Prenatal Urine Testing

1. Prenatal Urine Testing Mary Ann Rhode MS, CNM Exempla Certified Nurse Midwives Denver, Colorado

2. A Sacred Cow of Obstetrics

3. History of Urine Testing Practices 1843 Relationship between urinary protein and eclampsia noted 1903 Protein testing suggested by Edgar in The Practice of Obstetrics • Screening for glycosuria proposed in Williams Obstetrics • Urine testing was being taught to granny midwives in the movie "All My Babies" produced by Columbia University 1970 Nearly universal, expanded to include other substances such as nitrites and leukocyte esterase

4. Traditional Purpose of Prenatal Urine Testing Screen for: Gestational diabetes Preeclampsia Urinary tract infection

5. Gestational Diabetes Considerations Urine testing for GDM, as the primary screening test, not used for decades Diabetics no longer regulate insulin based on urine testing Glucose tolerance testing is widely accepted as the best screening method

6. Pre-eclampsia Considerations No current effective screening method for early detection Many early markers identified but either impractical to use or not predictive enough Urinary placental growth factor (PlGF) Most recently studied marker for preeclampsia Tested between 21-32 weeks gestation "Decreased urinary PIGF at mid gestation is strongly associated with subsequent early development of preeclampsia." Levine2005

7. Pre-eclampsia Considerations Protein testing is for diagnosis, 24 hour urine collection is preferred method Proteinuria rarely precedes an elevation in blood pressure "Dipstick urinalysis cannot be relied on either to detect or to exclude the presence of proteinuria in pregnant women." Kuo 1992

8. Urinary Tract Infection Considerations • Type of infection • Cystitis - 1 - 2 % incidence • Pyelonephritis - 1-2 % incidence • Asymptomatic bacteriuria • 2 - 7 % incidence • 20-30 % progress to pyelonephritis without treatment • Less than 1 % acquire bacteriuria in pregnancy after initial screening

9. Symptomatic vs asymptomatic • Sensitivities of tests vary based on presence or absence of symptoms Pregnant vs non-pregnant • Sensitivities vary by patient population • Many symptoms of pregnancy and UTI are similar • Prenatal urine screening is mostly for asymptomatic bacteriuria • Urine culture is considered the "gold standard" for ASB

10. Current Standard Screening Practices BP check each prenatal visit Urine dipstick testing each visit Glucose challenge test at 24-29 weeks Urinalysis or urine culture at first visit

11. Recommended Guidelines “During each regularly scheduled visit, the health care provider should evaluate the woman’s blood pressure, weight, urine for the presence of protein and glucose levels, uterine size for progressive growth and consistency with the estimated date of delivery, and fetal heart rate.” Guidelines for Perinatal Care, 2002 Routine testing: • Hct or Hgb levels • Urinalysis, including microscopic examination • Urine testing to detect asymptomatic bacteriuria (eg, urine culture) • Determination of blood group and CDE (Rh) type • ABS • Determination of immunity to rubella virus • Syphilis screen • Cervical cytology (as needed) • Hepatitis B virus surface antigen • HIV antibody testing

12. GDM Screening Recommendations ACOG and AAP • Do not recommend universal screening for GDM but strongly recommend screening pregnant women in high-prevalence populations ACP, ADA, & Third International Workshop Conference on Gestational Diabetes • Recommend universal screening for GDM at 24-28 weeks using a 1-hour glucose tolerance test Guide to Clinical Preventive Services 3rd edition, 2002 • Insufficient evidence to recommend for or against routine screening for GDM

13. Preeclampsia Screening Recommendations ACOG • BP measurements at initial visit • Every 4 weeks until 28 weeks gestation • Every 2-3 weeks until 36 weeks gestation • Every week thereafter Canadian Task Force on Periodic Health Examination • Systolic & diastolic BP at the first prenatal visit and periodically throughout the rest of pregnancy Guide to Clinical Preventive Services. 3rd edition, 2002 • BP measurement at each visit • Further diagnostic evaluation, including BP monitoring and urine testing for protein when indicated

14. Asymptomatic Bacteriuria Screening Recommendations ACOG and AAP • Urinalysis, including microscopic examination and infection screen at first visit • Additional evaluation such as culture, as needed, based on history and physical exam Canadian Task Force on Periodic Health Examination • Urine culture at 12-16 weeks of pregnancy (based on research that showed identification of 80 % who will eventually have ASB in pregnancy) Guide to Clinical Preventive Services 3rd edition, 2002 • Urine culture for all pregnant women at 12-16 weeks gestation • Routine screening for ASB with LE or nitrite testing in pregnant women not recommended

15. Questions about Urine Reagent Strip Testing • Redundant testing • Lack of evidence of improved pregnancy outcome with routine testing • Testing sources of error - tests need to be accurate and reliable, i.e. sensitive and specific

16. Problems with Urine Reagent Strip Testing • Different thresholds between dipstick urinalysis and 24 hour urinary protein excretion (Thresholds for dipstick test and standard 24 hour urine assay are only equivalent if the 24 hour urine specimen is about 1000 mL) • Sensitivity and specificity • Varying concentration of protein in random specimens • Observer error

17. Sensitivity and Specificity Definitions Term Definition Formula Sensitivity Proportion of persons with a condition who test positive a + c Specificity Proportion of persons without d condition who test negative b + d Positive predictive value Proportion of persons with positive test a who have condition a + b Negative predictive value Proportion of persons with negative test d who do not have condition c + d Condition ConditionLegend: PresentAbsent a = true positive Positive test a b b = false positive Negative test c d c = false negative d = true negative From: U.S. Preventive Task Force Guide to Clinical Preventive Services, 3rd. Ed.

18. Poor sensitivity • Misses cases - the false negative rate • Leads to delayed treatment Poor specificity • Identifies healthy people as having a condition - the false positive rate • Leads to over-investigation, over-treatment

19. Urine Reagent Strip Sensitivities* Test Sensitivity Specificity + predictive value Culture 100 Gram stain 83-92 % 89-95 17-28 Urinalysis 8 -25 % 99 37-40 Urinalysis w/ 75-83 59-60 4.5 bacteria or leukocytes Nitrites 19-68 99 69-90 Leukocyte 17 97 12 esterase LE and nitrites 13 100 100 LE or nitrites 50 97 27 Protein, nitrites 8-33 91 18 blood, LE * From: Bachman, Tincello, and Etherington, rounded to nearest whole percentage point

20. Sources of False Positive Results • Dipstick left too long in concentrated urine • Gross hematuria • Pus, semen, vaginal secretions • Penicillin, sulfonamides, tolbutamide use • False + for protein if refrigerated > 24 hours

21. Sources of False Negative Results • Nonalbumin or LMW proteins • High levels of ascorbic acid or aspirin • Dilute urine ( > 1.015) • Nitrite false negatives are common due to: Lack of dietary nitrates, insufficient urinary nitrate levels due to diuretics, low urinary retention, infection due to organisms that don't produce nitrites, Staphyloccocus sp. , Enterococcus sp., Pseudomonas sp. • Increased for WBC’s/RBC’s if refrigerated > 24 hours

22. Variation in Protein Concentration in Random Specimens • Contamination (false positive) • Exercise (increased excretion) • Posture (increased excretion in upright position) • Osmolality (increased false positives) • Urinary pH ( pH > 7.5) • Timing of collection - sensitivity improved with first morning specimen • Different assay methods, pattern of urinary protein composition (some proteins may be associated more with preeclampsia)

23. Observer Error • More false positives with less trained staff • Most common error is to "round up" • Training can reduce false positive rate • Specificity may deteriorate if strips storedin open containers • False negative rate unchanged by training, possibly due to concentration • Use of automated devices can improve accuracy

24. Obstacles to Changing Current Practice • We might miss something • It’s too slow if we have to get a specimen later • Somebody might die • What will the other care providers think • We’ve always done it that way • Remember, there are legal issues to consider • What about renal disease?

25. Sources of Benign Proteinuria • Dehydration • Emotional status • Fever • Heat injury • Inflammatory process • Intense activity • Acute illness • Orthostatic disorder Corral MF. Proteinuria in adults: a diagnostic approach. American Family Physician, 2000.

26. Some Pathologic Causesof Proteinuria • Primary glomerulonephropathy • ex. glomerulonephritis • Secondary glomerulonephropathy • ex. diabetes collagen vascular disease preeclampsia • Drug associated • Hemoglobulinuria • Multiple myeloma

27. Renal Disease Considerations • “Fewer than 2 % of positive dipsticks have serious and treatable urinary tract disorders.” Corral MF. Proteinuria in adults: a diagnostic approach. American Family Physician, 2000. • “It is likely that this occurrence of mild, intermittent proteinuria in the general population makes routine screening ineffective. It has been suggested that screening of urine be reserved for populations at high risk of renal disease such as patients with diabetes or hypertension.” Woolhandler S. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. JAMA, 1989. • Acute renal failure in pregnancy - 1 : 20,000 • Microalbuminuria – excretion below detection level of urine dipsticks • Persistent rates of 20 micrograms/minute predictive of diabetic neuropathy & chronic renal disease

28. Routine prenatal urine screening • Done at every prenatal visit Indicated prenatal urine testing • First prenatal visit • Whenever clinical symptoms are present • High risk conditions

29. Why Continue Urine Reagent Strip Testing? • Only testing available for many years • Easy and quick, compared to 24 hour urine collection • Requires little technical expertise • Less expensive than urine culture or 24 hour urine tests • No "absolute" proof of safety of indicated testing • Sometimes the information is needed, i.e. there is an indication for the test

30. Evidence to Discontinue Routine Screening • Changing practice at other institutions • Public Health Service Expert Panel on the Content of Prenatal Care, 1989 • US Preventive Services Task Force Guide to Clinical Preventive Services, 1996, 2004 • Previous research

31. Asymptomatic Bacteriuria Studies Lenke 1981 Recommended use of routine culture for women at risk of for recurrent pyelonephritis because positive cultures aren't accurately predicted by microscopic urinalysis or nitrite testing Robertson 1988 Nitrite or leukocyte esterase alone not sensitive enough to detect ASB, nitrites plus LE may be better Etherington 1993 Combination of leukocyte esterase, nitrite, protein and blood gives highest predictive value of negative culture (99.3) so conclude is reliable for screening to avoid culture for all. (Sensitivity - 8.2 %, specificity - 79 %, positive predictive value - 10.5 %) Bachman 1993 Screening with urinalysis cost more than cultures for all Reagent strips missed 50 % of ASB on initial exam Tincello 1998 Reagent strips OK to use to determine need for culture of symptomatic women. Not sensitive enough to screen for ASB McNair 2000 High false negative rates with urinalysis & reagent strips Urine cultures should be universally used to detect ASB Chance of detecting ASB best in first trimester "Urine culture remains the gold standard, and all pregnant women should have a screening culture during their early prenatal care." Gilstrap 2001

32. Proteinuria & Glycosuria Studies Study Year Type of Study Focus N Watson 1990 Observational glycosuria 500 Gribble 1995 Retrospective chart review glucosuria 2965 Gribble 1995 Retrospective chart review proteinuria 3104 Hooper 1996 Retrospective chart review glycosuria 600 proteinuria Murray 2002 Prospective observational proteinuria 913 Rhode 2006 Retrospective, non-inferiority proteinuria 1952 cohort design glycosuria ASB

33. Study Conclusions Watson Routine screening for glycosuria does not appear to be clinically useful Gribble 3rd trimester testing for glycosuria is not predictive of any clinically important pregnancy outcome Routine screening for glycosuria before the 3rd trimester may identify women at increased risk of GDM Gribble In low risk women with no signs of hypertensive disease, routine screening for proteinuria did not provide any clinically important information about pregnancy outcome Hooper Oral glucose diabetes screening and careful monitoring of blood pressure (and symptomatology) are better screens for GDM and preeclampsia than routine urinalysis Murray After an initial screening urinalysis, routine urinalysis could be eliminated without adverse outcomes for women

34. Research Setting & Population Aurora Nurse Midwives Clinic, Aurora Colorado. Started to provide care to medically underserved. Approximately 1000 visits per month, mostly obstetric Predominately Hispanic Population considered high risk due to low socio-economic status Only two bathrooms in the clinic

35. Study Objective To determine if asymptomatic bacteriuria, elevated blood pressure, and gestational diabetes are underdiagnosed if routine prenatal urine screening is replaced with clinically indicated testing.

36. Methodology Prior to August 2002 • Initial urinalysis, urine culture, BP • One-hour 50-g load glucose challenge test at about 28 weeks gestation, (130 mg/dL threshold used for 3 hour GTT), at weeks gestation and a repeat at 28 weeks if risk factors present • Urine dipstick testing and BP at each follow-up visit After August 15, 2002 • Same initial visit and GDM regimen • Urine dipstick testing done only when established criteria* were present Antepartum and intrapartum charts were reviewed after delivery

37. Study Conclusion A change to indicated urine reagent strip testing does not result in under-diagnosis of high blood pressure, urinary tract infection, or gestational diabetes.

38. Implications for Clinical Practice Changing long-standing clinical practices is difficult! • Conduct a prospective, randomized trial and publish the results • Have documentation articles available • Make sure all involved are on-board, no saboteurs • Give advance notice, educate everyone involved, including patients

39. We are making a change we hope you will like!Starting August 15, you will NOT need to give a urine specimen every time you come to the clinic. We will ask for a urine specimen ONLY if you have a problem. This change is based on scientific information that says urine testing of healthy women is not necessary every visit. We are always trying to improve the way we give you the best care. This does not mean you are getting less care.

40. Compliance with established criteria is essential to patient safety! Must get urine specimen whenever criteria are present No skipping, "just this one time" No repeating a blood pressure to avoid getting a urine specimen Must document No reason for 18.1% of indicated tests No urine testing done on some subjects in each group Not documented or not done? Pay more attention to preeclampsia symptomatology since blood pressures may be labile

41. Common Themes in Medico-legal Claims • Assuming proteinuria is from contamination or UTI • Failing to appreciate the significance of patient complaints on the phone Sibai, BM. Cutting the legal risks of hypertension in pregnancy. OBG Management. 2003.

42. Follow-up for Trace to 2 + Proteinuria • Repeat dipstick twice in the next month with a first morning specimen • If negative - transient proteinuria. No additional follow-up needed • If positive - persistent proteinuria. Needs 24 hr. urine or urine protein/creatinine ratio

43. Indicated prenatal urine testing is • Safe • Patient-centered • Reduces cost of clinic operation • Improves clinic flow • Improves patient satisfaction.