There are many reports of the harmful effects of proteinuria in pregnancy in relation to hypertension and preeclampsia [1,2]. The dipstick test, which can be used for semiquantitative determination of protein concentration in spot urine, is used as a screening test to detect significant proteinuria. Many pregnant women have random urine dipsticks positive for proteinuria, and there is minimal data on the impact of random urine proteinuria in pregnancy. The gold standard for measuring proteinuria is a 24-hour urine sample for total protein level [3], but this method may result in delayed diagnosis and treatment or possibly a prolonged hospital stay [4]. Several studies have suggested an acceptable correlation between single-voided protein-to-creatinine ratio and 24-hour urine protein in pregnancy [5,6]. However, the impact of random urine proteinuria on pregnancy has not yet been determined. The present study aimed to evaluate random proteinuria as a predictor for the maternal and fetal outcomes of pregnancy.

A total of 2,822 pregnant women were enrolled, and 536 of them had proteinuria. The patients’ mean age was 33.0 ± 4.7 years, gestational age was 235.6 ± 50.6 days, and body mass index was 25.9 ± 4.2 at the time of admission. Past obstetric history revealed full term deliveries in 1,609 patients (56.9%). Hypertension had previously been diagnosed in 67 patients (2.4%) and chronic kidney disease in 29 patients (1.0%) (Table 1).

Eight hundred and nine women (28.6%) had a history of an artificial abortion, and 617 women (21.9%) had a history of a spontaneous abortion. The mean creatinine concentration of the 2,822 women was 0.5 ± 0.4 mg/dL, and the mean eGFR was 128 ± 14 mL/min/1.73 m². A total of 536 women (19.0%) showed dipstick positive proteinuria (1+, 210 women [7.4%]; 2+, 205 women [7.3%]; 3+, 121 women [4.3%]). A total of 249 women (8.8%) showed hematuria on a urine dipstick test (Table 2).

Table 3 shows the demographic and functional data of patients with and without proteinuria after propensity score matching with age and gestational age at delivery. The proteinuria group shows a higher rate of previous preeclampsia and a lower rate of past full term deliveries. The prevalence of diabetes mellitus and CKD was higher in the proteinuria group. Serum albumin levels and eGFR were lower in the proteinuria group, and blood urea nitrogen levels, serum creatinine levels, and the incidence of hematuria was higher in the proteinuria group (Table 3).

Table 4 shows the clinical outcomes of patients with and without proteinuria. Fetal body weight trended lower in the proteinuria group. The incidence of preterm labor, PROM, IUGR, and preeclampsia was higher in the proteinuria group.

Preeclampsia was the outcome most significantly with proteinuria (Pearson correlation, correlation coefficient = 85%, p < 0.001). Thus, we performed ROC analysis of proteinuria for the predictive value of preeclampsia. The area of the ROC curve was 0.783 (p < 0.001) in propensity score matching samples (Fig. 1A) and 0.851 (p < 0.001) in unmatched whole samples (Fig. 1B).

Table 5 shows the clinical outcomes of patients before and after gestational week 20 showing proteinuria. Fetal body weight was significantly lower in the proteinuria before gestational week 20 group. Abortion and neonatal fetal death rate also showed significantly higher in the proteinuria before gestational week 20, but preeclampsia was higher in the proteinuria after gestational week 20 group.

This study shows that approximately one in five women have dipstick positive proteinuria at some time during their pregnancy. Our data suggest that random urine proteinuria during pregnancy was correlated with preterm labor, PROM, IUGR, and preeclampsia. Some studies have found that maternal and perinatal morbidity and mortality increased with the amount of proteinuria [11]. Several methods are available for measuring proteinuria, but 24-hour urine protein excretion has long been regarded as the gold standard. However, this test has some disadvantages such as inconvenience for patients, inaccuracy due to incomplete collection, cost, and delay of diagnosis and management, which makes its wide use difficult for clinicians. For this reason, many investigators have explored simpler and more convenient diagnostic methods to quantify proteinuria. The urine dipstick test is one of the most commonly used screening tests because of its simplicity and low cost. Nevertheless, this method has high rates of false positive and false negative results associated with fluctuations throughout the day due to water intake, exercise, diet, posture, or improperly trained laboratory staff [12-14]. Therefore, some investigators have explored other means of quantifying proteinuria in a shorter time period and they suggest a 2-hour collection, 4-hour collection, or using the protein-creatinine ratio [15-17]. The protein to creatinine ratio of a single sample has been shown to correlate significantly with a 24-hour collection for pregnant patients with protein values of less than 1 g in 24 hours, but not for those with protein values above 1 g, in which the variation between the samples was increased [18,19]. However, those studies evaluated the accuracy of dipstick testing for proteinuria compared to 24-hour urine collection and did not evaluate clinical outcomes. It has been recently reported that urine dipstick test results were closely related to urine creatinine concentration, and postpartum urine samples had significantly lower urine creatinine concentration compared to antepartum urine samples. It was likely to show a false positive result in concentrated urine samples with higher urine creatinine concentration for prediction of preeclampsia [20]. Unfortunately, our data did not consider urine creatinine concentration or urine osmolality.

Preeclampsia is a serious complication of pregnancy, and it is vital to diagnose the condition as early as possible. Preeclampsia is defined as the development of hypertension or proteinuria prior to week 20 or the development of both after week 20 in a woman previously having normal blood pressure [21]. Proteinuria is a defining dysfunction of preeclampsia, the degree of which may fluctuate widely over any 24-hour period due to the circadian variation of urinary albumin excretion [22,23]. Some researchers have concluded that the random urine protein to creatinine ratio is not a good predictor of significant proteinuria in patients with preeclampsia [24,25]. Other studies have shown that urine dipstick for protein results correlate poorly with 24-hour urine samples for differentiating patients with no disease or severe disease [15,26]. The results of our study indicate that random urine proteinuria is highly predictive for preeclampsia. This discrepancy with previous study results might be explained by the fact that our center is a university hospital and pregnant women with false-positive random urine dipstick protein tests might have been screened in private clinics before visiting our hospital. Moreover, our study showed proteinuria after gestational week 20 highly associated with preeclampsia compared to proteinuria before gestational week 20 group. However, the pregnant women who showed proteinuria before gestational week 20 associated with lower fetal body weight, higher abortion and neonatal death rate. Those results may be affected by known CKD women who were included in the proteinuria before gestational week 20 group.

The group with random urine positive for proteinuria also showed lower serum albumin values, lower eGFR, and a higher incidence of hematuria. These laboratory findings can explain poor fetal outcomes such as IUGR.

In conclusion, random urine proteinuria during pregnancy was correlated with preterm labor, PROM, and IUGR, and was also highly predictive for preeclampsia.