Proteinuria in pregnancy: Evaluation and management
- Ravi I Thadhani, MD, MPH
Ravi I Thadhani, MD, MPH
- Professor of Medicine
- Harvard Medical School
- Sharon E Maynard, MD
Sharon E Maynard, MD
- Associate Professor of Medicine
- Morsani College of Medicine
- University of South Florida
In non-pregnant individuals, abnormal total protein excretion is typically defined as greater than 150 mg daily. In normal pregnancy, urinary protein excretion increases substantially; hence, total protein excretion is considered abnormal in pregnant women when it exceeds 300 mg/24 hours .
Proteinuria is one of the cardinal features of preeclampsia (table 1), a common and potentially severe complication of pregnancy. However, two important points should be noted. First, the severity of proteinuria is only weakly associated with adverse maternal and neonatal outcomes, and should not be used to guide management [2-5]. Second, proteinuria may be absent: Up to 10 percent of women with clinical and/or histological manifestations of preeclampsia and 20 percent of women with eclampsia have no proteinuria at the time of initial presentation [6,7]. These observations are reflected in the 2013 American Society of Obstetrics and Gynecology Task Force on Hypertension in Pregnancy recommendations, which no longer require proteinuria for the diagnosis of preeclampsia if other severe preeclampsia features are present (table 1). (See "Preeclampsia: Clinical features and diagnosis".)
Although less prevalent, primary renal disease and renal disease secondary to systemic disorders, such as diabetes or primary hypertension (formerly called “essential” hypertension), are usually characterized by proteinuria and may first present in pregnancy. To further complicate this picture, 20 to 25 percent of women with chronic hypertension and diabetes develop superimposed preeclampsia [8,9].
It is important for clinicians caring for pregnant women to understand how to identify proteinuria, and how to determine whether preeclampsia or renal disease (or both) is the cause. This topic will discuss the approach to the evaluation of pregnant women with proteinuria and management of nephrotic syndrome in pregnancy. The evaluation of proteinuria in nonpregnant individuals and measurement of protein excretion are discussed in detail separately. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)
RENAL CHANGES IN NORMAL PREGNANCY
Glomerular filtration rate (GFR) and renal blood flow rise markedly during pregnancy, resulting in a physiologic fall in the serum creatinine concentration. Urinary protein excretion increases substantially due to a combination of increased GFR and increased permeability of the glomerular basement membrane . Additionally, tubular reabsorption of filtered protein is reduced in pregnancy, along with other nonelectrolytes, such as amino acids, glucose, and beta-microglobulin. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)
- Higby K, Suiter CR, Phelps JY, et al. Normal values of urinary albumin and total protein excretion during pregnancy. Am J Obstet Gynecol 1994; 171:984.
- Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach. Obstet Gynecol 2010; 115:365.
- von Dadelszen P, Payne B, Li J, et al. Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet 2011; 377:219.
- Payne B, Magee LA, Côté AM, et al. PIERS proteinuria: relationship with adverse maternal and perinatal outcome. J Obstet Gynaecol Can 2011; 33:588.
- van der Tuuk K, Holswilder-Olde Scholtenhuis MA, Koopmans CM, et al. Prediction of neonatal outcome in women with gestational hypertension or mild preeclampsia after 36 weeks of gestation. J Matern Fetal Neonatal Med 2015; 28:783.
- Thornton CE, Makris A, Ogle RF, et al. Role of proteinuria in defining pre-eclampsia: clinical outcomes for women and babies. Clin Exp Pharmacol Physiol 2010; 37:466.
- Sibai BM. Eclampsia. VI. Maternal-perinatal outcome in 254 consecutive cases. Am J Obstet Gynecol 1990; 163:1049.
- Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1998; 339:667.
- Ros HS, Cnattingius S, Lipworth L. Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study. Am J Epidemiol 1998; 147:1062.
- Roberts M, Lindheimer MD, Davison JM. Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy. Am J Physiol 1996; 270:F338.
- Smith NA, Lyons JG, McElrath TF. Protein:creatinine ratio in uncomplicated twin pregnancy. Am J Obstet Gynecol 2010; 203:381.e1.
- Osmundson SS, Lafayette RA, Bowen RA, et al. Maternal proteinuria in twin compared with singleton pregnancies. Obstet Gynecol 2014; 124:332.
- Waugh JJ, Clark TJ, Divakaran TG, et al. Accuracy of urinalysis dipstick techniques in predicting significant proteinuria in pregnancy. Obstet Gynecol 2004; 103:769.
- Viberti GC, Jarrett RJ, Keen H. Microalbuminuria as prediction of nephropathy in diabetics. Lancet 1982; 2:611.
- Piccoli GB, Cabiddu G, Attini R, et al. Risk of Adverse Pregnancy Outcomes in Women with CKD. J Am Soc Nephrol 2015; 26:2011.
- Côté AM, Firoz T, Mattman A, et al. The 24-hour urine collection: gold standard or historical practice? Am J Obstet Gynecol 2008; 199:625.e1.
- Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK). Am J Kidney Dis 2003; 42:617.
- Robert M, Sepandj F, Liston RM, Dooley KC. Random protein-creatinine ratio for the quantitation of proteinuria in pregnancy. Obstet Gynecol 1997; 90:893.
- Neithardt AB, Dooley SL, Borensztajn J. Prediction of 24-hour protein excretion in pregnancy with a single voided urine protein-to-creatinine ratio. Am J Obstet Gynecol 2002; 186:883.
- Hirshberg A, Draper J, Curley C, et al. A random protein-creatinine ratio accurately predicts baseline proteinuria in early pregnancy. J Matern Fetal Neonatal Med 2014; 27:1834.
- Chen BA, Parviainen K, Jeyabalan A. Correlation of catheterized and clean catch urine protein/creatinine ratios in preeclampsia evaluation. Obstet Gynecol 2008; 112:606.
- Verdonk K, Niemeijer IC, Hop WC, et al. Variation of urinary protein to creatinine ratio during the day in women with suspected pre-eclampsia. BJOG 2014; 121:1660.
- Rodriguez-Thompson D, Lieberman ES. Use of a random urinary protein-to-creatinine ratio for the diagnosis of significant proteinuria during pregnancy. Am J Obstet Gynecol 2001; 185:808.
- Young RA, Buchanan RJ, Kinch RA. Use of the protein/creatinine ratio of a single voided urine specimen in the evaluation of suspected pregnancy-induced hypertension. J Fam Pract 1996; 42:385.
- Ramos JG, Martins-Costa SH, Mathias MM, et al. Urinary protein/creatinine ratio in hypertensive pregnant women. Hypertens Pregnancy 1999; 18:209.
- Saudan PJ, Brown MA, Farrell T, Shaw L. Improved methods of assessing proteinuria in hypertensive pregnancy. Br J Obstet Gynaecol 1997; 104:1159.
- Jaschevatzky OE, Rosenberg RP, Shalit A, et al. Protein/creatinine ratio in random urine specimens for quantitation of proteinuria in preeclampsia. Obstet Gynecol 1990; 75:604.
- Durnwald C, Mercer B. A prospective comparison of total protein/creatinine ratio versus 24-hour urine protein in women with suspected preeclampsia. Am J Obstet Gynecol 2003; 189:848.
- Al RA, Baykal C, Karacay O, et al. Random urine protein-creatinine ratio to predict proteinuria in new-onset mild hypertension in late pregnancy. Obstet Gynecol 2004; 104:367.
- Wheeler TL 2nd, Blackhurst DW, Dellinger EH, Ramsey PS. Usage of spot urine protein to creatinine ratios in the evaluation of preeclampsia. Am J Obstet Gynecol 2007; 196:465.e1.
- Aggarwal N, Suri V, Soni S, et al. A prospective comparison of random urine protein-creatinine ratio vs 24-hour urine protein in women with preeclampsia. Medscape J Med 2008; 10:98.
- Dwyer BK, Gorman M, Carroll IR, Druzin M. Urinalysis vs urine protein-creatinine ratio to predict significant proteinuria in pregnancy. J Perinatol 2008; 28:461.
- Kyle PM, Fielder JN, Pullar B, et al. Comparison of methods to identify significant proteinuria in pregnancy in the outpatient setting. BJOG 2008; 115:523.
- Leaños-Miranda A, Márquez-Acosta J, Romero-Arauz F, et al. Protein:creatinine ratio in random urine samples is a reliable marker of increased 24-hour protein excretion in hospitalized women with hypertensive disorders of pregnancy. Clin Chem 2007; 53:1623.
- Yamasmit W, Chaithongwongwatthana S, Charoenvidhya D, et al. Random urinary protein-to-creatinine ratio for prediction of significant proteinuria in women with preeclampsia. J Matern Fetal Neonatal Med 2004; 16:275.
- Stout MJ, Scifres CM, Stamilio DM. Diagnostic utility of urine protein-to-creatinine ratio for identifying proteinuria in pregnancy. J Matern Fetal Neonatal Med 2013; 26:66.
- Côté AM, Brown MA, Lam E, et al. Diagnostic accuracy of urinary spot protein:creatinine ratio for proteinuria in hypertensive pregnant women: systematic review. BMJ 2008; 336:1003.
- Papanna R, Mann LK, Kouides RW, Glantz JC. Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol 2008; 112:135.
- Morris RK, Riley RD, Doug M, et al. Diagnostic accuracy of spot urinary protein and albumin to creatinine ratios for detection of significant proteinuria or adverse pregnancy outcome in patients with suspected pre-eclampsia: systematic review and meta-analysis. BMJ 2012; 345:e4342.
- Visintin C, Mugglestone MA, Almerie MQ, et al. Management of hypertensive disorders during pregnancy: summary of NICE guidance. BMJ 2010; 341:c2207.
- Gillon TE, Pels A, von Dadelszen P, et al. Hypertensive disorders of pregnancy: a systematic review of international clinical practice guidelines. PLoS One 2014; 9:e113715.
- Wilkinson C, Lappin D, Vellinga A, et al. Spot urinary protein analysis for excluding significant proteinuria in pregnancy. J Obstet Gynaecol 2013; 33:24.
- Nisell H, Trygg M, Bäck R. Urine albumin/creatinine ratio for the assessment of albuminuria in pregnancy hypertension. Acta Obstet Gynecol Scand 2006; 85:1327.
- Gangaram R, Naicker M, Moodley J. Comparison of pregnancy outcomes in women with hypertensive disorders of pregnancy using 24-hour urinary protein and urinary microalbumin to creatinine ratio. Int J Gynaecol Obstet 2009; 107:19.
- Baweja S, Kent A, Masterson R, et al. Prediction of pre-eclampsia in early pregnancy by estimating the spot urinary albumin: creatinine ratio using high-performance liquid chromatography. BJOG 2011; 118:1126.
- Khazardoost S, Abdollahi A, Shafaat M. Comparison of 8-h urine protein and random urinary protein-to-creatinine ratio with 24-h urine protein in pregnancy. J Matern Fetal Neonatal Med 2012; 25:138.
- Stout MJ, Conner SN, Colditz GA, et al. The Utility of 12-Hour Urine Collection for the Diagnosis of Preeclampsia: A Systematic Review and Meta-analysis. Obstet Gynecol 2015; 126:731.
- Ekiz A, Kaya B, Polat I, et al. The outcome of pregnancy with new onset proteinuria without hypertension: retrospective observational study. J Matern Fetal Neonatal Med 2016; 29:1765.
- Sarno L, Maruotti GM, Saccone G, et al. Pregnancy outcome in proteinuria-onset and hypertension-onset preeclampsia. Hypertens Pregnancy 2015; 34:284.
- Piccoli GB, Attini R, Parisi S, et al. Excessive urinary tract dilatation and proteinuria in pregnancy: a common and overlooked association? BMC Nephrol 2013; 14:52.
- Verlohren S, Galindo A, Schlembach D, et al. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia. Am J Obstet Gynecol 2010; 202:161.e1.
- Sunderji S, Gaziano E, Wothe D, et al. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study. Am J Obstet Gynecol 2010; 202:40.e1.
- Hadker N, Garg S, Costanzo C, et al. Financial impact of a novel pre-eclampsia diagnostic test versus standard practice: a decision-analytic modeling analysis from a UK healthcare payer perspective. J Med Econ 2010; 13:728.
- Moore AG, Young H, Keller JM, et al. Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia. J Matern Fetal Neonatal Med 2012; 25:2651.
- Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation 2012; 125:911.
- Rolfo A, Attini R, Nuzzo AM, et al. Chronic kidney disease may be differentially diagnosed from preeclampsia by serum biomarkers. Kidney Int 2013; 83:177.
- Chua S, Redman CW. Prognosis for pre-eclampsia complicated by 5 g or more of proteinuria in 24 hours. Eur J Obstet Gynecol Reprod Biol 1992; 43:9.
- Berks D, Steegers EA, Molas M, Visser W. Resolution of hypertension and proteinuria after preeclampsia. Obstet Gynecol 2009; 114:1307.
- ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002; 77:67.
- Katz AI, Davison JM, Hayslett JP, et al. Pregnancy in women with kidney disease. Kidney Int 1980; 18:192.
- Reece EA, Coustan DR, Hayslett JP, et al. Diabetic nephropathy: pregnancy performance and fetomaternal outcome. Am J Obstet Gynecol 1988; 159:56.
- Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in pregnancy: clinical-pathological correlations and remote prognosis. Medicine (Baltimore) 1981; 60:267.
- Yang JW, Choi SO, Kim BR, et al. Nephrotic syndrome associated with invasive mole: a case report. Nephrol Dial Transplant 2010; 25:2023.
- Strauch BS, Hayslett JP. Kidney disease and pregnancy. Br Med J 1974; 4:578.
- Piccoli GB, Daidola G, Attini R, et al. Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative review. BJOG 2013; 120:412.
- Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in pregnancy. Br Med J (Clin Res Ed) 1985; 290:17.
- RENAL CHANGES IN NORMAL PREGNANCY
- SCREENING FOR PROTEINURIA
- QUANTIFYING PROTEIN EXCRETION
- 24-hour collection
- Urine protein to creatinine ratio
- Urine albumin to creatinine ratio
- 8- or 12-hour collection
- DIFFERENTIAL DIAGNOSIS OF PROTEINURIA
- Renal disease versus preeclampsia
- Superimposed preeclampsia
- Nephrotic syndrome
- - Kidney biopsy in pregnancy
- MANAGEMENT OF NEPHROTIC SYNDROME IN PREGNANCY
- SOCIETY GUIDELINE LINKS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS