Академический Документы
Профессиональный Документы
Культура Документы
DOI: 10.1111/j.1471-0528.2011.02960.x
www.bjog.org
Department of Renal Medicine, Monash University, Box Hill, Victoria, Australia b Department of Nephrology, Royal Melbourne Hospital,
Parkville, Victoria, Australia c Division of Obstetrics, Sunshine Hospital, St Albans, Victoria, Australia
Correspondence: Professor LP McMahon, Department of Renal Medicine, Monash University, 2nd Floor, 5 Arnold Street, Box Hill, Victoria,
Australia. Email lawrence.mcmahon@easternhealth.org.au
Accepted 21 February 2011. Published Online 12 April 2011.
Australia.
Population A cohort of 265 women with a singleton pregnancy,
Please cite this paper as: Baweja S, Kent A, Masterson R, Roberts S, McMahon L. Prediction of pre-eclampsia in early pregnancy by estimating the spot
urinary albumin: creatinine ratio using high-performance liquid chromatography. BJOG 2011;118:11261132.
Introduction
Pre-eclampsia remains a major cause of perinatal and
maternal morbidity and mortality, and is one of the most
common medical complications of pregnancy.13 Although
there is no established preventative therapy, there is potential gain in being able to identify the women and fetuses at
risk, so that appropriate monitoring can ensue, as well as
1126
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
Methods
This was a prospective exploratory study of women with
singleton pregnancies attending an antenatal clinic at a tertiary teaching hospital in Victoria, Australia, from March
2006 to December 2007. All women attending clinics were
asked to participate in the study at the time of booking
(between 12 and 20 weeks of gestation), and were recruited
if they agreed. The study was approved by the regional ethics committee, and written informed consent was obtained
from all participating women. Inclusion criteria were
women over 18 years of age, singleton pregnancy,
20 weeks of gestation at the time of recruitment, and nil
proteinuria upon measurement with a dipstick. Women
with haematuria, dipstick-positive proteinuria, ongoing urinary tract infection, multiple pregnancy, acute renal failure,
chronic kidney disease (CKD), assisted reproduction, or a
poor obstetric history were excluded. However, women
with a past history of urinary tract infection, renal failure,
haematuria, or proteinuria were included if there was no
evidence of current disease, if the urine was dipstick-negative for proteinuria, and if the serum creatinine level was
within the normal range. CKD was diagnosed if the patient
had a personal history of CKD, if there was evidence of
impaired renal function, or if the patient was under a
nephrologists care. Chronic hypertension was diagnosed if
the patient was already taking anti-hypertensive medication
or displayed hypertension before 20 weeks of gestation.
Data regarding demographic profile, blood pressure, body
mass index (BMI), and medical and family history (history
of chronic hypertension, diabetes mellitus, and/or CKD)
were recorded. Obstetric history documented gravidity,
parity, past history of pre-eclampsia, prematurity, small for
gestational age (SGA), miscarriage, and family history of
pre-eclampsia.
Between 17 and 20 weeks of gestation, all women were
given a sterile urine container without preservative and,
after instruction, a mid-stream urine sample was collected.
Routine microscopic and dipstick examination of urine was
performed, and within 3060 minutes of collection the
sample was stored at 20C for ACR analysis at the end of
the study. Participants were then followed until delivery.
The primary outcome measure was pre-eclampsia, defined
according to standard clinical criteria.25 Secondary outcome
measures included gestational hypertension (GH), SGA,
gestational diabetes mellitus (GDM), gestational age, and
prematurity, and a normal range estimate of urinary ACR
was established.
The definition of GH was a blood pressure of 140/
90 mmHg occurring after 20 weeks of gestation in a previously normotensive woman.28 GDM was defined as a positive 50-g oral glucose challenge test [with a venous plasma
glucose level 1 hour after glucose challenge of at least
7.8 mmol/l (140 mg/dl)], and a positive 75-g oral glucosetolerance test at 2428 weeks of gestation [with venous
plasma glucose levels of <7.8 mmol/l after an overnight fast
and 7.811.0 mmol/l (198 mg/dl) at 2 hours).26 SGA was
diagnosed when the birthweight was below the tenth centile
for the gestational age,27 and prematurity was defined as
birth on or before the end of the last day of the 37th week
(259th day) following the onset of the mothers last menstrual period, or by initial ultrasound estimation.28
Total intact urinary albumin (immunoreactive plus immunounreactive) was determined by analysing urine samples
using a Hewlett Packard 1100 HPLC system with UVvisible
detector (Hewlett Packard, Waldbronn, Germany). Aliquots
of urine (25 ll) were injected onto a Zorbax Bio series
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
1127
Baweja et al.
preparative GF-250 column. The mobile phase was phosphate-buffered saline run at a flow rate of 0.5 or 2.0 ml/
minute in a gradient system. The urinary albumin peak
was identified to within 2% of the elution time of the
monomer albumin standard. Urine creatinine was measured by modified kinetic Jaffe reaction without deproteinization using COBAS INTEGRA systems.
Statistical analysis was performed by pasw statistics
v18 software. As this is the first exploratory study to use
this technique in pregnancy, a meaningful power calculation could not be performed. Comparison of spot urinary
ACR and birthweight between unaffected, gestational
hypertensive, and pre-eclamptic groups were performed by
KruskalWallis test or MannWhitney U-test. Comparison
of the mean of the continuous data (normally distributed)
was performed by analysis of variants (anova), and chisquare analysis was used to compare categorical data
between groups. For post hoc analysis of normally-distributed continuous data, Bonferonis test was applied. Sensitivity, specificity, positive predictive value (PPV), and
negative predictive value (NPV) at different values of ACR
for predicting pre-eclampsia were calculated from the receiver operating curve (ROC).
Results
After obtaining informed consent, 295 women were
enrolled at between 12 and 20 weeks of gestation. Thirty
(10.1%) women were excluded subsequently because of
missing outcome data (miscarriage, transferral to another
facility, withdrawal of consent, or misplaced urine sample
during transport); therefore, 265 women were included in
the final analysis (Tables 1 and 2).
The mean maternal age was 29.5 4.7 years and the
mean BMI was 26.9 6.2 kg/m2. Most women were of
Australian (44.5%) or European (33.2%) descent, and
91 (34.3%) were primigravid. Six (2.3%) developed preeclampsia, and 11 (4.2%) developed GH. The remainder
did not develop hypertensive complications during followup. Nine babies (3.4%) were SGA at birth, three of which
were born to mothers who had pre-eclampsia. Twenty-one
(7.9%) women developed GDM. Fifteen women (5.75%)
Age (years)
Ethnicity, n (%)
Australian
European
Asian
African
ATSI
Others
BMI, kg/m2
Primigravida, n (%)
SBP, mmHg
DBP, mmHg
MAP, mmHg
DM, n (%)
CHT, n (%)
PH renal disease, n (%)
PH PE, n (%)
FH DM, n (%)
FH HT, n (%)
FH CKD, n (%)
GDM, n (%)
Unaffected
(n = 248)
Gestational
hypertension
(n = 11)
Pre-eclampsia
(n = 6)
SGA
(n = 9)
P*
29.5 4.7
31.1 5.8
26.3 4.9
27.6 5.3
0.142
111 (44.8)
84 (33.9)
40 (16.1)
6 (2.4)
1 (0.4)
6 (2.4)
26.8 6.1
82 (33.0)
109 10.7
65 8
101 10
15 (6.0)
19 (7.7)
9 (3.6)
5 (2.0)
101 (40.7)
96 (38.7)
10 (4.0)
20 (8.15)
5 (45.5)
1 (9.1)
3 (27.3)
1 (9.1)
1 (9.1)
0
27.8 5.9
5 (45.4)
120 13
71 8
111 12
0
2 (18.2)
1 (9.1)
0
6 (54.5)
7 (63.6)
1 (9.1)
1 (9.1)
3 (50.0)
0
2 (33.3)
1 (16.7)
0
0
30.3 10.2
4 (66.7)
116 21
67 12
106 18
0
2 (33.3)
0
0
3 (50.0)
4 (66.7)
2 (33.3)
0
4 (44.4)
4 (44.4)
0
1 (11.1)
0
0
26.4 7.1
4 (44.4)
108 18
64 10
100 16
0
1 (11.1)
0
0
4 (44.4)
6 (66.7)
2 (22.2)
0
0.023
0.334
0.98
0.001**
0.054**
0.008**
0.580
0.046
0.004
0.840
0.612
0.110
0.004
0.762
ATSI, Australian Torres Strait islanders; CHT, chronic hypertension; DBP, Diastolic blood pressure; FH, family history; MAP, mean arterial pressure;
PE, pre-eclampsia; PH, past history; SBP, systolic blood pressure.
Data are means SDs, except as indicated.
*Reflects comparison between unaffected, gestational hypertension, and pre-eclampsia groups. (The SGA group was comprised of patients from
the unaffected and pre-eclampsia groups).
**Significant difference only between gestational hypertension and unaffected group.
1128
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
ACR (mg/mmol)
Gestational age at delivery
Mode of delivery
Normal vaginal delivery
Caesarean section
Birthweight (g)***
Prematurity, n (%)
Gestational
hypertension
(n = 11)
Pre-eclampsia
(n = 6)
SGA
(n = 9)
P*
28 (1646)
39.2 1.9
27 (835)
38.4 1.7
50 (3390)
36.7 2.4
55 (3276)
37.4 1.8
0.042
0.003**
179 (72.2)
69 (27.8)
3420 (30903740)
9 (3.6)
8 (72.7)
3 (27.3)
3270 (30383700)
1 (9.1)
2 (33.3)
4 (66.7)
2270 (13783420)
4 (66.7)
5 (55.6)
4 (44.4)
2250 (17312490)
3 (37.5)
0.115
0.024
<0.001
*Reflects the comparison between unaffected, gestational hypertension, and pre-eclampsia groups (as per Table 1).
**Significant difference between pre-eclampsia and other groups.
***Median and IQR.
Discussion
Pre-eclampsia remains a leading cause of maternal and fetal
mortality and morbidity.1 In the last few years some of the
molecular mechanisms underlying pre-eclampsia have been
clarified. Studies have shown that alterations in the regulation and signalling of angiogenic pathways that contribute to
the inadequate cytotrophoblast invasion are seen in preeclampsia. High levels of anti-angiogenic factors (soluble
fms-like tyrosine kinase-1 and soluble endoglin) and low
levels of pro-angiogenic factors (VEGF, PIGF) may subsequently contribute to widespread maternal endothelial dysfunction and the clinical syndrome of pre-eclampsia.10,20,29,30
Endothelial dysfunction has been demonstrated as early as
22 weeks of gestation,12 and the level of anti-angiogenic
factors start rising as early as 17 weeks of gestation.10 It could
be expected that microalbuminuria, a marker of endothelial
dysfunction, might also be apparent by this time, although perhaps at a level undetectable by immunochemical
methods. However, HPLC is more sensitive than any of the
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
1129
Baweja et al.
1130
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
Conclusion
When urinary albumin is measured by HPLC, spot urinary
ACR values are higher in uncomplicated pregnancy in
comparison with conventional methods. A spot urinary
ACR value of 35.5 mg/mmol (measured by HPLC
between 17 and 20 weeks of gestation) predicted future preeclampsia with a sensitivity and specificity of 83.3% and
61.2%, respectively. Additional studies and a costbenefit
analysis are required to confirm these findings before
recommending this test for screening purposes. The molecular nature of the excreted albumin fractions and the
underlying mechanisms of proteinuria in early pregnancy
also need to be explored.
Disclosure of interests
None.
Contribution to authorship
SB analysed the data and wrote the article. AK was
involved in planning strategies, recruitment, and sample
collection. SR was involved in conducting patient visits and
in the collection of data. RM was involved in planning
strategies and in the enrolment of the patients. LPM was
involved in planning strategies, recruitment, analysis of
data and writing the article.
Funding
Internal sources.
Acknowledgements
We thank the patients for their participation in the study
and the nursing staff of Sunshine Hospital for their cooperation. j
References
1 WHO. Make Every Mother and Child Count. World Health Report,
2005. Geneva, Switzerland: World Health Organization, 2005.
2 Lewis G, editor. Why Mothers Die 20002002: The Sixth Report of
Confidential Enquiries into Maternal Deaths in the United Kingdom.
London: RCOG Press, 2004.
3 ACOG Committee on Practice BulletinsObstetrics. ACOG practice
bulletin: diagnosis and management of pre-eclampsia and eclampsia:
number 33, January 2002. Obstet Gynecol 2002;99:15967.
4 Kozer E, Costei AM, Boskovic R, Nulman I, Nikfar S, Koren G. Effects
of aspirin consumption during pregnancy on pregnancy outcomes:
meta-analysis. Birth Defects Res Part B Dev Reprod Toxicol 2003;68:
7084.
5 Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S,
et al. Prevention of preeclampsia and intrauterine growth restriction
with aspirin started in early pregnancy: a meta-analysis. Obstet
Gynecol 2010;116:40214.
6 Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and
related problems. Cochrane Database Syst Rev 2010;8. CD001059.
DOI: 10.1002/14651858.CD001059.pub3.
7 North RA, Ferrier C, Gamble G, Fairley KF, Kincaid-Smith P. Prevention of preeclampsia with heparin and antiplatelet drugs in women
with renal disease. Aust N Z J Obstet Gynaecol 1995;35:35762.
8 Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live
births in patients with recurrent pregnancy loss and positive antiphospholipid antibodies: a meta-analysis of randomized controlled
trials and meta-regression. Rheumatology (Oxford) 2010;49:281
8.
9 Vucic N, Frleta M, Petrovic D, Ostojic V. Thrombophilia, preeclampsia
and other pregnancy complications. Acta Med Croatica 2009;63:
297305.
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG
1131
Baweja et al.
10 Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al.
Soluble endoglin and other circulating antiangiogenic factors in
preeclampsia. N Engl J Med 2006;355:9921005.
11 Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia.
Annu Rev Pathol 2010;5:17392.
12 Khan F, Belch JJ, MacLeod M, Mires G. Changes in endothelial function precede the clinical disease in women in whom preeclampsia
develops. Hypertension 2005;46:11238.
13 Yuyun MF, Khaw KT, Luben R, Welch A, Bingham S, Day NE, et al.
Microalbuminuria independently predicts all-cause and cardiovascular mortality in a British population: the European prospective investigation into cancer in Norfolk (EPIC-Norfolk) population study. Int J
Epidemiol 2004;33:18998.
14 Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, et al. Urinary albumin excretion predicts cardiovascular
and noncardiovascular mortality in general population. Circulation
2002;106:177782.
15 Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen
P, Scharling H, et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation
2004;110:325.
16 Bar J, Hod M, Erman A, Friedman S, Gelerenter I, Kaplan B, et al.
Microalbuminuria as an early predictor of hypertensive complications
in pregnant women at high risk. Am J Kidney Dis 1996;28:2205.
17 Salako BL, Olayemi O, Odukogbe TAA, Adedapo KS, Aimakhu CO,
Alu FE, et al. Microalbuminuria as an early predictor of hypertensive
complications in pregnant women at high risk. WAJM 2003;22:
295300.
18 Shaarawy M, Salem ME. The clinical value of microtransferrinuria
and microalbuminuria in the prediction of preeclampsia. Clin Chem
Lab Med 2001;39:2934.
19 Gaspari F, Perico N, Remuzzi G. Timed urine collections are not
needed to measure urine protein excretion in clinical practice. Am J
Kidney Dis 2006;47:17.
20 KDOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification part 5. Evaluation of laboratory
measurements for clinical assessment of kidney disease. Am J Kidney
Dis 2002;39:S76110.
21 Comper WD, Jerums G, Osicka TM. Differences in urinary albumin
detected by four immunoassays and high-performance liquid chromatography. Clin Biochem 2004;37:10511.
22 Owen WE, Roberts WL. Performance characteristics of an HPLC
assay for urinary albumin. Am J Clin Pathol 2005;124:21925.
23 Polkinghorne KR, Su Q, Chadban SJ, Shaw JE, Zimmet PZ, Atkins
RC. Population prevalence of albuminuria in the Australian diabetes,
obesity, and lifestyle (AusDiab) study: immunonephelometry compared with high-performance liquid chromatography. Am J Kidney
Dis 2006;47:60413.
24 Comper WD, Osicka TM, Clark M, MacIsaac RJ, Jerums G. Earlier
detection of microalbuminuria in diabetic patients using a new urinary albumin assay. Kidney Int 2004; 65:18505.
25 American College of Obstetricians Gynecologists. ACOG practice
bulletin. Diagnosis and management of preeclampsia and eclampsia.
Number 33, January 2002. Int J Gynaecol Obstet 2002;77:6775.
26 American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2002;25(Suppl 1):S946.
27 American College of Obstetricians and Gynecologists. ACOG practice bulletin. Intrauterine growth restriction. Number 12 January
2000. Int J Gynecol Obstet. 2001;72:8596.
28 Engle WA. A recommendation for the definition of Late Preterm
(near-term) and the birth weightgestational age classification system. Semin Perinatol 2006;30:27.
1132
2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2011 RCOG