outcomes The best P/C ratio cutoff values in women with preeclampsia to determine perinatal/neonatal outcomes based on ROC curves are shown in Fig. 3 and Table 2. The cutoff value to determine early-onset preeclampsia and EPB were 4.1 (Fig. 3A and B). That ratio corresponded to areas under the curve (AUC) of 0.773 and 0.800 (P < 0.001, respectively) and odds ratios (ORs) (95% confidence interval, CI) of 9.97 (3.79–26.2) and10.9 (4.08–29.2), respectively (Table 2). The cutoff values to determine the interval between preeclampsia diagnosis and delivery < 7 days and need for cesarean section were 1.8 and 1.5, respectively (Fig. 3C and D).
3.4. P/C ratio at delivery according to initial symptoms of preeclampsia before or at preeclampsia diagnosis The 94 women with preeclampsia were divided into three groups based on the initial symptoms of preeclampsia before or at 121
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Fig. 2. Relationships of the main parameters among the94 women with preeclampsia. A. GW at preeclampsia diagnosis and at delivery. B. GW and proteinuria at preeclampsia diagnosis. C. GW and proteinuria at delivery. D. Proteinuria at preeclampsia diagnosis and at delivery. E. Proteinuria at preeclampsia diagnosis and interval between preeclampsia diagnosis and delivery. F. Proteinuria at delivery and interval between at preeclampsia diagnosis and delivery. Abbreviations: PE, preeclampsia; GW, gestational weeks; P/C, protein:creatinine.
perinatal/neonatal outcomes among women with preeclampsia based on an ROC curve of the P/C ratio at delivery. In general, we think that severe proteinuria hastens pregnancy termination among women with preeclampsia. However, in our study, the interval between preeclampsia diagnosis and delivery was positively associated with the proteinuria at delivery (Fig. 2F) but not with the proteinuria at preeclampsia diagnosis (Fig. 2E). This could be because of obstetricians trying to lengthen pregnancy periods of women with preeclampsia, so that their proteinuria would be severe by the time they finally deliver. Obstetricians usually consider hypertension a more important factor than proteinuria while deciding whether to terminate a pregnancy (particularly in women with early-onset preeclampsia). Thus, more attention should be paid to proteinuria severity in women with preeclampsia. In this study, the best P/C ratio cutoff values in preeclampsia to determine EPB and maternal CSC were 4.1 and 4.8, respectively, according to the ROC curves and multivariate analysis (Table 2). Specifically, the results indicate that the best cutoff value of the P/C ratio at delivery for worsened perinatal outcomes in women with preeclampsia is 4.8. The findings from the results of the present study would be useful for the prediction and/or prevention of severe maternal outcomes in women with severe preeclampsia. The present study has three major strengths. First, the P/C ratio was measured both at preeclampsia diagnosis and at delivery in all women with preeclampsia included in the study population. Second, preeclampsia was diagnosed in all cases based on both gestational hypertension and proteinuria. Therefore, there was little variation in the P/C ratio despite the retrospective nature of the study. Last, this was a single hospital cohort study. Thus, the present study had no bias in perinatal/neonatal outcomes due to differences in the management of preeclampsia in participating facilities of a multicenter study.
preeclampsia diagnosis (Table 3): 14 (14.9%) in the PE-H group (preeclampsia developed from new-onset hypertension in the absence of proteinuria), 20 (21.3%) in the PE-P group (preeclampsia developed from new-onset proteinuria in the absence of hypertension), and 60 (63.8%) in the PE-S group (preeclampsia exhibited both proteinuria and hypertension simultaneously). The P/C ratio at preeclampsia diagnosis in the PE-P group (3.73 ± 2.33) was significantly higher than that of the PE-H group (0.83 ± 0.97, P = 0.005). The P/C ratios at delivery were similar among the three groups; however, frequency of women with P/C ratio at diagnosed preeclampsia was ≥4.8 in the PE-P group (60.0%) was significantly higher than that of the PE-H group (21.4%, P = 0.026). The interval between the preeclampsia diagnosis and delivery of the three groups was similar (9.2 ± 5.6, 5.8 ± 9.0, and 5.3 ± 7.6 days in the PE-H, PE-P, and PE-S groups, respectively); however, the frequencies of women with the interval between the preeclampsia diagnosis and delivery was < 7 days in the PE-P (80.0%) and PE-S (71.7%) groups were significantly higher than that of the PE-H group (28.6%, P = 0.003 and 0.003, respectively). Both perinatal/ neonatal outcomes were similar among all groups. 4. Discussion The results of the present study emphasized the following three points: 1) the frequencies of HELLP syndrome and maternal pulmonary edema in women with a P/C ratio ≥5.0 were significantly higher than in women with a P/C ratio < 5.0; 2) the best P/C ratio cutoff values in preeclampsia to determine EPB and maternal CSC were 4.1 and 4.8, respectively, according to the multivariate analysis; and 3) perinatal/ neonatal outcomes were similar in the three groups based on the initial symptoms of preeclampsia before or at preeclampsia diagnosis. To our knowledge, this is the first study to demonstrate the relationship between the severity of the P/C ratio at delivery and 122
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Fig. 3. Receiver operating characteristic (ROC)of the P/C ratio at delivery and perinatal/neonatal outcomes. A. P/C ratio cutoff value to determine early-onset preeclampsia. B. P/C ratio cutoff value to determine early preterm birth. C. P/C ratio cutoff value to determine interval between preeclampsia diagnosis and delivery < 7 days. D. P/C ratio cutoff value to determine the need to undergo cesarean section. E. P/C ratio cutoff value to determine the onset of maternal pulmonary edema. F. P/C ratio cutoff value to determine the onset of maternal CSC. Abbreviations: PE, preeclampsia; P/C, protein:creatinine; AUC, area under curve; CSC, central serous chorioretinopathy.
of the five risk factors for maternal postpartum complications, as assessed by a stepwise logistic regression. [2] Conversely, in one study, 209 women with preeclampsia who delivered at < 37 gestational weeks (GW) were divided according to their proteinuria levels: mild proteinuria (< 5g/24 h), severe proteinuria (5–9.9 g/24 h), and massive proteinuria (≥10 g/24 h); massive proteinuria appeared to be a marker for early-onset preeclampsia and progression to severe preeclampsia. However, massive proteinuria did not result in increased
Some previous studies, conducted from 1996 to 2006, have reported that severe proteinuria is associated with severe perinatal outcomes among women with preeclampsia, and others have reported that severe proteinuria is not associated them. In a study including 685 women with preeclampsia, stillbirths and neonatal deaths appeared to be associated with women whose proteinuria amounted to or exceeded 3 g/ 24 h. [1] In another study including 453 women with preeclampsia and/or HELLP syndrome, proteinuria of > 5 g/L (500 mg/dL) was one
Table 2 Relationship between the P/C ratio cutoff value at delivery based on the ROC curve and perinatal/neonatal outcomes. P/C ratio cutoff value at delivery
Odds ratio
95% CI
AUC
Sensitivity
Specificity
PPV
NPV
Univariate analysis P value
Multivariate analysis P value
4.1 4.1 1.8
9.97 10.9 2.97
3.79–26.2 4.08–29.2 1.16–7.63
0.7733 0.8002 0.6249
0.773 0.800 0.508
0.682 0.714 0.742
0.772 0.694 0.800
0.793 0.828 0.426
< 0.0001 < 0.0001 0.0082
< 0.0001
Perinatal outcomes Cesarean section HELLP syndrome or AFLP Abruptio placentae Eclampsia or PRES Pulmonary edema PPCM CSC
1.5 5.4 26.5 7.0 4.8 4.8 4.8
9.03 3.78 45.5 6.84 11.8 12.7 17.6
2.69–30.3 1.33–10.8 0.708–2924 1.06–44.4 3.02–46.1 0.617–262 0.898–344
0.7284 0.6379 0.5788 0.5573 0.7363 0.7747 0.8375
0.707 0.579 0.333 0.600 0.800 1.000 1.000
0.789 0.733 1.000 0.820 0.747 0.681 0.689
0.930 0.355 1.000 0.158 0.375 0.094 0.124
0.405 0.873 0.978 0.973 0.952 1.000 1.000
0.0015 0.2948 0.0578 0.5666 0.0204 0.3717 0.0142
Neonatal outcomes Light-for-date infant Stillbirth or END
1.0 1.2
3.20 9.29
1.08–9.46 0.510–169
0.6109 0.6535
0.828 1.000
0.400 0.402
0.381 0.119
0.839 1.000
0.0784 0.6239
Early-onset preeclampsia Early preterm birth Interval between preeclampsia diagnosis and delivery < 7 days
0.0008
P/C, protein:creatinine; ROC, receiver operating characteristic; CI, confidence interval; AUC, area under the curve; PPV, positive predictive value; NPV, negative predictive value; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; END, early neonatal death. 123
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Table 3 Overall and subgroup characteristics of the women with preeclampsia (PE). Overall (n = 94)
PE-H group (n = 14)
PE-P group (n = 20)
PE-S group (n = 60)
Age (years) Primipara (%) BMI before pregnancy
33.9 ± 5.3 66 (70.2%) 22.0 ± 4.4
35.6 ± 4.6 9 (64.3%) 23.0 ± 2.9
32.8 ± 5.7 14 (70.0%) 20.3 ± 2.6
33.9 ± 5.3 43 (71.7%) 22.4 ± 5.1
At preeclampsia diagnosis GW (weeks) Early-onset preeclampsia (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg)
33.9 ± 5.1 38 (40.4%) 158.6 ± 14.1 96.9 ± 9.8 2.36 ± 2.68 1.19 ± 1.37
33.8 ± 4.5 5 (35.7%) 159.7 ± 14.3 96.9 ± 7.8 0.83 ± 0.97 0.40 ± 0.48
34.0 ± 3.9 9 (45.0%) 115.9 ± 9.8 96.8 ± 7.2 3.73 ± 2.33 * 1.15 ± 1.50
33.9 ± 5.6 24 (40.0%) 159.3 ± 15.3 96.9 ± 11.0 2.26 ± 2.86 1.15 ± 1.06
At delivery GW (weeks) Preterm birth (GW < 37) (%) Early preterm birth (GW < 34) (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg) Interval between preeclampsia diagnosis and delivery (days) < 7 days (%)
34.7 ± 4.6 53 (56.4%) 35 (37.2%) 170.2 ± 16.8 100.9 ± 11.6 4.01 ± 4.28 1.73 ± 2.15 5.9 ± 7.7 63 (67.0%)
35.1 ± 4.3 9 (64.3%) 4 (28.6%) 178.4 ± 14.9 101.1 ± 11.5 2.85 ± 2.63 0.72 ± 1.45 9.2 ± 5.6 4 (28.6%)
34.8 ± 3.2 15 (75.0%) 8 (40.0%) 165.0 ± 13.2 102.3 ± 8.0 5.11 ± 3.44 2.05 ± 1.89 5.8 ± 9.0 16 (80.0%) †
34.6 ± 5.1 29 (48.3%) 23 (38.3%) 170.1 ± 17.7 100.4 ± 12.7 3.92 ± 4.77 1.86 ± 2.32 5.3 ± 7.6 43 (71.7%) ‡
75 (79.8%) 19 (20.2%)
16 (80.0%) 5 (25.0%) 1 (5.0%) 1 (5.0%) 3 (15.0%) 1 (5.0%) 2 (10.0%) 0 (0.0%)
46 (76.7%) 11 (18.3%) 2 (3.3%) 3 (5.0%) 9 (15.0%) 2 (3.3%) 2 (3.3%) 0 (0.0%)
−1.39 ± 1.33 8 (40.0%) 2 (10.0%) 1 (5.0%)
−1.04 ± 1.55 17 (28.3%) 10 (16.7%) 5 (8.3%)
Perinatal outcomes Cesarean section (%) HELLP syndrome or AFLP (%) Abruptio placentae (%) Eclampsia or PRES (%) Pulmonary edema (%) PPCM (%) CSC (%) Maternal death (%)
5 (5.3%) 15 (16.0%) 3 (3.2%) 4 (4.3%) 0 (0.0%)
13 (92.9%) 3 (21.4%) 0 (0.0%) 1 (7.1%) 3 (21.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Neonatal outcomes Birthweight SD Light-for-date infant (%) Apgar score < 8 at 5 min (%) Stillbirth or END (%)
−1.16 ± 1.46 29 (30.9%) 13 (13.8%) 87 (92.6%)
−1.33 ± 1.25 4 (28.6%) 1 (7.1%) 1 (7.1%)
Data are shown as the mean ± SD. PE, preeclampsia; GW, gestational weeks; BMI, body mass index; BP, blood pressure; P/C, protein:creatinine; SD, standard deviation; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; END, early neonatal death. *P = 0.0047 versus PE-H group, †P = 0.0027 versus PE-H group, ‡P = 0.0026 versus PE-H group.
P = 0.002), respectively. The authors mentioned that quantifying the severity of proteinuria could identify the subgroup of women with preeclampsia and an increased risk of adverse outcomes. However, the frequencies of HELLP syndrome, eclampsia, abruptio placentae, visual symptoms, respiratory symptoms, FGR, and stillbirth were similar among the three groups. In another report, [14] compared with 60 women with preeclampsia and proteinuria 300–499 mg/24 h, the GW at delivery of 161 women with preeclampsia and proteinuria ≥500 mg/24 h was earlier (33.2 versus 37.3 weeks, P < 0.001); the latter group also had significantly higher frequencies of preterm delivery (61.5% versus 25.0%, P < 0.001), EPB (26.7% versus 13.3%, P < 0.05), and cesarean section (78.3% versus 48.3%, P < 0.001). Thus, the authors noted that women with proteinuria ≥500 mg/24 h should be considered at a substantially greater risk of pregnancy complications than women with proteinuria of 300 mg/24 h. Japanese guidelines recommend admission for women with preeclampsia and proteinuria (P/C ratio > 0.3) [6]. In the same study [14], compared with women managed as outpatients (non-proteinuric women with chronic hypertension or women with gestational hypertension), women with preeclampsia and proteinuria 300–499 mg/24 h had higher rates of complications. The authors noted that the use of the 300 mg/24 h threshold for proteinuria in clinical practice as guidance for admission appeared appropriate and should be continued. In another report of 239 women with preeclampsia who were divided into four groups based on proteinuria/24 h (< 0.3, 0.3–2.9, 3.0–4.9, and ≥5.0 g/L) [15], the frequencies of severe preeclampsia were significantly higher according to the severity of proteinuria (43%, 62%, 70%, and 84%, respectively);
maternal/neonatal morbidity compared with severe or mild proteinuria. [3] In another study including 445 women with severe preeclampsia and eclampsia, proteinuria (dipstick test > 3+) was not an independent variable of abruptio placentae but was associated with eclampsia, as assessed by univariate analysis; however, it did not remain a significant independent variable according to results of multivariate analysis. [4] Furthermore, in another study that assessed 66 women with preeclampsia who managed their condition conservatively before 32 GW and for whom proteinuria levels were measured for 24 h (proteinuria per 24 h) at least twice (when the women were pregnant) after a minimum of four days of admission, the rates of occurrence of HELLP syndrome, abruptio placentae, and cesarean delivery because of fetal distress and Apgar score at 5 min ≤6 were similar between women with proteinuria of ≥2 g/24 h and < 2 g/24 h [5]. In a previous systematic review published in 2009 with 16 primary articles and 6749 women, proteinuria level was a poor predictor of perinatal/neonatal complications in women with preeclampsia [12]. In the last decade, some reports have noted that proteinuria in women with preeclampsia was positively associated with perinatal/neonatal outcomes. In a recent report in which 293 women with preeclampsia were divided into three groups based on proteinuria/24 h (0.3–1.9 g, 2.0–4.9 g, and ≥5.0 g) [13], pregnancy duration at the onset of preeclampsia (weeks) was the longest in the 0.3–1.9 g group (35.9 ± 3.1), and decreased with increasing proteinuria severity (33.4 ± 3.6 and 31.8 ± 4.0, respectively, P < 0.001). The 0.3–1.9 g group had the lowest incidences of preterm birth (35.2% versus 76.7% and 90.8%, P < 0.001) and severe preeclampsia (61.4% versus 80.6% and 81.6%, 124
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regarding the association between proteinuria severity and maternal outcomes may not be representatives of those in other populations. For example, the incidence of peripartum cardiomyopathy (PPCM) in Japan is low: approximately 1 in 10,000–15,000 pregnancies [20], In this study, 3 women with preeclampsia had PPCM, and 1 woman without preeclampsia had had PPCM for 9 years. The incidence of PCCM was high at 1 in 726 (4/2904) in our institution in Sapporo city with approximately 1.9 million people and approximately 10,000 deliveries per year. Thus, approximately one half of pregnant women with PPCM in Sapporo city deliver in our institution representing approximately 1/ 30 of all deliveries. Moreover, CSC occurs in 1.7 per 1,00,000 women [21] and pregnant CSC women accounted for 5.8% of all cases of CSC occurring in women in a case-control study [22]. Thus, the incidence of pregnant women with CSC onset would be 0.1 per 1,00,000 pregnancies. According to the demographics in Sapporo city, at most one woman with preeclampsia should present CSC every 9 years. However, 4 women with preeclampsia in our study had CSC. Second, this was a retrospective cohort study without a control group. Further prospective case-control studies are necessary. Few of the pregnant women had both preeclampsia and proteinuria. Therefore, future multicenter prospective randomized studies are required to determine the best cutoff value for the severity of the P/C ratio at delivery for worsened perinatal/neonatal outcomes in women with preeclampsia.
however, the frequencies of severe eclampsia were similar among all groups. Furthermore, the incidences of FGR and stillbirth in the ≥5.0 g/L group (29.7% and 18.9%) were significantly higher than those in the < 0.3 g/L group (11.4% and 2.9%), respectively. The authors noted that the severity of proteinuria was not associated with severe preeclampsia once proteinuria was detected, but it was related to the severity of preeclampsia. Moreover, adverse fetal outcomes appear to be a function of prematurity rather than proteinuria itself. In the present study, a higher P/C ratio led to a higher frequency of EPB; however, the severity of the P/C ratio was not related to the frequency of FGR or stillbirth/early neonatal death. Thus, it is highly controversial whether there was an association between proteinuria severity in women with preeclampsia and perinatal/neonatal outcomes. In the present study, a higher P/C ratio led to a higher frequency of cesarean section in the univariate analysis; however, there was no association between higher P/C ratios and frequencies of perinatal/neonatal outcomes, except EPB, or between higher P/C ratios and frequencies of maternal visual symptoms (CSC) in the multivariate analysis. In our previous report [16], 4 (5.5%) of 73 women with preeclampsia were identified as having developed maternal CSC after the onset of preeclampsia; however, none of the 1808 women without preeclampsia developed CSC (P < 0.0001). The stepwise regression analysis identified four risk factors for CSC: hematocrit value > 38.0%, serum creatinine > 0.7 mg/dL, interval between diagnosed preeclampsia to delivery > 14 days, and P/C ratio > 4.5. A hematocrit value > 38.0% was finally identified as the only independent risk factor (OR, 22.9; 95%CI, 2.12–1716) for CSC in women with preeclampsia. For the risk factors of CSC in women with preeclampsia, the OR (95%CI) for a P/C ratio > 4.5was 15.7 (0.81–304) in the previous study and 17.6 (0.898–344) for a P/C ratio > 4.8 in the present study. Few pregnant women have CSC. Thus, further study of CSC in pregnant women should be conducted. In our previous study, 33 women with preeclampsia from 2001 to 2005 were divided into the PE-H group (n = 5, 16.9%), the PE-P group (n = 19, 57.6%), and the PE-S group (n = 9, 27.3%). The intervals between preeclampsia diagnosis and delivery were 1.0, 1.9, and 2.5 weeks in the PE-H, PE-P, and PE-S groups, respectively [17]. Compared to the previous study, the frequency of the PE-P group decreased to 21.3% and that of the PE-S group increased to 63.8%in the present study. Furthermore, the interval between preeclampsia diagnosis and delivery in the PE-P (5.8 days) and PE-S (5.3 days) groups was shorter compared with women from 2001 to 2005. Thus, proteinuria during pregnancy might have been overlooked in the past decade, and delays in the diagnosis of preeclampsia can easily occur. The present study has some limitations. First, the study population was small. Preeclampsia is a systemic vascular disorder (vascular endothelial dysfunction) of pregnancy characterized by hypertension in association with proteinuria, and the disorder can affect virtually every organ system causing preeclampsia-related complications such as eclampsia, HELLP syndrome, abruptio placentae, and fetal growth restriction [18]. Thus, among the women with preeclampsia, the women with massive proteinuria had high incidences of eclampsia and/or HELLP syndrome. The development of eclampsia and PRES can be prevented with magnesium sulfate treatments [19], but HELLP syndrome and AFLP cannot be prevented using medical drugs. Thus, the women with massive proteinuria in our study had high incidences of HELLP syndrome or AFLP, but not of eclampsia or PRES. Among the 94 women with preeclampsia, 19 women (20.2%) had HELLP syndrome or AFLP and only 5 women (5.3%) had eclampsia or PRES. If our study would have included more women with preeclampsia, the women with massive proteinuria would probably have had the highest incidences of eclampsia or PRES. If our study would have included more women with preeclampsia, the women with massive proteinuria would probably have had the highest incidences of eclampsia or PRES. In addition, our calculation of the incidence of preeclampsia (3.2%, 94/2904) was similar to published incidences around the world, but our results
5. Conclusion A higher P/C ratio at delivery in women with preeclampsia might cause EPB and maternal CSC. The best P/C ratio cutoff value at delivery for worsened perinatal outcomes of women with preeclampsia is 4.8. Conflicts of interest statement The authors report no conflicts of interest. Funding information None. 8. Key message The best protein:creatinine ratio cutoff values of early preterm birth and maternal central serous chorioretinopathy with preeclampsia were 4.1 and 4.8, respectively, as assessed by multivariate analysis. Acknowledgement The authors would like to thank Enago (www.enago.jp) for the English language review. Tweetable abstract The best P/C ratio cutoff value at delivery to detect early preterm birth and CSC in women with preeclampsia is 4.8. References [1] A.A. Al-Mulhim, A. Abu-Heija, F. Al-Jamma, El-H.A. El-Harith, Pre-eclampsia: maternal risk factors and perinatal outcome, Fetal Diagn. Ther. 18 (2003) 275–280. [2] P. Deruelle, E. Coudoux, A. Ego, V. Houfflin-Debarge, X. Codaccioni, D. Subtil, Risk factors for post-partum complications occurring after preeclampsia and HELLP syndrome. A study in 453 consecutive pregnancies, Eur. J. Obstet. Gynecol. Reprod. Biol. 125 (2006) 59–65. [3] M.G. Newman, A.G. Robichaux, C.M. Stedman, et al., Perinatal outcomes in preeclampsia that is complicated by massive proteinuria, Am. J. Obstet. Gynecol. 188 (2003) 264–268. [4] A.G. Witlin, G.R. Saade, F. Mattar, B.M. Sibai, Risk factors for abruptio placentae
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Severe proteinuria as a parameter of worse perinatal/neonatal outcomes in women with preeclampsia
T
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Mamoru Morikawa , Michinori Mayama, Yoshihiro Saito, Kinuko Nakagawa-Akabane, Takeshi Umazume, Kentaro Chiba, Satoshi Kawaguchi, Kazutoshi Cho, Hidemichi Watari Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
A R T I C LE I N FO
A B S T R A C T
Keywords: Preeclampsia Proteinuria Pulmonary edema Central serous chorioretinopathy Preterm birth
Objectives: The present study aimed to determine the relationship between the severity of proteinuria and maternal/neonatal outcomes among women with preeclampsia. Study design: Proteinuria severity was measured at preeclampsia diagnosis and at delivery in 94 women with preeclampsia (among 2904 women with singleton pregnancies, who delivered after 22 gestational weeks). Preeclampsia was defined as hypertension with proteinuria. Main outcome measures: Protein:creatinine (P/C) ratio to worse the maternal outcome was 4.8 among women with preeclampsia. Results: The frequencies of HELLP syndrome and maternal pulmonary edema in women with a P/C ratio ≥5.0 (35.5% and 35.5%, respectively) were significantly higher than those in women with a P/C ratio < 5.0 (12.7%, P = 0.014 and 6.4%, P < 0.001, respectively). The best P/C ratio cutoff value to determine early-onset preeclampsia and early preterm birth (EPB) was 4.1 (P < 0.001 and P < 0.001, respectively). The best P/C ratio cutoff values to determine the interval between the preeclampsia diagnosis and delivery < 7 days and the need to undergo cesarean section were 1.8 and 1.5, respectively. The best P/C ratio cutoff value to determine maternal pulmonary edema and central serous chorioretinopathy (CSC) was 4.8 (P = 0.020 and P = 0.014, respectively). Finally, the best P/C ratio cutoff values to determine EPB and maternal CSC in women with preeclampsia were 4.1 (odds ratio, 10.9; 95% confidence interval; 4.08 to 29.2, P < 0.0001) and 4.8 (odds ratio, 17.6; 95% confidence interval; 0.898 to 344, P = 0.0008), respectively, according to the multivariate analysis. Conclusions: A higher P/C ratio at delivery in women with preeclampsia might cause EPB and CSC.
1. Introduction Over the past two decades, proteinuria during pregnancy has not been considered significant. Previous studies [1,2] have reported that severe proteinuria was associated with severe perinatal outcomes among women with preeclampsia. Conversely, other previous studies [3–5] have reported no relation between severe proteinuria and severe perinatal outcomes among women with preeclampsia. The American College of Obstetricians and Gynecologists (ACOG) defined proteinuria/24 h ≥5.0 g as severe proteinuria. In Japan, women with severe preeclampsia who develop severe proteinuria are recommended to consider undergoing induced delivery at ≥37 GW [6].
However, in 2013, the ACOG removed the severity criteria of proteinuria from the diagnostic criteria for preeclampsia [7]. Thus, in 2015, the Japan Society for the Study of Hypertension in Pregnancy recommended that the termination of pregnancy among women with conservatively managed preeclampsia is not necessary merely because they have severe proteinuria. In 2018, the International Society for the Study of Hypertension in Pregnancy (ISSHP) defined presence of proteinuria is not necessary to diagnose preeclampsia [8]. In the current Japanese criteria for “Hypertension disorders in pregnancy” since 2018, preeclampsia was defined as onset hypertension since 20 GW with one or more other maternal complication(s) following proteinuria, including liver dysfunction without underlying liver diseases, perinatal
Abbreviations: AUC, area under curve; AFLP, acute fatty liver of pregnancy; BP, blood pressure; CI, confidence interval; CSC, central serous chorioretinopathy; EPB, early preterm birth; FGR, fetal growth restriction; GW, gestational weeks; OR, odds ratio; P/C, protein:creatinine ratio; PPCM, peripartum cardiomyopathy; PRES, posterior reversible encephalopathy syndrome ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Hokkaido University Graduate School of Medicine, Kita-ku N15 W7, Sapporo 060-8638, Japan. E-mail address: [email protected] (M. Morikawa). https://doi.org/10.1016/j.preghy.2019.12.013 Received 2 August 2019; Received in revised form 12 December 2019; Accepted 23 December 2019 Available online 10 January 2020 2210-7789/ © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
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(AFLP), eclampsia, posterior reversible encephalopathy syndrome (PRES), pulmonary edema, peripartum cardiomyopathy (PPCM), abruptio placentae; and 4) non-reassuring fetal state on cardiotocography and biophysical profile score on ultrasonography. In addition, termination was discussed in the presence of severe proteinuria (P/C ratio ≥5.0) or kidney dysfunction (glomerular filtration rate < 50 mL/ min/1.73 m2) or maternal blood examination abnormalities (low platelet counts or antithrombin activity, high AST/ALT/LDH, etc.). 2.3. Statistical analyses Data are shown as the mean ± SD or frequencies. The statistical analyses were performed using the statistical software JMP Pro, version 14.0 (SAS Institute Inc., Cary, NC, USA). Tukey–Kramer HSD (honestly significant difference) tests or student ttests were used to compare means. Fisher’s exact test was used to compare categorical variables. Pearson’s product–moment correlation coefficient was used to measure linear correlations between two variables. A stepwise multiple logistic regression was used in the multivariate analysis to compare parameters with P < 0.1 in the univariate analysis. Receiver operating characteristic (ROC) curves were used to assess the ability of parameters to differentiate the onset of perinatal/ neonatal complications. In all analyses, P < 0.05 indicated statistical significance. Both a P value less than 0.05 and a correlation coefficient (r) greater than 0.25 or less than −0.25 were required to indicate statistical significance for linear correlations.
Fig. 1. Study flowchart of women with preeclampsia.
progressive kidney dysfunction, perinatal cerebral stroke or neuropathy, blood coagulation disorder, and uterus/placental dysfunction (fetal growth restriction; FGR, stillbirth without fetal chromosomal abnormality, or fetal anomalad/fetal anomalies) [9]. The present study aimed to determine the association between proteinuria severity and perinatal/neonatal outcomes. Thus, in the present study, preeclampsia was defined as hypertension with proteinuria, according to the previous criteria of the Japan Society of Obstetrics and Gynecology (JSOG) [10]. 2. Material and methods
2.4. Ethical approval
This retrospective hospital cohort study was conducted at the Hokkaido University Hospital between January 2009 and December 2017. TP levels and proteinuria were measured at the time of preeclampsia diagnosis and at delivery in the 94 women with preeclampsia (among 2904 singleton pregnancies) who delivered at ≥22 GWs (Fig. 1).
This study was conducted after receiving approval from the Institutional Review Board of Hokkaido University Hospital (No. 017405, No. 015-115). All women provided informed consent prior to participation in the study.
2.1. Diagnosis of preeclampsia
3.1. Characteristics of women with preeclampsia
Preeclampsia was diagnosed according to the classical criteria of JSOG [10]. Hypertension was defined as systolic blood pressure (BP) ≥140 mmHg and/or diastolic BP ≥90 mmHg; gestational hypertension was defined as hypertension occurring on/after 20 GW in the absence of significant proteinuria defined as a spot-urine protein:creatinine (P/C) ratio > 0.27 or > 0.3 g/24 h urine collection. Preeclampsia was diagnosed in women who developed both hypertension and significant proteinuria on/after 20 GW. Women with superimposed preeclampsia (chronic hypertension or proteinuria as an underlying disease at < 20 GW) were excluded in the present study. A final diagnosis of preeclampsia required the absence of both hypertension and proteinuria at 12 weeks after delivery.
Proteinuria severity was measured in 94 women with preeclampsia (3.2%) at preeclampsia diagnosis and at delivery. Table 1 shows the characteristics of the women with preeclampsia. Fig. 2 shows the associations of the main parameters among all women with preeclampsia. There was a positive association between GW at preeclampsia diagnosis and GW at delivery (r = 0.980, P < 0.001, Fig. 2A) and between proteinuria at preeclampsia diagnosis and proteinuria at delivery (r = 0.758, P < 0.001, Fig. 2D). Proteinuria severity was negatively associated with GW at preeclampsia diagnosis (r = 0.280, P = 0.005, Fig. 2B) and at delivery (r = 0.439, P < 0.001, Fig. 2C). The interval between preeclampsia diagnosis and delivery was positively related to proteinuria at delivery (r = 0.326, P = 0.001, Fig. 2F); however, there was no relation to proteinuria at preeclampsia diagnosis (r = 0.000, P = 0.931, Fig. 2E). Furthermore, at delivery, proteinuria severity was positively associated with systolic (r = 0.267, P = 0.009) and diastolic (r = 0.333, P = 0.011) BP.
3. Results
2.2. Management and termination of pregnancy among women with preeclampsia All women with preeclampsia were admitted to the Hokkaido University Hospital for treatment, and preeclampsia management (proteinuria measurements and blood examinations once or twice per week) were performed according to the recommendations of the JSOG guidelines [6]. Pregnancy was terminated if maternal and fetal well-being deteriorated to the point where the pregnancy could not be continued [6]: 1) severe hypertension (systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg) without effective antihypertensive agents; 2) emergent hypertension (systolic BP ≥180 mmHg and/or diastolic BP ≥120 mmHg); 3) HELLP syndrome, acute fatty liver of pregnancy
3.2. Characteristics of women with P/C ratios of < 5.0 and ≥5.0 at delivery The 94 women were divided into those with a P/C ratio (or proteinuria/24 h) at delivery < 5.0 (< 5.0 group, n = 63) and those with a P/C ratio ≥5.0 (≥5.0 group, n = 31) (Table 1). The frequencies of early-onset preeclampsia (< 34 GW at preeclampsia diagnosis) and EPB (< 34GW at delivery) in ≥5.0 group (67.7% and 64.5%, respectively) were significantly higher than those in < 5.0 group (27.0% and 23.8%, P < 0.001, respectively). The frequencies of women with severe 120
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Table 1 Characteristics of the 94 women with preeclampsia (PE). Overall (n = 94)
P/C ratio at delivery < 5.0 (n = 63)
P/C ratio at delivery ≥5.0 (n = 31)
P-value
Age (years) Primipara (%) BMI before pregnancy
33.9 ± 5.3 66 (70.2%) 22.0 ± 4.4
34.4 ± 5.3 41 (65.1%) 22.6 ± 4.7
32.6 ± 5.1 25 (80.7%) 20.9 ± 3.5
0.112 0.153 0.061
At preeclampsia diagnosis GW (weeks) Early-onset preeclampsia (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg)
33.9 ± 5.1 38 (40.3%) 158.6 ± 14.1 96.9 ± 9.8 2.36 ± 2.68 1.19 ± 1.37
36.0 ± 4.1 17 (27.0%) 160.0 ± 14.3 96.3 ± 10.3 1.18 ± 1.16 1.10 ± 1.46
32.2 ± 4.7 21 (67.7%) 155.7 ± 13.5 98.1 ± 8.5 4.77 ± 3.26 1.34 ± 1.18
< 0.001 < 0.001 0.155 0.366 < 0.001 0.409
At delivery GW (weeks) Preterm birth (GW < 37) (%) Early preterm birth (GW < 34) (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg) Interval between preeclampsia diagnosis to delivery < 7 days (%)
34.7 ± 4.6 53 (56.4%) 35 (37.2%) 170.2 ± 16.8 100.9 ± 11.6 4.01 ± 4.28 1.19 ± 1.37 5.9 ± 7.7 63 (67.0%)
36.0 ± 4.1 27 (42.9%) 15 (23.8%) 168.4 ± 17.8 99.0 ± 12.2 1.66 ± 1.38 1.16 ± 1.87 4.7 ± 6.7 45 (71.4%)
32.2 ± 4.7 26 (83.9%) 20 (64.5%) 173.8 ± 14.1 104.8 ± 9.1 8.79 ± 4.19 2.88 ± 2.24 6.7 ± 9.0 18 (58.1%)
< 0.001 < 0.001 < 0.001 0.118 0.011 < 0.001 < 0.001 0.0495 0.245
Perinatal outcomes Cesarean section (%) HELLP syndrome or AFLP (%) Abruptio placentae (%) Eclampsia or PRES (%) Pulmonary edema (%) PPCM (%) CSC (%) Maternal death (%)
75 (79.8%) 19 (20.2%) 3 (3.2%) 5 (5.3%) 15 (16.0%) 3 (3.2%) 4 (4.3%) 0 (0.0%)
47 (74.6%) 8 (12.7%) 2 (3.2%) 2 (3.2%) 4 (6.4%) 1 (1.6%) 1 (1.6%) 0 (0.0%)
28 (90.3%) 11 (35.5%) 1 (3.2%) 3 (9.7%) 11 (35.5%) 2 (6.5%) 3 (9.7%) 0 (0.0%)
0.102 0.014 1.000 0.327 < 0.001 0.252 0.103 1.000
Neonatal outcomes Birthweight SD Light-for-date infant (%) Apgar score < 8 at 5 min (%) Stillbirth or END (%)
−1.16 ± 1.46 29 (30.9%) 13 (13.8%) 7 (7.5%)
−0.96 ± 1.53 17 (27.0%) 8 (12.7%) 3 (4.8%)
−1.55 ± 1.23 12 (38.7%) 5 (16.1%) 4 (12.9%)
0.049 0.342 0.753 0.213
Data are presented as the mean ± SD. PE, preeclampsia; GW, gestational weeks; BMI, body mass index; P/C, protein:creatinine; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; SD, standard division; END, early neonatal death. Early-onset preeclampsia, GW at preeclampsia diagnosis < 34 GW; Early preterm birth, GW at delivery < 34 GW.
hypertension and emergent severe hypertension at delivery in ≥5.0 group were similar to those in < 5.0 group (data not shown in Table 1). The frequencies of HELLP syndrome or AFLP and pulmonary edema in ≥5.0 group (35.5% and 35.5%, respectively) were significantly higher than those in < 5.0 group (12.7%, P = 0.014, and 6.4%, P < 0.001, respectively). However, the frequencies of abruptio placentae, eclampsia or PRES, PPCM, and maternal central serous chorioretinopathy (CSC) were similar in both groups. The birthweight SD in ≥5.0 group (−1.55 ± 1.23) was significantly lower than that in < 5.0 group (0.96 ± 1.53, P = 0.049). However, the frequencies of light-fordate infants (with newborn birthweight SD based on normative birthweight for Japanese newborns [11] ≤−1.5) were similar in both groups.
The cutoff to determine maternal pulmonary edema and CSC was 4.8 (Fig. 3E and F). Those AUCs were 0.736 and 0.838 (P = 0.020 and 0.014, respectively), and the ORs (95% CIs) were 11.8 (3.02–46.1) and 17.6 (0.898–344), respectively (Table 2). According to the multivariate analysis, EPB and CSC were the perinatal outcomes used to determine the cutoff values in preeclampsia (P < 0.001 and P < 0.001, respectively). In Table 1, the mean diastolic BP at delivery in women with a P/C ratio ≥5.0 was significantly higher than that in women with a P/C ratio < 5.0 (P = 0.011). Based on ROC curves, the diastolic BP cutoff values at delivery to determine early preterm birth (EPB) and central serous chorioretinopathy (CSC) were 97 mmHg and 105 mmHg, respectively. The cutoff values for EPB and CSC corresponded to areas under the curve (AUC) at 0.655 and 0.806 (P = 0.015 and P = 0.041, respectively) and ORs (95% CI) at 5.00 (1.81–13.8) and 15.3 (0.780–297), respectively. However, according to the multivariate analysis, the variable associated with EPB and CSC was the P/C ratio at delivery (P < 0.001 and P < 0.001, respectively), not the diastolic BP at delivery. Thus, the diastolic BP at delivery was not a confounding factor at delivery for maternal outcomes among women with preeclampsia.
3.3. The best P/C ratio cutoff in preeclampsia to determine perinatal/ neonatal outcomes The best P/C ratio cutoff values in women with preeclampsia to determine perinatal/neonatal outcomes based on ROC curves are shown in Fig. 3 and Table 2. The cutoff value to determine early-onset preeclampsia and EPB were 4.1 (Fig. 3A and B). That ratio corresponded to areas under the curve (AUC) of 0.773 and 0.800 (P < 0.001, respectively) and odds ratios (ORs) (95% confidence interval, CI) of 9.97 (3.79–26.2) and10.9 (4.08–29.2), respectively (Table 2). The cutoff values to determine the interval between preeclampsia diagnosis and delivery < 7 days and need for cesarean section were 1.8 and 1.5, respectively (Fig. 3C and D).
3.4. P/C ratio at delivery according to initial symptoms of preeclampsia before or at preeclampsia diagnosis The 94 women with preeclampsia were divided into three groups based on the initial symptoms of preeclampsia before or at 121
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Fig. 2. Relationships of the main parameters among the94 women with preeclampsia. A. GW at preeclampsia diagnosis and at delivery. B. GW and proteinuria at preeclampsia diagnosis. C. GW and proteinuria at delivery. D. Proteinuria at preeclampsia diagnosis and at delivery. E. Proteinuria at preeclampsia diagnosis and interval between preeclampsia diagnosis and delivery. F. Proteinuria at delivery and interval between at preeclampsia diagnosis and delivery. Abbreviations: PE, preeclampsia; GW, gestational weeks; P/C, protein:creatinine.
perinatal/neonatal outcomes among women with preeclampsia based on an ROC curve of the P/C ratio at delivery. In general, we think that severe proteinuria hastens pregnancy termination among women with preeclampsia. However, in our study, the interval between preeclampsia diagnosis and delivery was positively associated with the proteinuria at delivery (Fig. 2F) but not with the proteinuria at preeclampsia diagnosis (Fig. 2E). This could be because of obstetricians trying to lengthen pregnancy periods of women with preeclampsia, so that their proteinuria would be severe by the time they finally deliver. Obstetricians usually consider hypertension a more important factor than proteinuria while deciding whether to terminate a pregnancy (particularly in women with early-onset preeclampsia). Thus, more attention should be paid to proteinuria severity in women with preeclampsia. In this study, the best P/C ratio cutoff values in preeclampsia to determine EPB and maternal CSC were 4.1 and 4.8, respectively, according to the ROC curves and multivariate analysis (Table 2). Specifically, the results indicate that the best cutoff value of the P/C ratio at delivery for worsened perinatal outcomes in women with preeclampsia is 4.8. The findings from the results of the present study would be useful for the prediction and/or prevention of severe maternal outcomes in women with severe preeclampsia. The present study has three major strengths. First, the P/C ratio was measured both at preeclampsia diagnosis and at delivery in all women with preeclampsia included in the study population. Second, preeclampsia was diagnosed in all cases based on both gestational hypertension and proteinuria. Therefore, there was little variation in the P/C ratio despite the retrospective nature of the study. Last, this was a single hospital cohort study. Thus, the present study had no bias in perinatal/neonatal outcomes due to differences in the management of preeclampsia in participating facilities of a multicenter study.
preeclampsia diagnosis (Table 3): 14 (14.9%) in the PE-H group (preeclampsia developed from new-onset hypertension in the absence of proteinuria), 20 (21.3%) in the PE-P group (preeclampsia developed from new-onset proteinuria in the absence of hypertension), and 60 (63.8%) in the PE-S group (preeclampsia exhibited both proteinuria and hypertension simultaneously). The P/C ratio at preeclampsia diagnosis in the PE-P group (3.73 ± 2.33) was significantly higher than that of the PE-H group (0.83 ± 0.97, P = 0.005). The P/C ratios at delivery were similar among the three groups; however, frequency of women with P/C ratio at diagnosed preeclampsia was ≥4.8 in the PE-P group (60.0%) was significantly higher than that of the PE-H group (21.4%, P = 0.026). The interval between the preeclampsia diagnosis and delivery of the three groups was similar (9.2 ± 5.6, 5.8 ± 9.0, and 5.3 ± 7.6 days in the PE-H, PE-P, and PE-S groups, respectively); however, the frequencies of women with the interval between the preeclampsia diagnosis and delivery was < 7 days in the PE-P (80.0%) and PE-S (71.7%) groups were significantly higher than that of the PE-H group (28.6%, P = 0.003 and 0.003, respectively). Both perinatal/ neonatal outcomes were similar among all groups. 4. Discussion The results of the present study emphasized the following three points: 1) the frequencies of HELLP syndrome and maternal pulmonary edema in women with a P/C ratio ≥5.0 were significantly higher than in women with a P/C ratio < 5.0; 2) the best P/C ratio cutoff values in preeclampsia to determine EPB and maternal CSC were 4.1 and 4.8, respectively, according to the multivariate analysis; and 3) perinatal/ neonatal outcomes were similar in the three groups based on the initial symptoms of preeclampsia before or at preeclampsia diagnosis. To our knowledge, this is the first study to demonstrate the relationship between the severity of the P/C ratio at delivery and 122
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Fig. 3. Receiver operating characteristic (ROC)of the P/C ratio at delivery and perinatal/neonatal outcomes. A. P/C ratio cutoff value to determine early-onset preeclampsia. B. P/C ratio cutoff value to determine early preterm birth. C. P/C ratio cutoff value to determine interval between preeclampsia diagnosis and delivery < 7 days. D. P/C ratio cutoff value to determine the need to undergo cesarean section. E. P/C ratio cutoff value to determine the onset of maternal pulmonary edema. F. P/C ratio cutoff value to determine the onset of maternal CSC. Abbreviations: PE, preeclampsia; P/C, protein:creatinine; AUC, area under curve; CSC, central serous chorioretinopathy.
of the five risk factors for maternal postpartum complications, as assessed by a stepwise logistic regression. [2] Conversely, in one study, 209 women with preeclampsia who delivered at < 37 gestational weeks (GW) were divided according to their proteinuria levels: mild proteinuria (< 5g/24 h), severe proteinuria (5–9.9 g/24 h), and massive proteinuria (≥10 g/24 h); massive proteinuria appeared to be a marker for early-onset preeclampsia and progression to severe preeclampsia. However, massive proteinuria did not result in increased
Some previous studies, conducted from 1996 to 2006, have reported that severe proteinuria is associated with severe perinatal outcomes among women with preeclampsia, and others have reported that severe proteinuria is not associated them. In a study including 685 women with preeclampsia, stillbirths and neonatal deaths appeared to be associated with women whose proteinuria amounted to or exceeded 3 g/ 24 h. [1] In another study including 453 women with preeclampsia and/or HELLP syndrome, proteinuria of > 5 g/L (500 mg/dL) was one
Table 2 Relationship between the P/C ratio cutoff value at delivery based on the ROC curve and perinatal/neonatal outcomes. P/C ratio cutoff value at delivery
Odds ratio
95% CI
AUC
Sensitivity
Specificity
PPV
NPV
Univariate analysis P value
Multivariate analysis P value
4.1 4.1 1.8
9.97 10.9 2.97
3.79–26.2 4.08–29.2 1.16–7.63
0.7733 0.8002 0.6249
0.773 0.800 0.508
0.682 0.714 0.742
0.772 0.694 0.800
0.793 0.828 0.426
< 0.0001 < 0.0001 0.0082
< 0.0001
Perinatal outcomes Cesarean section HELLP syndrome or AFLP Abruptio placentae Eclampsia or PRES Pulmonary edema PPCM CSC
1.5 5.4 26.5 7.0 4.8 4.8 4.8
9.03 3.78 45.5 6.84 11.8 12.7 17.6
2.69–30.3 1.33–10.8 0.708–2924 1.06–44.4 3.02–46.1 0.617–262 0.898–344
0.7284 0.6379 0.5788 0.5573 0.7363 0.7747 0.8375
0.707 0.579 0.333 0.600 0.800 1.000 1.000
0.789 0.733 1.000 0.820 0.747 0.681 0.689
0.930 0.355 1.000 0.158 0.375 0.094 0.124
0.405 0.873 0.978 0.973 0.952 1.000 1.000
0.0015 0.2948 0.0578 0.5666 0.0204 0.3717 0.0142
Neonatal outcomes Light-for-date infant Stillbirth or END
1.0 1.2
3.20 9.29
1.08–9.46 0.510–169
0.6109 0.6535
0.828 1.000
0.400 0.402
0.381 0.119
0.839 1.000
0.0784 0.6239
Early-onset preeclampsia Early preterm birth Interval between preeclampsia diagnosis and delivery < 7 days
0.0008
P/C, protein:creatinine; ROC, receiver operating characteristic; CI, confidence interval; AUC, area under the curve; PPV, positive predictive value; NPV, negative predictive value; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; END, early neonatal death. 123
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Table 3 Overall and subgroup characteristics of the women with preeclampsia (PE). Overall (n = 94)
PE-H group (n = 14)
PE-P group (n = 20)
PE-S group (n = 60)
Age (years) Primipara (%) BMI before pregnancy
33.9 ± 5.3 66 (70.2%) 22.0 ± 4.4
35.6 ± 4.6 9 (64.3%) 23.0 ± 2.9
32.8 ± 5.7 14 (70.0%) 20.3 ± 2.6
33.9 ± 5.3 43 (71.7%) 22.4 ± 5.1
At preeclampsia diagnosis GW (weeks) Early-onset preeclampsia (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg)
33.9 ± 5.1 38 (40.4%) 158.6 ± 14.1 96.9 ± 9.8 2.36 ± 2.68 1.19 ± 1.37
33.8 ± 4.5 5 (35.7%) 159.7 ± 14.3 96.9 ± 7.8 0.83 ± 0.97 0.40 ± 0.48
34.0 ± 3.9 9 (45.0%) 115.9 ± 9.8 96.8 ± 7.2 3.73 ± 2.33 * 1.15 ± 1.50
33.9 ± 5.6 24 (40.0%) 159.3 ± 15.3 96.9 ± 11.0 2.26 ± 2.86 1.15 ± 1.06
At delivery GW (weeks) Preterm birth (GW < 37) (%) Early preterm birth (GW < 34) (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) P/C ratio Weight gain of last 1 week (kg) Interval between preeclampsia diagnosis and delivery (days) < 7 days (%)
34.7 ± 4.6 53 (56.4%) 35 (37.2%) 170.2 ± 16.8 100.9 ± 11.6 4.01 ± 4.28 1.73 ± 2.15 5.9 ± 7.7 63 (67.0%)
35.1 ± 4.3 9 (64.3%) 4 (28.6%) 178.4 ± 14.9 101.1 ± 11.5 2.85 ± 2.63 0.72 ± 1.45 9.2 ± 5.6 4 (28.6%)
34.8 ± 3.2 15 (75.0%) 8 (40.0%) 165.0 ± 13.2 102.3 ± 8.0 5.11 ± 3.44 2.05 ± 1.89 5.8 ± 9.0 16 (80.0%) †
34.6 ± 5.1 29 (48.3%) 23 (38.3%) 170.1 ± 17.7 100.4 ± 12.7 3.92 ± 4.77 1.86 ± 2.32 5.3 ± 7.6 43 (71.7%) ‡
75 (79.8%) 19 (20.2%)
16 (80.0%) 5 (25.0%) 1 (5.0%) 1 (5.0%) 3 (15.0%) 1 (5.0%) 2 (10.0%) 0 (0.0%)
46 (76.7%) 11 (18.3%) 2 (3.3%) 3 (5.0%) 9 (15.0%) 2 (3.3%) 2 (3.3%) 0 (0.0%)
−1.39 ± 1.33 8 (40.0%) 2 (10.0%) 1 (5.0%)
−1.04 ± 1.55 17 (28.3%) 10 (16.7%) 5 (8.3%)
Perinatal outcomes Cesarean section (%) HELLP syndrome or AFLP (%) Abruptio placentae (%) Eclampsia or PRES (%) Pulmonary edema (%) PPCM (%) CSC (%) Maternal death (%)
5 (5.3%) 15 (16.0%) 3 (3.2%) 4 (4.3%) 0 (0.0%)
13 (92.9%) 3 (21.4%) 0 (0.0%) 1 (7.1%) 3 (21.4%) 0 (0.0%) 0 (0.0%) 0 (0.0%)
Neonatal outcomes Birthweight SD Light-for-date infant (%) Apgar score < 8 at 5 min (%) Stillbirth or END (%)
−1.16 ± 1.46 29 (30.9%) 13 (13.8%) 87 (92.6%)
−1.33 ± 1.25 4 (28.6%) 1 (7.1%) 1 (7.1%)
Data are shown as the mean ± SD. PE, preeclampsia; GW, gestational weeks; BMI, body mass index; BP, blood pressure; P/C, protein:creatinine; SD, standard deviation; AFLP, acute fatty liver of pregnancy; PRES, posterior reversible encephalopathy syndrome; PPCM, peripartum cardiomyopathy; CSC, central serous chorioretinopathy; END, early neonatal death. *P = 0.0047 versus PE-H group, †P = 0.0027 versus PE-H group, ‡P = 0.0026 versus PE-H group.
P = 0.002), respectively. The authors mentioned that quantifying the severity of proteinuria could identify the subgroup of women with preeclampsia and an increased risk of adverse outcomes. However, the frequencies of HELLP syndrome, eclampsia, abruptio placentae, visual symptoms, respiratory symptoms, FGR, and stillbirth were similar among the three groups. In another report, [14] compared with 60 women with preeclampsia and proteinuria 300–499 mg/24 h, the GW at delivery of 161 women with preeclampsia and proteinuria ≥500 mg/24 h was earlier (33.2 versus 37.3 weeks, P < 0.001); the latter group also had significantly higher frequencies of preterm delivery (61.5% versus 25.0%, P < 0.001), EPB (26.7% versus 13.3%, P < 0.05), and cesarean section (78.3% versus 48.3%, P < 0.001). Thus, the authors noted that women with proteinuria ≥500 mg/24 h should be considered at a substantially greater risk of pregnancy complications than women with proteinuria of 300 mg/24 h. Japanese guidelines recommend admission for women with preeclampsia and proteinuria (P/C ratio > 0.3) [6]. In the same study [14], compared with women managed as outpatients (non-proteinuric women with chronic hypertension or women with gestational hypertension), women with preeclampsia and proteinuria 300–499 mg/24 h had higher rates of complications. The authors noted that the use of the 300 mg/24 h threshold for proteinuria in clinical practice as guidance for admission appeared appropriate and should be continued. In another report of 239 women with preeclampsia who were divided into four groups based on proteinuria/24 h (< 0.3, 0.3–2.9, 3.0–4.9, and ≥5.0 g/L) [15], the frequencies of severe preeclampsia were significantly higher according to the severity of proteinuria (43%, 62%, 70%, and 84%, respectively);
maternal/neonatal morbidity compared with severe or mild proteinuria. [3] In another study including 445 women with severe preeclampsia and eclampsia, proteinuria (dipstick test > 3+) was not an independent variable of abruptio placentae but was associated with eclampsia, as assessed by univariate analysis; however, it did not remain a significant independent variable according to results of multivariate analysis. [4] Furthermore, in another study that assessed 66 women with preeclampsia who managed their condition conservatively before 32 GW and for whom proteinuria levels were measured for 24 h (proteinuria per 24 h) at least twice (when the women were pregnant) after a minimum of four days of admission, the rates of occurrence of HELLP syndrome, abruptio placentae, and cesarean delivery because of fetal distress and Apgar score at 5 min ≤6 were similar between women with proteinuria of ≥2 g/24 h and < 2 g/24 h [5]. In a previous systematic review published in 2009 with 16 primary articles and 6749 women, proteinuria level was a poor predictor of perinatal/neonatal complications in women with preeclampsia [12]. In the last decade, some reports have noted that proteinuria in women with preeclampsia was positively associated with perinatal/neonatal outcomes. In a recent report in which 293 women with preeclampsia were divided into three groups based on proteinuria/24 h (0.3–1.9 g, 2.0–4.9 g, and ≥5.0 g) [13], pregnancy duration at the onset of preeclampsia (weeks) was the longest in the 0.3–1.9 g group (35.9 ± 3.1), and decreased with increasing proteinuria severity (33.4 ± 3.6 and 31.8 ± 4.0, respectively, P < 0.001). The 0.3–1.9 g group had the lowest incidences of preterm birth (35.2% versus 76.7% and 90.8%, P < 0.001) and severe preeclampsia (61.4% versus 80.6% and 81.6%, 124
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regarding the association between proteinuria severity and maternal outcomes may not be representatives of those in other populations. For example, the incidence of peripartum cardiomyopathy (PPCM) in Japan is low: approximately 1 in 10,000–15,000 pregnancies [20], In this study, 3 women with preeclampsia had PPCM, and 1 woman without preeclampsia had had PPCM for 9 years. The incidence of PCCM was high at 1 in 726 (4/2904) in our institution in Sapporo city with approximately 1.9 million people and approximately 10,000 deliveries per year. Thus, approximately one half of pregnant women with PPCM in Sapporo city deliver in our institution representing approximately 1/ 30 of all deliveries. Moreover, CSC occurs in 1.7 per 1,00,000 women [21] and pregnant CSC women accounted for 5.8% of all cases of CSC occurring in women in a case-control study [22]. Thus, the incidence of pregnant women with CSC onset would be 0.1 per 1,00,000 pregnancies. According to the demographics in Sapporo city, at most one woman with preeclampsia should present CSC every 9 years. However, 4 women with preeclampsia in our study had CSC. Second, this was a retrospective cohort study without a control group. Further prospective case-control studies are necessary. Few of the pregnant women had both preeclampsia and proteinuria. Therefore, future multicenter prospective randomized studies are required to determine the best cutoff value for the severity of the P/C ratio at delivery for worsened perinatal/neonatal outcomes in women with preeclampsia.
however, the frequencies of severe eclampsia were similar among all groups. Furthermore, the incidences of FGR and stillbirth in the ≥5.0 g/L group (29.7% and 18.9%) were significantly higher than those in the < 0.3 g/L group (11.4% and 2.9%), respectively. The authors noted that the severity of proteinuria was not associated with severe preeclampsia once proteinuria was detected, but it was related to the severity of preeclampsia. Moreover, adverse fetal outcomes appear to be a function of prematurity rather than proteinuria itself. In the present study, a higher P/C ratio led to a higher frequency of EPB; however, the severity of the P/C ratio was not related to the frequency of FGR or stillbirth/early neonatal death. Thus, it is highly controversial whether there was an association between proteinuria severity in women with preeclampsia and perinatal/neonatal outcomes. In the present study, a higher P/C ratio led to a higher frequency of cesarean section in the univariate analysis; however, there was no association between higher P/C ratios and frequencies of perinatal/neonatal outcomes, except EPB, or between higher P/C ratios and frequencies of maternal visual symptoms (CSC) in the multivariate analysis. In our previous report [16], 4 (5.5%) of 73 women with preeclampsia were identified as having developed maternal CSC after the onset of preeclampsia; however, none of the 1808 women without preeclampsia developed CSC (P < 0.0001). The stepwise regression analysis identified four risk factors for CSC: hematocrit value > 38.0%, serum creatinine > 0.7 mg/dL, interval between diagnosed preeclampsia to delivery > 14 days, and P/C ratio > 4.5. A hematocrit value > 38.0% was finally identified as the only independent risk factor (OR, 22.9; 95%CI, 2.12–1716) for CSC in women with preeclampsia. For the risk factors of CSC in women with preeclampsia, the OR (95%CI) for a P/C ratio > 4.5was 15.7 (0.81–304) in the previous study and 17.6 (0.898–344) for a P/C ratio > 4.8 in the present study. Few pregnant women have CSC. Thus, further study of CSC in pregnant women should be conducted. In our previous study, 33 women with preeclampsia from 2001 to 2005 were divided into the PE-H group (n = 5, 16.9%), the PE-P group (n = 19, 57.6%), and the PE-S group (n = 9, 27.3%). The intervals between preeclampsia diagnosis and delivery were 1.0, 1.9, and 2.5 weeks in the PE-H, PE-P, and PE-S groups, respectively [17]. Compared to the previous study, the frequency of the PE-P group decreased to 21.3% and that of the PE-S group increased to 63.8%in the present study. Furthermore, the interval between preeclampsia diagnosis and delivery in the PE-P (5.8 days) and PE-S (5.3 days) groups was shorter compared with women from 2001 to 2005. Thus, proteinuria during pregnancy might have been overlooked in the past decade, and delays in the diagnosis of preeclampsia can easily occur. The present study has some limitations. First, the study population was small. Preeclampsia is a systemic vascular disorder (vascular endothelial dysfunction) of pregnancy characterized by hypertension in association with proteinuria, and the disorder can affect virtually every organ system causing preeclampsia-related complications such as eclampsia, HELLP syndrome, abruptio placentae, and fetal growth restriction [18]. Thus, among the women with preeclampsia, the women with massive proteinuria had high incidences of eclampsia and/or HELLP syndrome. The development of eclampsia and PRES can be prevented with magnesium sulfate treatments [19], but HELLP syndrome and AFLP cannot be prevented using medical drugs. Thus, the women with massive proteinuria in our study had high incidences of HELLP syndrome or AFLP, but not of eclampsia or PRES. Among the 94 women with preeclampsia, 19 women (20.2%) had HELLP syndrome or AFLP and only 5 women (5.3%) had eclampsia or PRES. If our study would have included more women with preeclampsia, the women with massive proteinuria would probably have had the highest incidences of eclampsia or PRES. If our study would have included more women with preeclampsia, the women with massive proteinuria would probably have had the highest incidences of eclampsia or PRES. In addition, our calculation of the incidence of preeclampsia (3.2%, 94/2904) was similar to published incidences around the world, but our results
5. Conclusion A higher P/C ratio at delivery in women with preeclampsia might cause EPB and maternal CSC. The best P/C ratio cutoff value at delivery for worsened perinatal outcomes of women with preeclampsia is 4.8. Conflicts of interest statement The authors report no conflicts of interest. Funding information None. 8. Key message The best protein:creatinine ratio cutoff values of early preterm birth and maternal central serous chorioretinopathy with preeclampsia were 4.1 and 4.8, respectively, as assessed by multivariate analysis. Acknowledgement The authors would like to thank Enago (www.enago.jp) for the English language review. Tweetable abstract The best P/C ratio cutoff value at delivery to detect early preterm birth and CSC in women with preeclampsia is 4.8. References [1] A.A. Al-Mulhim, A. Abu-Heija, F. Al-Jamma, El-H.A. El-Harith, Pre-eclampsia: maternal risk factors and perinatal outcome, Fetal Diagn. Ther. 18 (2003) 275–280. [2] P. Deruelle, E. Coudoux, A. Ego, V. Houfflin-Debarge, X. Codaccioni, D. Subtil, Risk factors for post-partum complications occurring after preeclampsia and HELLP syndrome. A study in 453 consecutive pregnancies, Eur. J. Obstet. Gynecol. Reprod. Biol. 125 (2006) 59–65. [3] M.G. Newman, A.G. Robichaux, C.M. Stedman, et al., Perinatal outcomes in preeclampsia that is complicated by massive proteinuria, Am. J. Obstet. Gynecol. 188 (2003) 264–268. [4] A.G. Witlin, G.R. Saade, F. Mattar, B.M. Sibai, Risk factors for abruptio placentae
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