Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Morris, 2012

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis

Literature search up to January, 2011

A: Al, 2004

B: Aggarwal, 2008

C: Durnwald, 2003

D: Dwyer, 2008

E: Leanos, 2007

F: Ramos, 1999

G: Robert, 1997

H: Rodriquez-Thompson, 2001

I: Saudan, 1997

J: Schubert, 2006

K: Shahbazian, 2008

L: Skweres, 2006

M: Taherian, 2006

N: Wheeler, 2007

O: Yamasmit, 2004

Study design: cohort, case-control

(prospective / retrospective)

A: cohort (retrospective)

B: diagnostic accuracy study (prospective)

C: cohort (prospective)

D: cohort (prospective)

E: cohort (cross-sectional)

F: cohort (cross-sectional)

G: cohort (unclear)

H: case-control study

I: cohort (prospective)

J: not reported

K: cohort (prospective)

L: cohort (unclear)

M: cohort (prospective/cross-sectional)

N: cohort (unclear)

O: cohort (prospective)

Setting and Country:

A: secondary care, Turkey

B: secondary care, India

C: tertiary care, USA

D: tertiary care, USA

E: secondary care, Mexico

F: secondary care, Brazil

G: tertiary care, cohort

H: secondary care, USA

I: secondary care, Australia

J: secondary care, USA

K: tertiary care, Iran

L: secondary care, Poland.

M: secondary care, Iran

N: secondary care, USA

O: tertiary care, Thailand.

Source of funding and conflicts of interest:

(commercial / non-commercial funding/ industrial co-authorship / potential conflicts of interest )

Not reported per study.

Funding: RKM is funded by a National Institute for Health Research clinical lectureship. RR and JD are supported by funding from the Medical Research Council Hub for Trials Methodology Research at the University of Birmingham (MRC grant ID G0800808).

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Inclusion criteria SR: population—pregnant women with suspected pre-eclampsia (hypertension with or without proteinuria); index test—urinary protein to creatinine ratio or albumin to creatinine ratio; reference standard—urinary protein excretion over 24 hours or adverse pregnancy outcome (as defined by authors of included studies); study design—diagnostic accuracy studies, observational studies, and randomised controlled trials

Exclusion criteria SR: ase series with fewer than 10 cases. We also excluded studies that evaluated the protein to creatinine ratio or albumin to creatinine ratio in women with medical conditions other than hypertension and those that used a reference test other than 24 hour collection or adverse pregnancy outcome.

15 studies included. Five studies on ACR were included by Morris (2012) as well, but are left out of this analysis.

Important patient characteristics:

Number of patients; characteristics important to the research question; for example, age, sex, bmi,...

N total (N analyzed), mean age, mean gestational age at test, % nulliparous:

A: 221 (185), median 30 (17-44), median 32 (22-40), 54%

B: 155 (120), mean 29 (SD not reported), mean 32 (SD not reported), 66%

C: 220 (220), mean 26.1 (SD not reported), mean 36.5 (SD not reported), % not reported

D: 155 (116), not reported, mean 30.8 (SD 6.2), 41%

E: 1198 (927), 28.6 (SD 6.2), 33 (SD not reported, 75%. F: 47 (47), 29.3 (SD 6.7), ≥20, 52%

G: 71 (71), 29 (15-39), 34 (22-41), % not reported.

H: 138 (138), 30 (16-49), not reported, 52%.

I: 100 (100), not reported, not reported, % not reported.

J: 15 (15), not reported, >20 weeks, % not reported.

K: 117 (81), 26.5+/-3.6 (17-

36), 34.4+/-4.7

(21-41), % not reported.

L: 44 (44), 30.05 (20-42),

35+3 (21-41), % not reported.

M: 100 (100), 27.3, 33.26, % not reported.

N: 154 (126), 26.6+/-5.8,

34.0+/-3.3, % not reported

O: 55 (42), 30.6+/-5.83,

35.0+/-3.63,

47.6%

Sex: 100%F

Describe index and comparator tests* and

cut-off point(s):

All index tests: PCR

A: 0.13-0.49

B: 0.66-1.35

C: 0.15-0.3 (significant)

1.9-5.0 (severe)

D: 0.15-0.39 (significant)

2-13.53 (severe)

E: 0.3

F: 0.5

G: 0.3

H: 0.14-0.21

I: 0.2-0.45

J: 0.15-0.16

K: 0.2

L: 0.15-0.3

M: 0.14-0.20

N: 0.21-0.30

O: 0.19-0.32

Describe reference test and cut-off point(s):

All reference tests: 24-hour urine (≥300mg/24 hrs)

Prevalence (%)

(based on refence test at specified cut-off point)

A: 21%

B: 87%

C: 76% (significant), 8% severe

D: 48%

(significant)

3% (severe)

E: 30%

F: 55%

(significant)

52% (severe)

G: 41%

H: 50%

I: 14%

J: 60%

K: 47%

L: 45%

M: 73%

N: 54%

(significant)

0% (severe)

O: 69%

For how many participants were no complete outcome data available?

This was unclear, but Morris (2012) did report the number of women included (n women analysed), discrepancies can be observed here.

A: 221 (185)

B: 155 (120)

C: 220 (220)

D: 155 (116)

E: 1198 (927)

F: 47 (47)

G: 71 (71)

H: 138 (138)

I: 100 (100)

J: 15 (15)

K: 117 (81)

L: 44 (44)

M: 100 (100)

N: 154 (126)

O: 55 (42)

Reasons for incomplete outcome data described?

Not described by Morris (2012), unclear.

Endpoint of follow-up:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Outcome measure-1/2: sensitivity / specificity

A multivariate random effects meta-analysis was performed to synthesize all estimates, accounting for within and between study correlation. With these summary estimates per threshold value, a regression model was fitted to plot a receiver operating characteristics curve (ROC curve). The ROC curve was used to analyze the optimum summary estimate.

See Table 1 in text for complete overview of summary estimate per threshold value of the PCR.

Figure 1 shows the summary receiver operating characteristics curve for the constrained estimates. The optimum threshold for PCR to detect significant proteinuria (>300mg/24 hours), that optimizes sensitivity and specificity combined, was between 0.30 to 0.35 (relating to sensitivity and specificity values above 75%). No threshold gave a summary estimate above 80% for both sensitivity and specificity, and considerable heterogeneity existed in diagnostic accuracy across studies at most thresholds.

Outcome measure-3/4: positive and negative predictive value.

Morris (2012) calculated the positive and negative predictive value of the PCR compared to 24-hour urine for three different prevalences: 0.2, 0.5 and 0.8. The predicted values depended on the cut-off value chosen and the prevalence assumed. Complete overview of results is presented in appendix C-D-E of the paper by Morris (2012), which can be shown by request but due to its size it is not incorporated here in text.

Results show that, For example, with a high prevalence (0.8) high positive and negative predictive values above 0.85 were achieved. However, when the prevalence was low (for example, 0.2), the negative predictive value remained above 0.85, but positive predictive value is then around 0.4.

PS. pooling of test accuracy data should be based on bivariate analysis of sensitivity and specificy; always mention the cut-off points used

Study quality (ROB): Morris (2012) used QUADAS to assess the quality of the papers and used the STARD checklist to assess elements of study design that were likely to have a direct relation to bias in a study of test accuracy.

“We found good compliance with appropriate population spectrum, selection criteria adequately described, appropriate reference standard, and adequate description of index and reference standard. Blinding of the assessors of the outcome measure to the results of the albumin to creatinine ratio or protein to creatinine ratio was poorly reported (3/20 studies). No studies reported on the use of any treatment in between the albumin to creatinine ratio or protein to creatinine ratio and delivery or whether the results of the tests were used in determining patients’ management. Verification bias was minimised, as the number of eligible women progressing to the reference standard in included studies was more than 90% in 18/20. Five out of the 20 included studies used less than 80% of included women in the final analysis; reasons for this included exclusion after trial entry, lack of verification with reference standard, and loss to follow-up. In 379 (13%) cases this was due to incomplete 24 hour urine collection.”

Place of the index test in the clinical pathway: replacement (24-hour is golden standard, PCR could replace 24-hour standard).

Choice of cut-off point: all cut-off points for the PCR were studied, included studies examined cut-off values between 0.13-0.50.

Facultative:

Brief description of author’s conclusion

“The optimum threshold for the spot protein to creatinine ratio to detect proteinuria >0.3 g/day is between 0.30 and 0.35, giving summary sensitivity and specificity values above 0.75

Insufficient evidence exists for determination of how protein to creatinine ratio should be used in clinical practice, owing to large heterogeneity in diagnostic accuracy and prevalence across studies.”

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question

Sensitivity analyses (excluding small studies; excluding low quality studies; excluding case-control type of studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question

Heterogeneity: clinical and statistical heterogeneity; clinical: enough similarities in patient characteristics, diagnostic tests (strategy) to allow pooling? For pooled data: assessment of statistical heterogeneity and, more importantly, assessment of the reasons for heterogeneity (if present)? Note: sensitivity and specificity depend on the situation in which the test is being used and the thresholds that have been set, and sensitivity and specificity are correlated; therefore, the use of heterogeneity statistics (p-values; I2) is problematic, and rather than testing whether heterogeneity is present, the reasons for heterogeneity should be examined.

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Amin, 2014

Type of study: retrospective? Observational cohort study

Setting and country: Tertiary care centre, India

Funding and conflicts of interest: Funding not reported. The authors declare that there is no conflict of interests regarding the publication of this paper

Inclusion criteria: hypertensive disorders of the pregnancy were recruited after 20 weeks of gestation and these patients had detailed medical and obstetrical history ,general physical & systemic examinations, and other investigations required for the management.

Exclusion criteria: all cases of chronic renal disease, secondary hypertension due to immunological diseases such as lupus erythematosus, and overt diabetes mellitus. Patients who were delivered due to urgent indications for termination of pregnancy and hence could not complete 24 hour collection were also excluded.

N=102

Prevalence: 76.5%

Mean age ± SD: 27.4 (4.3)

Sex: 100% F

Other important characteristics:

Type of hypertension n(%):

Chronic hypertension 4(3.9%) Gestational hypertension 17(16.7%)

Mild preeclampsia 22(21.6%) Severe preeclampsia 43(42.2%) Imminent eclampsia 13(12.7%) Eclampsia 3(2.9%)

Describe index test: PCR

PCR = protein creatine concentrations in mg per 100 mL

Urinary total protein was analysed using Turbidimetric method with benzethonium chloride precipitation

Yrine creatine measurement was based upon Jaffe’s reaction.

Cut-off point(s): 0.30, 0.45, 0.60, 0.75, 0.90

Comparator test[1]: idem, different cut-off points

Cut-off point(s): see above

Describe reference test: 24 hour urine test

Expressed as mg/dL, estimated by formula

Total 24 hour urine protein excretion = urine protein concentration (mg/dL) x 24 hour urine volume in mL/100

Cut-off point(s): ≥300 mg/day

Time between the index test and reference test: random urine sample for PCR was collected prior to admission, 24 hour urine protein estimation was carried out after admission, exact timing unclear.

For how many participants were no complete outcome data available? 0

N (%) 0

Reasons for incomplete outcome data described? No, presumably sample with complete data selected.

Outcome measures and effect size (include 95%CI and p-value if available):

95%CI and p values not available.

1. Sensitivity and specificity

 Sens Spec

0.30 89.7 54.2

0.45 82.1 87.5

0.60 75.6 87.5

0.75 67.9 100

0.90 61.5 100

2. Positive and negative predictive value

 PPV NPV

0.30 86.4 61.9

0.45 95.5 60

0.60 95.2 52.5

0.75 100 49.0

0.90 100 44.4

See full text for elaborate description of tests.

Cheung, 2016

Type of study: retrospective observational study

Setting and country: single centre, Hong Kong

Funding and conflicts of interest: All authors have disclosed no conflicts of interest. Funding not reported.

Inclusion criteria: All Chinese pregnant women with a diagnosis of pre-eclampsia (new-onset proteinuric hypertension after 20 weeks of gestation) and who delivered at Queen Elizabeth Hospital in Hong Kong from January 2011 to December 2013 (36 months) were eligible for initial inclusion in this retrospective study

Exclusion criteria: Women were excluded from the study if they had pre-existing renal disease, chronic hypertension, or co-existing urinary tract infection (defined by a positive mid-stream urine culture).

N= 120

Prevalence:

Mean age ± SD: 34 (18-46)

Sex: 100%F

Other important characteristics:

Describe index test: uPCR

uPCR expressed as mg/mmol

Collected at any time of day.

Urine protein was measured with turbidimetric method based on benzthonium chloride reaction.

Urine creatine was measured using a kinetic colorimetric assay based on the Jaffé method.

The imprecision (coefficient of variation) of the urine protein assay was 3.7% at 0.18 g/L and 1.9% at 0.54 g/L. The imprecision of the urine creatinine assay was 6.9% at 7.0 mmol/L and 2.2% at 20.8 mmol/L.

Cut-off point(s): 20, 30, 33, 52

Comparator test: idem, see above, different cut-off values

Cut-off point(s): see above

Describe reference test: 24 hour urine

Collected within 24 hours.

Cut-off point(s): ≥300 mg/day

Time between the index test and reference test: exact timing unclear, but tests collected >1 day apart were excluded.

For how many participants were no complete outcome data available?

N (%) 22 (18%) were not collected. 98 samples were collected, but 12 (12/98= 12%) were inadequate, 20 (20/98=20%) were collected more than 1 day apart.

N=66 (66/120 (55%) with uPCR and 24 hour urine available.

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available):

p-values not reported

1. Sensitivity and specificity

2. Positive and negative predictive value

Of 432 cases of pre-eclampsia identified during the 36month study period, 175 (40.5%) had uPCR analysed after excluding cases without collection of uPCR before delivery or ordering because of individual clinician’s preference or because immediate delivery was expected. Of these 175 cases, 55 (31.4%) were excluded after review of medical records, including 28 non-Chinese patients, 24 cases with pre-existing hypertension or pre-existing renal disease, one woman with active urinary tract infection, one with missing information, and one who did not deliver at our hospital.

NB: Cheung 2016 reports adverse maternal and perinatal outcomes based on uPCR (not 24 hour urine). Given the diagnostic accuracy of the uPCR, the outcomes were not reported, because not all women are accurately classified. In addition, for this analysis 95 women (95/120) were selected, which includes women with incomplete samples. The data were therefore unreliable for inclusion.

Kumari, 20 13

Type of study[2]: prospective, cross-sectional study

Setting and country: single centre, India.

Funding and conflicts of interest: not reported.

Inclusion criteria: gestational age ≥32 weeks who were admitted in the maternity ward with signs and symptoms suggestive of preeclampsia were enrolled.

Exclusion criteria: chronic hypertension, diabetes mellitus, pre-existing renal disease, UTI, intrauterine fetal death, multiple gestations, preterm rupture of membrane, post term pregnancy.

N= 400

Prevalence: 77.5%

Mean age ± SD: 24.3 (2.6)

Sex: 100%F

Other important characteristics:

Describe index test: PCR

PCR = protein creatine concentrations in mg per dl

Urine protein concentration was estimated on Synchron CX-9 automated analyzer from Beckman, using the kits obtained from Randox. It was based on the principle that the coomassie reagent reacts with protein in an acidic milieu to form a colored complex and that the color intensity is proportional to the protein concentration.

Urine creatinine concentration was measured by modified Jaffe’s reaction which is based on the principle that creatinine in alkaline solution reacts with picric acid to form a colored complex. The intensity of the color formed is directly proportional to the creatinine concentration.

The UPCR was calculated by dividing the quantum of urine protein measured in mg/dl by urine creatinine in mg/dl.

Cut-off point(s): 0.2, 0.25, 0.3, 0.35, 0.4, 0.45

Comparator test[3]: idem, different cut-off points

Cut-off point(s): see above

Describe reference test[4]: 24 hour urine test.

Cut-off point(s): ≥300 mg/day

Time between the index test and reference test: within 1 day

For how many participants were no complete outcome data available?

N (%) 0

Reasons for incomplete outcome data described? Presumably only complete cases selected.

Outcome measures and effect size (include 95%CI and p-value if available)⁴:

1. Sensitivity and specificity

2. Positive and negative predictive value

Stout, 2013

Type of study[5]: retrospective cohort study

Setting and country: single centre, USA

Funding and conflicts of interest: Funding: not reported. The authors report no declarations of interest

Inclusion criteria: all patients with signs or symptoms concerning for the diagnosis of preeclampsia who were seen in the obstetrical triage unit and underwent blood pressure monitoring and laboratory evaluation, which included UPC ratio assessment prior to initiation of a 24-h urine collection for total protein. Patients were identified for inclusion in the cohort by searching a hospital database using the CPT code for 24-h urine collection (84156). Only pregnant women after 20 weeks gestation who underwent evaluation for suspected preeclampsia were included in the final cohort

Exclusion criteria: Patients with proteinuria ≥300 mg in 24 h before 20 weeks of gestation were excluded

N= 356

Prevalence: 40.5%

Mean age ± SD:

Protenuria: 27.5 (SD 6.7)

No proteinuria: 26.8 (SD 6.5)

Sex: 100%F

Other important characteristics:

Describe index test: PCR

PCR = protein creatine concentrations in mg/dL (presumed, not confirmed in text)

The first preeclampsia evaluation was used for each patient.

Random urine protein was assessed with end-point assay colorimetric (benzenethonium chloride) technique

Random urine creatine was assessed with enzymatic creatinase

Cut-off point(s): 0.08, 0.12, 0.19, 0.40, 0.45, 1.19

Comparator test[6]: idem, different cut-off points

Cut-off point(s): see above

Describe reference test[7]: 24 hour urine collection

Urine protein was assessed with end-point assay colorimetric (benzenethonium chloride) technique

Cut-off point(s): ≥300 mg/24 hours

Time between the index test and reference test: “Laboratory methodology during the study time frame remained constant”, 93.7% had a 24-h collection performed as an in-patient

For how many participants were no complete outcome data available?

N (%) 0

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available)⁴:

1. Sensitivity and specificity

2. Positive and negative predictive value

We defined preeclampsia based on the American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria including hypertension (systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg) persisting for at least 6 h and significant proteinuria defined as greater than or equal to 300 mg in a 24-h urine collection

Wilkinson, 2013

Type of study[8]: prospective diagnostic accuracy study

Setting and country: single centre, Ireland.

Funding and conflicts of interest: Funding not reported. The authors report no conflicts of interest. Th e authors alone are responsible for the content and writing of the paper.

Inclusion criteria: all women with a gestation of 20 weeks or longer who were admitted for suspected pre-eclampsia. Consecutive recruitment.

Exclusion criteria: none.

N= 89 women (with 132 24-hour urine collections).

Prevalence: 44%

Mean age ± SD: not reported.

Sex: 100%F

Other important characteristics:

Describe index test: PCR

PCR = protein creatine concentrations in mg/mmol

Protein analysis was performed using the turbidimetric method.

The Roche Cobas 6000 (Roche Diagnostics GmbH, D68298, Mannheim) performed the protein, albumin and creatinine assays

Cut-off point(s): 30, 25, 20, 15, 10

Comparator test[9]: idem, different cut-off points

Cut-off point(s): see above

Describe reference test[10]: 24-hour urine test

The 24UP were commenced at random daytimes to quantify urinary protein and creatinine excretion over a 24-hour period

Cut-off point(s): ≥300 mg/24 hr

Time between the index test en reference test: First void sample of 24-hour urine was used for PCR. 24-hour urine commenced at random daytimes.

For how many participants were no complete outcome data available?

N (%) 0

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available)⁴:

1. Sensitivity and specificity

2. Positive and negative predictive value

Not reported.

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Assessment of scientific quality of included studies?⁵

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁶

Yes/no/unclear

Potential risk of publication bias taken into account?⁷

Yes/no/unclear

Potential conflicts of interest reported?⁸

Yes/no/unclear

Morris, 2012

Yes

Yes

Yes

Yes

Yes

Unclear, high heterongenity among studies in methods of testing index and reference test, difference in prevalence of disease (18-87%) etc.

Unclear

No, not reported per included study.

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Amin, 2014

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes (*see patient selection)

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Nos

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Cheung, 2016

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear, non-Chinese women were excluded, which was not explained.

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes, 24 hour urine and urine PCR must have been collected within 1 day.

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

No, patients with inadequate collected samples were excluded. Eventually only 66/120 patients could be studied.

Are there concerns that the included patients do not match the review question?

Unclear

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Kumari 2013

Was a consecutive or random sample of patients enrolled?

Yes, consecutive

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: Unclear, presumably a sample with complete data was selected.

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Stout, 2013

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Wilkinson, 2013

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Unclear, there were no exclusion criteria. Therefore, patients with renal disease or other risk factors might have been included. Population characteristics were not reported, so this cannot be checked.

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Bramham,

2013

Type of study: nested case-control cohort study, secondary analysis of the Vitamins in Pre-eclampsia (VIP) trial. The VIP trial was a RCT of vitamin C and E supplementation to prevent pre-eclampsia in women at increased risk

Setting and country: 25 hospitals in 10 geographical areas between August 2003 and June 2005, UK

Funding and conflicts of interest: The original trial was funded by the Wellcome Trust (registered charity number 210183) with additional support from Tommy’s Charity (registered

charity number 1060508). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Lucy C Chappell is a PLOS ONE Editorial Board member. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

Inclusion criteria:

-gestational age 14⁺⁰ to

21⁺⁶ weeks

-one or more pre-existing risk factors for pre-eclampsia

Exclusion criteria:

-being treated with warfarin or taking vitamin supplements with

>200 mg of vitamin C or >40 IU of vitamin E

daily

-twin pregnancies

-pre-existing proteinuria

-pre-eclampsia without quantification of proteinuria by 24-hour urine collection

-developing HELLP syndrome

N total at baseline:

Intervention:

-PE500, n=161

-CHT, n=615

-GH, n=110

Control:

PE300, n=60

Important prognostic factors²:

Age mean ± SD:

PE300: 32.5 ± 5.5

PE500: 31.6 ± 5.6

CHT: 33.0 ± 5.0

GH: 29.6 ±5.6

Groups comparable at baseline?

Women with CHT (19.3%) were less likely to have had previous pre-eclampsia /HELLP or eclampsia than women with PE300 (37.7%) or PE500 (42.9%)

or GH (40.0%) (P<0.0001). Black ethnicity was more common in both PE300 (24.6%) and PE500 (21.5%) than CH (11.7%) or GH groups (4.5%) (P<0.0001).

Describe intervention (treatment/procedure/test):

1) PE500

pre-eclampsia with proteinuria of at least 500

mg/24h.

Used definition of PE: GH with proteinuria; proteinuria: excretion

of 300 mg protein or more over 24 h.

2) CHT

non-proteinuric chronic hypertension without pre-eclampsia

Used definition CHT: on

antihypertensive treatment pre-pregnancy or as defined by GH, but occurring before 20 weeks’ gestation.

3) GH

non-proteinuric

gestational hypertension

Used definition GH: two or more readings of a diastolic blood pressure of 90 mm Hg or more taken at least 4 h and up to 168 h apart and occurring after 20 weeks of

pregnancy, excluding labour

Describe control (treatment/procedure/test):

PE300

Preeclampsia with maximal quantified proteinuria of 300-499 g/24h

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

one woman (0.1%)

Reasons: was excluded due to incomplete outcome data

Outcome measures and effect size (include 95%CI and p-value if available):

PE300 is the reference group.

Gestational age at delivery, weeks

PE300: 37.3±3.2

PE500: 33.2±4.1; Mean difference (95%CI) 2.02 (-3.01

to -1.03)

P≤0.001

CHT: 38.3±3.7; Mean difference (95%CI) 0.99 (-0.13 to 1.84)

P≤0.05

GH: 39.1±1.7; Mean difference (95%CI) 1.77 (0.89 to 2.64)

P≤0.001

SGA (<10^th adjusted centile)

PE300: 24 (40%)

PE500: 84 (52.5%); RR 1.30 (0.93 to 1.82)

CHT: 122 (20.1%); RR 0.49 (0.35 to 0.69)

GH: 28 (25.7%); RR 0.63 (0.40 to 0.97)

SGA (<5^th adjusted centile)

PE300: 19 (31.7%)

PE500: 79 (49.4%); RR 1.56 (1.04 to 2.33)

CHT: 81 (13.3%); RR 0.48 (0.32 to 0.72)

GH: 18 (16.5%); RR 0.48 (0.32 to 0.72)

Preterm delivery <37 weeks

PE300: 15 (25%)

PE500: 99 (61.5%); RR 2.41 (1.56 to 3.89)

CHT: 83 (13.5%) ; RR 0.60 (0.38 to 0.95)

GH: 10 (9.1%); RR 0.51 (0.23 to 1.10)

Spontaneous preterm delivery

PE300: 2 (3.3%)

PE500: 4 (2.5%)

CHT: 32 (5.2%)

GH: 4 (3.6%)

Iatrogenic preterm delivery

PE300: 13 (21.7%)

PE500: 95 (59.0%); RR 2.72 (1.66 to 4.48)

CHT: 51 (8.3%); RR 0.41 (0.24 to 0.71)

GH: 6 (5.5%)

Preterm delivery < 34 weeks

PE300: 8 (13.3%)

PE500: 43 (26.7%); RR 1.97 (1.01 to 3.85)

CHT: 41 (6.7%); RR 0.64 (0.32 to 1.28)

GH: 0 (0.0%)

Total perinatal deaths

PE300: 2 (3.3%)

PE500: 4 (2.5%)

CHT: 21 (3.4%)

GH: 0 (0.0%)

The reported risk ratios are adjusted for age and ethnicity.

NB: data on group 2 (nonproteinuric GH) will not be used in the guideline text, as this group does not fit the PICO.

Brown, 1996

Type of study: prospective study

Setting and country: two primary referral hospitals (community hospitals), between March 1987 and July 1994, Australia

Funding and conflicts of interest:

No funding or conflicts of interest are reported in the article.

Inclusion criteria: all pregnant women with hypertension who were referred by their obstetrician.

Hypertension was defined as: a sitting systolic blood pressure ≥140 mmHG and/or diastolic blood pressure ≥90 mmHG, or a rise in systolic blood pressure of ≥25 mmHg and/or diastolic blood pressure ≥15 mmHg from first-trimester blood pressure (two readings taken six hours apart)

Indications for referral were:

-hypertension failing to settle after overnight rest in hospital, or repeated measurement in a day-only unit;

-the presence of proteinuria or other abnormal urinalysis;

-recurrent admissions for hypertension; or

-a suspected secondary cause for hypertension.

825 women with pre-eclampsia (development of hypertension after 20 weeks gestation) were included

(mild, 502; severe 323). Mild pre-eclampsia was defined as hypertension only. Severe pre-eclampsia was defined as hypertension and evidence of maternal organ dysfunction.

Exclusion criteria:

-very mild cases of hypertension in pregnancy

N total at baseline:

Intervention: proteinuric hypertension, n=160

Control: non-proteinuric hypertension, n=665

Important prognostic factors²:

Maternal age mean (SD):

I: 28 (5)

C: 28 (5)

Nulliparae (%)

I: 68%

C: 60%

Groups comparable at baseline?

Groups did not differ significantly on maternal age (p=0.82) or parity (p=0.09).

Describe intervention (treatment/procedure/test):

Proteinuric hypertension:

≥ 300 mg/day (24-hour urine collection) or persistently (≥2 days) ≥2+ protein (1 g/L) on urinalysis (dipstick testing). As urinalysis was performed daily, non-proteinuric hypertension was always detected.

Describe control (treatment/procedure/test):

Non-proteinuric hypertension

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

SGA (<10^th centile for gestation, corrected for sex

I: 24%

C: 17%

P=0.044

PNM (per 1000)

Defined as stillbirths and neonatal deaths per 1000 hypertensive pregnancies

I: 38

C: 6

P=0.001

Gestation at delivery (weeks)

I: 36 (4)

C: 38 (2)

p<0.0001

Renal impairment

Defined as serum creatinine level ≥0.10 mmol/L

I: 21%

C: 1%

p<0.0001

Liver disease

Defined as an elevated serum aspartate aminotransferase level >40 IU/L, with or without severe epigastric pain

I: 21%

C: 7%

p<0.0001

Neurological disturbances

Defined as visual scotoma; severe headaches with hyperreflexia; hyperreflexia with sustained clonus (>3 beaths)

I: 33%

C: 7%

p<0.0001

-Brown concluded that proteinuria was associated with higher rates of maternal and fetal complications. However, in Table 4 of their publication the headings ‘No proteinuria’ and ‘Proteinuria’ appeared to mistakenly converted (i.e., showing more maternal and fetal complications in the No proteinuria group). Therefore, we assumed that the data under the heading No proteinuria was presenting the proteinuria group and vice versa.

-Dipstick could be used to assess proteinuria.

Dong, 2017

Type of study: retrospective study

Setting and country: university teaching hospital (main maternal care referral hospital) from September 2011 to June 2013, China.

Funding and conflicts of interest:

Funding was not reported by the article. None of authors have a conflict of interest.

Inclusion criteria:

Women with

preeclampsia.

Preeclampsia was defined as maternal systolic blood pressure

≥140 mmHg and/or diastolic blood pressure ≥90 mmHg measured on two occasions separated by at least 6 h, and proteinuria

>300 mg in a 24 h period, or impaired liver function and lower platelet count, after 20 weeks of gestation.

Exclusion criteria

-Risk factors for developing preeclampsia such as pre-existing hypertension, a previous pregnancy with

preeclampsia, or other underlying medical disorders such as gestational/pre-existing diabetes, or autoimmune diseases

-pregnancies conceived by in vitro fertilisation

N total at baseline:

Intervention

Group 2, n=121

Group 3, n=46

Group 4, n=37

Control

Group 1, n=35

-Early onset, n=135

-Mild PE, n=97

-Severe PE, n=142

Early-onset was defined as pre-eclampsia <34 weeks of gestation. Severe pre-eclampsia was defined as maternal systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg.

Important prognostic factors²:

Age median (range):

Early onset: 30 (18–44)

Mild PE: 30 (18–44)

Severe PE: 29 (19–44)

Groups comparable at baseline?

Not clear.

Describe intervention (treatment/procedure/test):

Group 2:

proteinuria in a 24 h urine collection was between 0.3 g/L and 3 g/L

Group 3:

proteinuria in a 24 h urine collection was between 3 g/L and 5 g/L

Group 4:

proteinuria in a 24 h urine collection was ≥5 g/L.

Describe control (treatment/procedure/test):

Group 1:

proteinuria in a 24h urine collection was <0.3 g/L

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

­Outcome measures and effect size (include 95%CI and p-value if available):

Mild preeclampsia

Group 1: 20 (57%)

Group 2: 46 (38%)

Group 3: 14 (30%)

Group 4: 6 (16%)

Severe preeclampsia

Defined as maternal systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥110 mmHg

Group 1: 15 (43%)

Group 2: 75 (62%)

Group 3: 32 (70%): P < 0.03 compared to group 1.

Group 4: 31 (84%): P < 0.03 compared to group 1.

Fetal grow restriction

FGR was not defined.

Group 1: 4 (11%)

Group 2: 18 (15%)

Group 3: 8 (17.3%)

Group 4: 11 (29.7%)

P= 0.038 group 4 versus group 1 or group 2.

Stillbirth

Group 1: 1 (3%)

Group 2: 4 (3.4%)

Group 3: 9 (19.5%): P = 0.043 compared to group 1 or group 2.

Group 4: 7 (18.9%): P = 0.036 compared to group 1.

Birthweight n=216* (g, mean, 95% CI)

Group 1: 2560 (2401, 2791)

Group 2: 2398 (2313, 2482)

Group 3: 2152 (1987, 2316)

Group 4: 2201 (2022, 2380)

P=0.002 group 4 or group 3 versus group 1 or group 2.

P=0.653 group 4 versus group 3.

 *Texts reports that there were 23 still births in study population, while the outcome measure reports n=21 still births.

Gangaram, 2009

Type of study: prospective study

Setting and country:

hospitals from January 2006 to September 2007, South Africa (Durban Metropolitan region)

Funding and conflicts of interest: Funding was not reported by the article. The authors declare no conflict of interests.

Inclusion criteria:

-hypertension after 20 weeks of gestation

Hypertension was

defined as a blood pressure of at least 140 mm Hg (systolic) or at least 90 mm Hg (diastolic) on 2 occasions 4–6 hours apart.

Exclusion criteria:

-eclampsia

-diabetes

-chronic renal disease

-urinary tract infections

N total at baseline:

Intervention: pre-eclampsia, n=90

Control: gestational hypertension, n=65

Important prognostic factors²:

Maternal age not reported.

Parity

PE

0: 14 (14.9%)

1-4: 79 (84.0%)

>4: 1 (1.1%)

GH

0: 6 (8.7%)

1-4: 62 (89.9%)

>4: 1 (1.4%)

Groups comparable at baseline?

No statistical analyses reported on baseline characteristics.

Describe intervention (treatment/procedure/test):

pre-eclampsia:

hypertension with significant proteinuria (≥0.3 g/24 hours as measured by quantitative 24-hour urine collection)

Describe control (treatment/procedure/test):

gestational hypertension:

hypertension without significant proteinuria (<0.3 g/24 hours as measured by quantitative 24-hour urine collection)

Length of follow-up:

women recruited to the study were followed-up until 1 week post delivery.

Loss-to-follow-up:

Missing data for 8 women (4.9%)

Reasons: patients who delivered at other healthcare

facilities or who delivered prior to coming to hospital because of no access to transport accounted for missing data for 8 women.

Incomplete outcome data:

Not reported.

Outcome measures and effect size (include 95%CI and p-value if available):

Gestational age at delivery, wk (median, (interquartile range)

GH: 38 (3)

PE: 36 (8)

Placental abruption

GH: 2 (3.1%)

PE: 1 (1.1%)

p-value not reported

Eclampsia

GH: 0 (0.0%)

PE: 1 (1.1%)

p-value not reported

Birth weight, g

GH: 2854± 0.755

PE: 2351±0.960

p= 0.001

Stillbirth

GH: 1 (1.5%)

PE: 6 (6.7%)

p-value not reported

Early neonatal death

GH: 1 (1.5%)

PE: 3 (3.3%)

p-value not reported

Perinatal death (including stillbirth and early neonatal death)

GH: 2 (3.1%)

PE: 9 (10%)

P=0.121

The results of the secondary analysis concerning the diagnostic accuracy of the UACR dipstick versus the 24-hour urinary protein test have been left out in this evidence table.

Homer, 2008

Type of study: retrospective study of database

Setting and country: three hospitals (one public hospital, two private hospitals, from 1987 to 2005, Australia

Funding and conflicts of interest: No funding or conflicts of interest are reported in the article.

Inclusion criteria:

-Women referred to the obstetric medicine renal team

Indications for referral were:

-Hypertension failing to settle after overnight rest in hospital or repeated high

measures in a day-only unit

-The presence of proteinuria, neurological factors, abnormal biochemistry

(elevated serum transaminase or creatinine levels) or thrombocytopenia

-Recurrent admissions for hypertension

-A suspected secondary cause for hypertension

Exclusion criteria:

There were no specific exclusion criteria but it is possible that women with very

mild or transient gestational hypertension may not have been referred to this

service.

N total at baseline:

Intervention:

proteinuric PE, n=958

Control:

-non-proteinuric PE, n=357

-GH, n=1192

Important prognostic factors²:

Age mean ± SD:

-Proteinuric PE: 30.0 ±?

-GH: 29.2 ± 5.3

-Non-proteinuric PE: 30.0 ± 4.7

Primigravida

-Proteinuric PE: 71%

-GH: 59.9%

-Non-proteinuric

PE: 66.7%

Multiple pregnancy

-Proteinuric PE: 8.0%

-GH: 3.9%

-Non-proteinuric

PE: 9.9%

Groups comparable at baseline?

Women in the nonproteinuric PE group were older (30.0 years) than in the GH group (29.2 years) (p=0.01). The proportion of primigravida (66.7% versus 59.9%, p=0.03) and multiple pregnancy (9.9% versus 3.9%, p<0.001) was higher in nonproteinuric PE compared to GH.

There were no significant differences between PE with and without proteinuria

in terms of age (30 years in both groups), primiparity (71% versus 67%, p=0.2), or

proportion of multiple pregnancies (8% versus 10%, p=0.2)

Describe intervention (treatment/procedure/test):

proteinuric PE

The definition of

proteinuria was:

-a spot urine protein/ creatinine ratio (≥ 30mg protein per mmol creatinine) used for the past eight years,

- ≥ 300mg per day in the years before this.

-or consistently ≥ ‘2+’ (1g/L) dipstick proteinuria

Describe control (treatment/procedure/test):

1) GH

Average SBP ≥ 140mmHg and/or DBP ≥ 90mmHg (phase 5) (after overnight rest in hospital, or after completion of a

day assessment visit), developing after 20 weeks gestation, without any

evidence of multi-system dysfunction (e.g., kidneys, brain, liver, clotting)

2) non-proteinuric PE

Development of SBP ≥ 140mmHg and/or DBP ≥

90mmHg after 20 weeks gestation in women with no previous history of

hypertension, cardiac or renal disease plus evidence of other organ

involvement (e.g., renal

insufficiency, liver disease, neurological problems, haematological disturbances, fetal growth restriction).

Length of follow-up:

Not reported.

Loss-to-follow-up:

Not reported

Incomplete outcome data:

In 33 (3%) of cases there was uncertainty about the proteinuric status so they were excluded from the analysis.

Outcome measures and effect size (include 95%CI and p-value if available):

Adjusted OR is with adjustments for parity.

PROTEINURIC PE VERSUS NON-PROTEINURIC PE

Gestation at birth, weeks (SD)

Proteinuric PE: 36.7 (2.8)

Non-proteinuric PE: 37.3 (2.2)

p< 0.001

Renal insufficiency

Proteinuric PE: 10.6%

Non-proteinuric PE: 15.1%

P=0.04

Liver disease

Proteinuric PE: 15.9%

Non-proteinuric PE: 28.8%

p< 0.001

Unadjusted OR (95% CI): 0.46 (0.34–0.63), p<0.001

Adjusted OR (95% CI): 0.41 (0.30–0.57)

Preterm delivery (<37 weeks)

Proteinuric PE: 39%

Non-proteinuric PE: 30%

P=0.007

Unadjusted OR: 1.44 (1.11-1.88), p=0.006

Adjusted OR: 1.46 (1.11-1.92)

Perinatal mortality (per 1000 births? Not reported)

Proteinuric PE: 25.2

Non-proteinuric PE: 5.67

P=0.02

Unadjusted OR: 4.70 (1.11-

19.96), p=0.026

Adjusted OR: 4.28 (1.01-

18.16)

GH GROUP VERSUS NON-PROTEINURIC PE GROUP

Gestation at birth, weeks (SD)

GH: 38.4 (1.7)

Non-proteinuric PE: 37.3 (2.2)

p<0.001

Renal insufficiency

GH: 0.0%

Non-proteinuric PE: 14.9%

p<0.001

Liver disease

GH: 0.0%

Non-proteinuric PE: 28.8%

P<0.001

Neurological complications

GH: 0.0%

Non-proteinuric PE: 15.1%

P<0.001

Preterm delivery (<37 weeks)

GH: 11.3%

Nonproteinuric PE: 30.2%

p<0.001

Unadjusted OR: 3.32 (2.48–4.45), p<0.001

Adjusted OR: 3.52 (2.57–4.81)

SGA <10th percentile

GH: 12.7%

Non-proteinuric PE: 20.9%

p<0.001

Unadjusted OR: 1.96 (1.41-2.63), p<0.001

Adjusted OR: 2.03 (1.47-2.80)

Dipstick may be used to assess proteinuria. The authors postulate that dipstick urine was rarely relied upon in this study to make the diagnosis of proteinuria.

Lao, 1988

Type of study: prospective study

Setting and country:

Hospital, between 1985-1986, Hong Kong

Funding and conflicts of interest:

No funding or conflicts of interest are reported in the article.

Inclusion criteria:

-nulliparous

patients who developed pre-eclampsia before the onset of labour

-the final study group comprised patients whose blood pressure had returned to

normal in the puerperium, and in whom proteinuria, if present before, disappeared.

Exclusion criteria

-untreated urinary infection,

history of or suspected renal disease

-history of chronic hypertension

-multiple

pregnancies

-other significant medical complications such as diabetes

mellitus, systemic lupus erythematosus

N total at baseline:

Intervention:

Group A, n=46

Control:

Group B, n=41

Important prognostic factors²:

Maternal age mean ± SD:

Group A: 26.8 ± 4.8

Group B: 26.4 ± 2.7

Not significant

Groups comparable at baseline?

Not reported.

Describe intervention (treatment/procedure/test):

Group A proteinuric group:

urine was tested four times daily with a dipstick. Significant proteinuria was diagnosed when a reading of one-plus or more was found on two or more occasions in samples of clean-catch mid-stream urine.

Describe control (treatment/procedure/test):

Group B non-proteinuric group:

pre-eclampsia was diagnosed according to the criteria of the American College of Obstetricians and Gynaecologists with the modification that both systolic and diastolic pressures had to reach or exceed 140 mm Hg and 90 mm Hg.

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Gestation at delivery (weeks)

Group A: 37.8 ± 2.4

Group B: 38.8 ± 1.4

P<0.03

Birth weight (g)

Group A: 2748 ± 594

Group B: 3103 ± 493

p < 0.004

Birth weight <10^th centile (%)

Group A: 13 (28.3%)

Group B: 6 (14.6%)

Admission into neonatal unit(%)

Group A: 7(15.2%)

Group B: 3(7.3%)

Perinatal mortality

Outcome was reported descriptively as:

“There was only one perinatal loss. This was in a patient with unsuspected hydrops fetalis due to homozygous alpha thalassaemia who developed proteinuric pre-eclampsia at 30 weeks. Labour was induced and resulted in a successful vaginal delivery. The baby died shortly after birth.”

-Dipstick was used to assess proteinuria.

-Only nulliparous women were included.

Li, 2018

Type of study: retrospective study

Setting and country: 11 hospitals in 10 provinces across China between January to December 2015 (tertiary hospitals

managing both low- and high-risk obstetric patients).

Funding and conflicts of interest: This study was supported by the National Natural Science Foundation of China (Grant No. 81490745), the Major National Scientific Research Program of China (Grant No.

2015CB943304), the Beijing Science and Technology Project

(Grant No. Z151100001615051), and the National Science and Technology Support Program of China (Grant No.

2015BAI13B06).

No potential conflict of interest was reported by the authors.

Inclusion criteria:

-pregnancies

 complicated by hypertensive disorders of pregnancy (HDP)

-records of 24h proteinuria

Exclusion criteria:

-delivery<20 gestational weeks

-presence of renal disease

-complicated systemic lupus erythematosus

-chronic

hypertension without superimposed preeclampsia.

N total at baseline:

Intervention:

-Group 2, n=638

-Group 3, n=353

-Group 4, n=419

Control:

Group 1, n=328

Important prognostic factors²:

Maternal age mean ± SD:

Group 1: 32.00 ± 5.40

Group 2: 31.09 ± 5.33

Group 3: 30.65 ± 5.72

Group 4: 30.77 ± 5.39

(p=0.005)

Primiparity:

Group 1: 212 (64.6%)

Group 2: 406 (63.6%)

Group 3: 221 (62.6%)

Group 4: 249 (59.4%)

(p=0.445)

Groups comparable at baseline?

Significant differences were found for maternal age (p=0.005),

maternal weight before pregnancy (p<0.001), and BMI before pregnancy (P<0.001) among the four groups.

Describe intervention (treatment/procedure/test):

Group 2 mild proteinuria:

≥ 0.3 and < 2.0 g/24 h

Group 3 severe proteinuria: ≥ 2.0 and < 5.0 g/24 h

Group 4 massive proteinuria: ≥ 5.0 g/24 h

Describe control (treatment/procedure/test):

Group 1 non-proteinuria:

< 0.3 g/24 h

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Adjusted p: adjusted for age and BMI.

Delivery week, weeks

Group 1: 37.48±3.35

Group 2: 36.94±6.79

Group 3: 34.37±5.20

Group 4: 32.89±4.94

p< 0.001

Renal insufficiency

Defined as serum creatinine (Scr) greater than 97.25 μmol/L (1.2 mg/dL).

Group 1: 2 (0.7%)

Group 2: 13 (2.3%)

Group 3: 13 (4.0%)

Group 4: 21 (5.6%)

p=0.001; adjusted p=0.125

Elevated liver enzyme

Defined as serum aspartate aminotransferase (AST) greater than 40 U/L.

Group 1: 31 (10.0%)

Group 2: 63 (10.5%)

Group 3: 35 (10.3%)

Group 4: 57 (14.2%)

p=0.199; adjusted p=0.801

Episode of eclampsia

Group 1: 0 (0%)

Group 2: 1 (0.2%)

Group 3: 2 (0.6%)

Group 4: 7 (1.7%)

p= 0.005; adjusted p= 0.379

Placenta abruption

Group 1: 5 (1.5%)

Group 2: 11 (1.7%)

Group 3: 6 (1.7%)

Group 4: 9 (2.1%)

p=0.934; adjusted p=0.405

Pulmonary edema

Group 1: 1 (0.3%)

Group 2: 2 (0.3%)

Group 3: 4 (1.1%)

Group 4: 1 (0.2%)

p=0.196; adjusted p=0.972

Maternal death

Group 1: 0 (0.0%)

Group 2: 1 (0.2%)

Group 3: 0 (0.0%)

Group 4: 1 (0.2%)

p=1.000; adjusted p=1.000

Mateus, 2017

Type of study: a secondary analysis of the multicentre PE Triage by Rapid Assay (PETRA) prospective cohort study

Setting and country: 24 centres between June 2010 and July 2012, US

and Canada

Funding and conflicts of interest: No funding or conflicts of interest are reported in the article.

Inclusion criteria:

-pregnant women 16 to 45 years of age

-20^0/7 to 40^0/7 weeks of gestation -signs or symptoms of PE*

Exclusion criteria:

-more than three viable fetuses

-active substance abuse

-on dialysis

-received blood product transfusion within the previous 48 hours

-had known or suspected HIV infection, hepatitis C virus, hepatitis B virus, or other infectious hepatitis

-underlying renal disease.

N total at baseline:

Intervention:

Massive-proteinuria PE, n=36

Control:

-non-proteinuria PE, n=102

-mild-proteinuria PE, n=268

Important prognostic factors²:

Age n (%)

Non-proteinuria PE:

16-24: 28 (27.5%)

25-34: 54 (52.9%)

35-45: 20 (19.6%)

Mild-proteinuria PE:

16-24: 90 (33.6%)

25-34: 130 (48.5%)

35-45: 48 (17.9%)

Massive proteinuria PE:

16-24: 13 (36.1%)

25-34: 18 (50.0%)

35-45: 5 (13.9%)

Groups comparable at baseline?

Nulliparity was more prevalent in women with massive-proteinuria PE (80.6% versus non-proteinuria PE 52% and mild proteinuria PE 62.7% (p=0.003).

Describe intervention (treatment/procedure/test):

Massive-proteinuria PE: proteinuria > 2.7 g in 12 hours or > 5.0 g in 24

hours.

Describe control (treatment/procedure/test):

1) non-proteinuria PE:

proteinuria < 165 mg in 12 hours or < 300 mg in

24 hours

2) mild-proteinuria PE:

proteinuria between 165 mg and 2.7 g in 12 hours or from 300 mg to 4.9 g in 24 hours

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Acute renal failure

Non: 0 (0%)

Mild: 0 (0%)

Massive: 1 (2.8%)

p=0.094

Liver hematoma/rupture

Non: 0 (0%)

Mild: 0 (0%)

Massive: 0 (0%)

p-value: N/A

Renal detachment

Non: 0 (0%)

Mild: 0 (0%)

Massive: 0 (0%)

p-value: N/A

Pulmonary edema/acute respiratory distress syndrome (ARDS)

Non: 3 (2.9%)

Mild: 4 (1.5%)

Massive: 1 (2.8%)

p=0.06

Cortical blindness

Non: 0 (0%)

Mild: 0 (0%)

Massive: 0 (0%)

p-value: N/A

Placental abruption

Non: 0 (0%)

Mild: 5 (1.9%)

Massive: 1 (2.8%)

p=0.09

Eclampsia

Non: 0 (0%)

Mild: 0 (0%)

Massive: 1 (2.8%)

p=0.09

Maternal death

Non: 0 (0%)

Mild: 0 (0%)

Massive: 0 (0%)

p-value: N/A

Estimated fetal weight<10^th percentile

Non: 11 (10.1%)

Mild: 30 (10.2%

Massive: 4 (9.5%)

p=0.99

Estimated fetal weight<5^th percentile

Non: 4 (3.7%)

Mild: 15 (5.1%)

Massive: 2 (4.8%)

p=0.83

Birth weight (g; mean ± SD)

Non: 2,456 ± 885.3

Mild: 1,937 ± 892.8

Massive: 1,392 ± 557.0

p<0.001^a

Gestational age at delivery (median, interquartile range)

Non: 36.6 (34.1–38.4)

Mild: 34.0 (30.6–36.7)

Massive: 31.3 (28.6–33.6)

p<0.001^a

Delivery <37^0/7 weeks

Non: 66 (64.7%)

Mild: 190 (70.9%)

Massive: 31 (86.1%)

p-value: 0.001^a

Delivery <34^0/7 weeks

Non: 23 (22.5%)

Mild: 132 (49.3%)

Massive: 29 (80.6%)

p<0.0001^a

Stillbirth

Non: 0 (0%)

Mild: 2 (0.7%)

Massive: 0 (0%)

p-value: N/A

NICU admission > 48 h for full-term infant

Non: 2 (1.8%)

Mild: 0 (0.0%)

Massive: 0 (0.0%)

p-value: N/A

Neonatal death

Non: 0 (0%)

Mild: 0 (0%)

Massive: 0 (0%)

p-value: N/A

^aSignificant differences noted in all multiple comparisons between the PE groups.

*Signs or symptoms of PE that warranted initial evaluation

were new onset of hypertension defined as SBP ≥ 140 mm Hg or DBP ≥90 mm Hg or rise of SBP ≥30 mm Hg or DBP ≥15 mm Hg from patient’s BP baseline; worsening BP in patients with chronic hypertension; proteinuria defined

as ≥1+ dipstick, ≥0.30 UP/creatinine ratio (UP/CR), or ≥300 mg in 24 hours.

Symptoms potentially associated with PE included persistent epigastric or right upper abdominal pain, nausea, vomiting, or headaches/visual disturbances; excessive weight gain ≥5 pounds per week;

laboratory abnormalities such as thrombocytopenia (platelets < 100,000/µL), aspartate aminotransferase (AST), and alanine transaminase (ALT) twice normal, serum creatinine

> 1.1 mg/dL or having doubled, uric acid > 6.0 mg/dL; unexplained clinical events including oliguria, pulmonary edema, and seizure; fetal growth restriction defined as

sonographic estimated fetal weight (EFW) ≤10th percentile for GA; and suspected fetal/placental hydrops, uterine artery Doppler notching, or placental abruption.

Sheikh, 2015

Type of study: prospective cohort study

Setting and country:

University hospital between April and September 2012, Pakistan.

Funding and conflicts of interest:

No funding or conflicts of interest are reported in the article.

Inclusion criteria:

-primigravidas ≥ 20th weeks of

gestation

-blood pressure >140/90 mm Hg.

Exclusion criteria:

-history of chronic hypertension without

proteinuria

-previous history of renal disease

-chronic hypertension with superimposed preeclampsia (new onset proteinuria)

N total at baseline:

Intervention:

GH proteinuria, n=56

Control:

GH nonproteinuria, n=56

Important prognostic factors²:

Maternal age mean ± SD:

I: 28.3±4.5

C: 26.1±4.58

P-value not reported.

Groups comparable at baseline?

Not reported

Describe intervention (treatment/procedure/test):

Gestational hypertension with proteinuria: hypertension in pregnancy with proteinuria of one 24-hour collection with total protein excretion >300mg/24 hours or two clean catch midstream or catheter specimen of urine collected >4 hours apart with >2+ on reagent strip.

Describe control (treatment/procedure/test):

Gestational hypertension without proteinuria:

diastolic blood pressure >110mmHg on any

one occasion or diastolic blood pressure >90mmHg on two or more consecutive occasions >4 hours apart after 20th week of pregnancy without proteinuria.

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Preterm delivery <37 weeks

I: 20 (35.7%)

C: 8 (14.3%)

p=0.009; RR=3.33

-Only primigravidas were included.

-Dipstick may be used to assess proteinuria.

Thorton 2010

Type of study: retrospective individual patient medical note review

Setting and country:

Tertiary referral centre, between the calendar years 2003–2006, Australia.

Funding and conflicts of interest: This research was conducted towards the award of PhD for CET. CET received a PhD scholarship from the Pre-eclampsia Research

Laboratories (PEARLS), a not-for-profit registered charity, and an

Australian Postgraduate Award.

No conflicts of interest are reported in the article.

Inclusion criteria:

Women with pre-eclampsia in accordance with the Australian Society for the

Study of Hypertension in Pregnancy (ASSHP)^a consensus statement.

^aHypertension and one of the following clinical features:

proteinuria, renal insufficiency, liver disease, neurological problems,

haematological disturbance and ⁄ or fetal growth restriction.

Exclusion criteria:

Twin neonate

N total at baseline:

Intervention proteinuric PE, n=253

Control non-proteinuric PE, n=417

Important prognostic factors²:

Maternal age mean ± SD:

I: 32 ± 6

C: 34 ± 6

P< 0.001

Groups comparable at baseline?

Women with proteinuric pre-eclampsia (32 ± 6) were younger than non-proteinuric women (34 ± 6)

(P<0.001).

Describe intervention (treatment/procedure/test):

Proteinuric PE:

proteinuria was diagnosed by 24 h protein excretion of > 300 mg, a spot protein ⁄ creatinine ratio of 30 mg ⁄ mmol or by 2+ on standard dipstick urinalysis.

Describe control (treatment/procedure/test):

Non-proteinuric PE

Length of follow-up:

Not reported

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

Outcome measures and effect size (include 95%CI and p-value if available):

Gestation at delivery, weeks

I: 32 ± 6

C: 34 ± 6

p< 0.001

Maternal mortality

I: 0

C: 0

P=1.00

Pulmonary oedema

I: 1

C: 0

P=1.00

Acute renal failure

I: 3

C: 1

P=1.00

Eclampsia

I: 0

C: 4

P=1.00

Perinatal mortality rate (per 1000)

I: 12 ⁄ 1000

C: 31 ⁄ 1000

P=0.006

Birth weight < 10th centile (%)

I: 15.8%

C: 15.6%

P=1.00

Birth weight < 3rd centile (%)

I: 4.0%

C: 4.6%

P=0.845

Of the proteinuric cohort, only 31% of women with 2+ protein on dipstick were tested further for protein excretion via the spot protein: creatinine ratio or a 24 h urine collection.

Waugh, 2017

Type of study: prospective diagnostic accuracy study

Setting and country:

36 obstetric units in England

Funding and conflicts of interest: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Edward Lamb (author) reports that he was a member of the development groups for both the National Institute for Health and Care Excellence chronic kidney disease and Kidney Disease Improving Global Outcomes clinical guidelines, which have considered the relative accuracies of proteinuria and albuminuria testing.

Inclusion criteria:

Pregnant women aged ≥16 years who were at >20 weeks’ gestation with confirmed gestational hypertension (systolic BP of ≥140mmHg and/or diastolic BP of ≥90mmHg) and trace or greater of proteinuria on an automated dipstick urinalysis, who are able to given written informed consent.

Exclusion criteria:

Women aged <16 years or women with new hypertension but no proteinuria on automated dipstick urinalysis, proteinuria before 20 weeks’ gestation, pre-existing renal disease, pre-gestational diabetes and chronic hypertension. Women who were unable to provide written informed consent could not take part.

N total at baseline:

Intervention proteinuria (based on 24-h urine) n=475

Control non-proteinuric (based on 24-h urine), n=484

Important prognostic factors²:

Maternal age mean ± SD:

N total median age 30 (26-34) years

Groups comparable at baseline?

Not tested.

Describe intervention (treatment/procedure/test):

Proteinuria:

≥300 mg/24 hour urine based on BZC assay was considered the golden standard.

However, results for outcome measures were only reported based on protein creatinine ratio in urine sample at recruitment, and in 1 case also based on PCR from 24 hour urine sample.

Urine sample:

A small amount of urine (five 1-ml aliquots) was taken from each participant’s POC sample, frozen and stored at –80°C for secondary analysis. The remainder of the POC sample was sent to the local laboratory to obtain quantitative assessments of SPCR.

Participants were then asked to collect urine for 24 hours in a collection container provided by the research midwife. The research midwife gave detailed instructions on when the collection should start and finish. The start of 24-hour urine collection could be up to 24 hours after the POC test. When a woman returned her 24-hour urine sample, a small amount (five 1-ml aliquots) was frozen and stored at –80°C. If clinically indicated from the initial recruitment urine sample, the remainder of the 24-hour urine sample was sent to the local biochemical laboratory to determine the 24-hour measurement of proteinuria. Participants were asked for a third, and final, urine sample immediately before delivery and, again, five 1-ml aliquots were stored at –80°C (delivery urine).

The aliquots of urine were sent from each of the participating sites to a central laboratory, East Kent Hospitals Trust, for analysis using standardised methods. All data were entered into a clinical data management software package supplied by MedSciNet (Stockholm, Sweden) that was configured to allow web-based entry from each of the 36 clinical sites as well as the Kent laboratory.

Clinical information and POC test results were not available to the central laboratory that conducted assessments of 24-hour proteinuria.

Proteinuria was determined based on different methods, 24 hour urine, spot PCR (and spot ACR).

Spot PCR was reported for different measurements:

1. a SPCR test from a local laboratory 2. a SPCR test using the BZC assay at a central laboratory (Kent) 3. a SPCR test using the pyrogallol red (PGR) assay at a central laboratory (Kent) (4. a SACR test from a central laboratory (Kent).> left out of results here, not PICO proof).

Describe control (treatment/procedure/test):

Non-proteinuric:

<300 mg/24 hours urine

Length of follow-up:

Not reported, recruitment was open for 33 months.

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Patients with complete data were included.

At selection n=1 was excluded due to no data to determine adverse perinatal outcome; n=486 due to missing an index test for the primary analysis.

In total, 487/1446 eligible were excluded (33.7%)

Outcome measures and effect size (include 95%CI and p-value if available):

1. Pre-eclampsia

Waugh (2017) reported the outcome measure severe pre-eclampsia for the following comparisons: 1) proteinuria (≥30 mg/mmol) based on protein/creatinine ratio in recruitment urine sample compared to NICE diagnosis of severe pre-eclampsia; 2) proteinuria based on protein/creatinine ratio in recruitment urine sample compared to clinician diagnosis of severe pre-eclampsia; 3) proteinuria based on protein/creatinine ration in 24 hour urine sample stratified for clinician diagnosis of severe pre-eclampsia.

A NICE diagnosis of severe pre-eclampsia was defined as pre-eclampsia with severe hypertension, symptoms, biochemical and/or haematological impairment. A clinician diagnosis of severe pre-eclampsia was defined as treatment with magnesium sulphate or when women were put on severe PE protocol (not further defined) (Waug, 2017).

1:

I: 388/597

C: 29/362

2:

I: 162/597

C: 31/362

3.

I: 161/589

C: 32/370

NB: severe pre-eclampsia was reported based on NICE diagnosis and clinician diagnosis.

For the analysis between 24-hour urine and severe PE data were only compared for severe PE defined by clinician diagnosis.

There is, however, a difference between the clinician and NICE diagnosis:

NICE diagnosis severe PE:

I: 417

C: 542

Clinician diagnosis severe PE:

I: 193

C: 766

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Bramham, 2013

Likely

Women with one or more pre-existing risk factors for pre-eclampsia were included.

Unclear

Nested case-control cohort study: length of follow-up and loss to follow-up not reported.

Unclear

Definitions of several outcome measures were not given, for example perinatal death.

Unlikely

The reported risk ratios are adjusted for age and ethnicity

Brown, 2013

Unclear

Women with mild pre-eclampsia (defined as hypertension only) and severe pre-eclampsia (defined as hypertension and evidence of maternal organ dysfunction) were both included. Subsequently, women were divided into 2 groups: proteinuric hypertension and non-proteinuric hypertension. Thus, it appears that the comparison group exists of both women with and without organ dysfunction.

Dipstick

Unclear

Prospective study: length of follow-up and loss to follow-up not reported.

Unclear

Definitions of the outcome measures are given.

Unlikely

No statistical adjustments have been made to raw results

Dong, 2017

Unlikely

Unlikely

Length and loss to follow-up not described.

Retrospective study

Unclear

Definitions of several outcome measures were not given, for example mild pre-eclampsia and fetal grow restriction.

Unlikely

No statistical adjustments have been made to raw results

Gangaram, 2009

Unlikely

Unlikely

Prospective study

-women recruited to the study were followed-up until 1 week post delivery.

-missing data for 8 women (4.9%). Reasons: patients who delivered at other healthcare

facilities or who delivered prior to coming to hospital because of no access to transport.

Unclear

Definitions of several outcome measures were not given, for example stillbirth and early neonatal death.

Unlikely

No statistical adjustments have been made to raw results

Homer, 2008

Unlikely

Dipstick

Unlikely

Length and loss to follow-up not described.

Retrospective study of database

Unclear

Definitions of several outcome measures were not given, for example renal insufficiency, neurological complications, and liver disease.

Unlikely

Adjusted ORs are with adjustments for parity.

Lao, 1988

Unlikely

Adjustment to the ACOG criteria of pre-eclampsia that both the systolic

and diastolic pressures have to reach or exceed 140 mm Hg and 90 mm Hg,

respectively, for a diagnosis of pre-eclampsia to be made.

Sole use of dipstick

Nulliparous

Unclear

Prospective study: length of follow-up and loss to follow-up not reported.

Unclear

Outcome measures gestation at deliver (weeks) and birth weight in grams and <10^th centile are not clear enough. In addition, it is unclear whether admission into neonatal unit the same is as NICU admission.

Unlikely

No statistical adjustments have been made to raw results

Li, 2018

Unclear

Included were women with pregnancies complicated by hypertensive disorders of pregnancy, but no further definition was given.

Unlikely

Length and loss to follow-up not described.

Retrospective study

Unclear

Definitions of several outcome measures were not given, for example pulmonary oedema, episode of eclampsia, and placenta abruption.

Unlikely

Adjusted for age and BMI.

Mateus, 2017

Unlikely

Twins and triplets included

Unclear

Secondary analysis of prospective cohort study. Length of follow-up and loss to follow-up not reported.

Unclear

Definitions of several outcome measures are not given, for example pulmonary oedema/ARDS.

Unlikely

No statistical adjustments have been made to raw results

Sheikh, 2015

Unlikely

Primigravidas

Dipstick

Unclear

Prospective cohort study: length of follow-up and loss to follow-up not reported.

Unlikely

Only one outcome measure in the study: preterm delivery<37 weeks.

Unlikely

No statistical adjustments have been made to raw results

Thorton, 2009

Unlikely

Dipstick

Unlikely

Length of follow-up and loss to follow-up not described.

Retrospective individual patient medical note review

Unclear

Definitions of several outcome measures were not given, for example pulmonary oedema and acute renal failure.

Unlikely

No statistical adjustments have been made to raw results.

Waugh, 2017

Unlikely

Unlikely

Unclear

The only outcome measure that can be used is severe pre-eclampsia, which was reported based on NICE diagnosis and clinician diagnosis.

NICE diagnosis severe PE:

I: 417

C: 542

Clinician diagnosis severe PE:

I: 193

C: 766

Unlikely

No statistical adjustments have been made to raw results.