Abstract
Background
Myocardial dysfunction occurs in a variety of fetal disorders. Findings from adult cardiology, where n-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established biomarker of left ventricular dysfunction have been extended to fetal life. Since fetal blood sampling is technically challenging we investigated amniotic fluid nt-proBNP for its suitability to diagnose fetal myocardial dysfunction.
Methods
Ultrasound, Doppler examination and echocardiography was applied to classify cases and controls. Amniotic fluid nt-proBNP to amniotic fluid total protein ratio was calculated and compared to the gestational age-dependent reference intervals. In a subset of cases, fetal and maternal plasma nt-proBNP levels were determined.
Results
Specimen from 391 fetuses could be analyzed (171 cases, 220 controls). There was a high correlation between amniotic fluid and fetal blood nt-proBNP levels (r = 0.441 for cases; r = 0.515 for controls), whereas no correlation could be detected between maternal and fetal (blood and amniotic fluid) nt-proBNP concentrations. Specificity and positive likelihood ratio of amniotic fluid nt-proBNP to amniotic fluid total protein ratio were high (0.97 and 4.3, respectively).
Conclusion
Amniotic fluid nt-proBNP measurement allows diagnostic confirmation of fetal myocardial dysfunction. It may serve as a useful adjunct in addition and correlation to existing tests of myocardial function, particularly in the context of invasive fetal therapy, where access to the amniotic cavity is part of the procedure.
Introduction
Myocardial dysfunction accompanies a variety of fetal conditions. These include not only structural cardiac defects, primary myocardial diseases and cardiomyopathies. Diseases which imply an increased cardiac output or altered intrathoracic volume relations (anemia, arterio-venous malformations, sacrococcygeal teratoma, congenital pulmonary airway malformation), chronic twin-transfusion syndrome (TTS) in monochorionic pregnancies, and fetal growth restriction (FGR) have also been shown to impact on cardiac function [1–8]. Minimally invasive surgical techniques have been developed for intrauterine therapy of some of the aforementioned conditions. Serial assessment and timely delivery remain the standard of care for the others [9–12]. Methods available for the assessment of fetal myocardial function include echocardiography, Doppler sonography of the fetal vasculature, myocardial tissue Doppler, and speckle tracking. The influence of cardiac loading conditions and the inter- and intraobserver variability limit the application of these image-based methods [13, 14].
In adult and pediatric patients with heart failure, the cardiac peptide hormone B-type natriuretic peptide (BNP) or its inactive cleavage product, n-terminal pro-B-type natriuretic peptide (nt-proBNP) is an established biomarker for the diagnosis and management of myocardial dysfunction as it allows a comprehensive assessment of the myocardial structure, function and loading. Nt-proBNP- guided therapy has been incorporated into clinical practice [15–20]. Cardiac myocytes secrete BNP in response to stretch; together with A-type natriuretic factor (ANF) BNP regulates pre- and afterload by increasing natriuresis and antagonizing the renin-angiotensin-aldosteron system. Additionally, BNP plays a central role in cardiac remodeling; it has been shown that knock-out mice develop myocardial fibrosis [21]. Recently, nt-proBNP has been analyzed in fetal blood samples, where its role as biomarker in fetal medicine could be established [22–29].
Fetal blood sampling is a technically challenging procedure. In comparison, amniocentesis has a higher success and a lower complication rate. Additionally, access to the amniotic cavity is gained for invasive intrauterine therapies. Difficulties in quantitative amniotic fluid (AF) analysis however arise from the dynamic changes of its composition and volume. Urin and lung fluid are contributors of AF, swallowing and intramembranous transport reduce AF volume; the latter occurs at the amnion covering the placenta and allows direct exchange between AF and fetal blood. Hydrostatic and osmotic gradients additionally act on AF volume and composition. Despite these difficulties in AF reseach, available evidence allows the assumption that AF-nt-proBNP is of fetal origin [30–34].
We previously established reference intervals for AF-nt-proBNP [22]. The aim of our present study was to examine the role of AF-nt-proBNP as a biomarker in pregnancies complicated by fetal conditions associated with myocardial load.
Material and methods
Patients
The study was approved by the Medical School Ethics Committee of the University of Bonn (registration number 305/11). All participating women gave their written consent. Patients with gestational age (GA) between 10 and 34 weeks, presenting at our Center for Prenatal Diagnosis between November 2011 and March 2015 who were scheduled to undergo any invasive intervention that implies access to the amniotic cavity were eligible. No procedure was undertaken for the sole purpose of the study. Additionally, a subset of women who underwent scheduled cesarean delivery between 35 and 40 weeks of gestation were invited to participate. In all cases a detailed assessment of the fetal anatomy and cardiovascular status including echocardiography and Doppler examination was performed. We previously established reference values for AF-ntproBNP and extended these findings by further recruitment of controls. Classification of patients as cases and controls was undertaken according to the following criteria:
Fetuses with conditions that imply an impact on the cardiovascular function such as cardiac, thoracic and urinary tract malformations, congenital diaphragmatic hernia, tumors or intrauterine infections with alterations in cardiovascular loading, chronic TTS, FGR and hydrops were classified as cases. Fetuses with cerebral and skeletal malformations, neural tube defects, and aneuploidies without associated malformations were assigned to the control group, which otherwise consisted of fetuses without any structural abnormality. Further classification criteria were estimated fetal weight, Doppler examination of the umbilical and middle cerebral artery, and qualitative echocardiography. Maternal exclusion criteria were the presence of cardiac or renal diseases. Inclusion and exclusion criteria for controls have been described in detail [35, 36].
In a subset of patients, maternal and fetal blood samples were collected for analysis of hemoglobin and nt-proBNP concentrations. Neonatal notes were reviewed in all cases that ended in a life birth.
Ultrasound, Doppler examination and echocardiography
A detailed description of the fetal assessment, including ultrasound technique, Doppler studies and echocardiography has been published [22]. All examinations followed a standardized protocol and were performed with high-resolution equipment by specialists in fetal diagnostic imaging.
Sample analysis
Nt-proBNP was analyzed with a commercially available chemiluminescence immunoassay on a Dimension Vista 1500, and amniotic fluid total protein concentration (AF-TP) by photometry on a Dimension RxL Max System (Siemens Healthcare Diagnostics, Eschborn, Germany). For nt-proBNP, inter- and intra-assay coefficients of variation were 3.5% and 2.3%, respectively. All samples were processed within two hours after retrieval.
Statistical analysis
To adjust for a potential dilutional effect, the AF-nt-proBNP / AF-TP ratio was calculated and used for analysis. The previously established reference curve was extended to incorporate samples from 34 to 40 weeks of gestation [35, 37]. Non-parametric tests were used for between group analysis of quantitative variables; Pearson’s coefficient was calculated to analyze correlations. Fetal hemoglobin values were transformed into Multiples of the Median (MoM) [38]. We used the statistical software package SPSS 22.0 (SPSS Inc., Chicago, Ill., USA) and SAS Version 9.2 (SAS Institute Inc., Cary, North Carolina, USA) for analysis.
Results
In total, 395 samples were collected. Fig 1 illustrates the flow of the cases through the study. Clinical, obstetric and laboratory details are presented in Table 1, fetal conditions in Table 2. Multiple pregnancies were present in 59 cases. For life births, information on the outcome was retrieved from neonatal reports; prenatal diagnosis was confirmed in all cases.
Fig 1. Study flow diagram.
Table 1. Clinical, obstetric and laboratory details; cases and controls.
| Group 1 (n = 171) Cases |
Group 2 (n = 220) Controls |
p-value | |
|---|---|---|---|
| Gestational age (weeks) | |||
|
Median IQR |
23.0 7 |
21.0 12 |
< 0.001 |
| Parity, n (%) | |||
|
0 1–2 ≥3 Median IQR |
68 (39.8) 85 (49.7) 18 (10.5) 1 2 |
71 (32.3) 124 (56.4) 25 (11.3) 1 2 |
n.s. |
| Body mass index (kg/m2) | (n = 100) | (n = 215) | |
|
Median Range IQR |
25.9 23.7 6.1 |
25.8 26.0 6.6 |
n.s. |
| Indication for invasive procedure, n (%) | |||
|
Amniocentesis Fetocide / embryoreduction Cesarean delivery Amniotic fluid drainage Fetal blood sampling Intrauterine transfusion |
87 (50.9) 59 (34.5) 4 (2.3) 13 (7.6) 6 (3.5) 2 (1.2) |
129 (58.6) 62 (28.2) 28 (12.7) 0 1 (0.5) 0 |
|
| Multiple pregnancies, n | 31 | 28 | |
|
Monochorionic twins Dichorionic twins Higher order |
22 7 2 |
0 19 9 |
|
| Maternal hemoglobin (g/dL) | (n = 55) | (n = 42) | |
|
Median IQR |
11.8 1.2 |
11.9 1.4 |
n.s. |
| MoM* fetal hemoglobin, n (%) | (n = 55) | (n = 40) | |
|
>0.84 0.65–0.84 0.55–0.64 <0.55 |
48 (87.3) 5 (9.1) 0 2 (3.6) |
40 (100) 0 0 0 |
|
| Maternal plasma nt-proBNP (ng/L) | (n = 42) | (n = 34) | |
|
Median IQR |
40 27 |
49 44 |
n.s. |
| Fetal plasma nt-proBNP (ng/L) | (n = 61) | (n = 61) | |
|
Median IQR |
2628 2871 |
1376 1550 |
<0.001 |
*MoM, multiples of the median
Table 2. Fetal diagnoses at enrolment and delivery; cases and controls.
| At enrolment, n (%) | At delivery, n (%) | |
|---|---|---|
| Group 1, cases | 171 (100) | 65 (100) |
| Cardiac malformation | 27 (15.8) | 10 (15.4) |
| syndromal disorder, nos* | 25 (14.6) | 6 (9.2) |
| Twin-transfusion syndrome | 23 (13.5) | 13 (20.0) |
| Trisomy 13+18 | 20 (11.7) | 3 (4.6) |
| Trisomy 21 with associated malformations | 15 (8.8) | 2 (3.1) |
| Diaphragmatic hernia | 13 (7.6) | 5 (7.7) |
| Hydrops | 12 (7.0) | 3 (4.6) |
| Fetal growth restriction | 11 (6.4) | 9 (13.8) |
| Tumor | 7 (4.1) | 5 (7.7) |
| Thoracic malformation | 6 (3.5) | 4 (6.2) |
| Urinary tract malformation | 4 (2.3) | 0 |
| Others | 8 (4.7) | 5 (7.7) |
| Group 2, controls | 220 (100) | 111 (100) |
| Healthy | 122 (55.6) | 94 (84.7) |
| Brain malformation | 33 (15.0) | 4 (3.6) |
| Skeletal malformation | 17 (7.7) | 6 (5.4) |
| Neural tube defect | 15 (6.8) | 1 (0.9) |
| Trisomy 21, isolated | 13 (5.9) | 2 (1.8) |
| Syndromal disorder, nos* | 6 (2.7) | 0 |
| Trisomy 13+18 | 6 (2.7) | 0 |
| Others | 8 (3.6) | 4 (3.6) |
*nos, not otherwise specified
Fetal hemoglobin and plasma nt-proBNP concentrations were determined in 95 cases (122, respectively). A very good correlation was found between nt-proBNP concentration in amniotic fluid and fetal blood (r = 0.441 for cases and r = 0.515 for controls; p < 0.01 for both). Maternal plasma nt-proBNP concentrations, analyzed in a subset of women, were within normal range. No correlation was present between nt-proBNP levels in fetal and maternal blood (maternal blood and amniotic fluid, respectively).
Fig 2 depicts the curves for the mean and 90% confidence limits of the logarithm of the AF-nt-proBNP / AF-TP ratio, with cases and controls plotted. The equation for the curve is: y = 8.965–3.696 * ln (GA). The variation around the curve was found to be constant (sd = 1.282); 5% and 95% percentile curves are calculated as mean + / - 1.282 * 1.645, the 95% quantile of the standardized normal distribution.
Fig 2. Ln (AF-nt-proBNP/AF-TP) in cases (group 1, n = 171) and controls (group 2, n = 220).
Lines represent the mean and the 5% and 95% reference interval.
Specificity (0.97) and positive likelihood ratio (4.3) were high, whereas sensitivity and negative likelihood ratio were low (0.13 and 0.9, respectively).
Discussion
We examined nt-proBNP in amniotic fluid for its role as a biomarker of myocardial dysfunction in fetal medicine, analyzing a large group of fetuses with a broad variety of disorders. The low test sensitivity precludes its application for screening purposes. However, in case of suspected myocardial dysfunction, AF-nt-proBNP determination permits confirmation. It is the only investigation in fetal medicine not based on diagnostic imaging.
Like other amniotic fluid constituents, AF-ntproBNP and AF-TP concentrations are affected by the multitude of compartments contributing to AF inflow and outflow, the hydrostatic and osmotic gradients, and the changes that occur during the course of pregnancy and in fetal disease. Although AF-ntproBNP is of fetal origin [35] we assume that these factors exert an influence on the plasma to AF ratio, act as confounders and interfere with AF analysis [30–34].
Previous investigations on AF-ntproBNP were undertaken in chronic TTS. Here, concentrations correlated with the degree of myocardial dysfunction or disease severity. However, controls were either not available or of small sample size [39–41]. A further study reported on amniotic fluid and umbilical cord BNP at delivery in monochorionic twin pregnancies, whereby higher levels were present in newborns with weight discordance >20% or myocardial dysfunction [42].
We consider AF-nt-proBNP analysis a useful adjunct method in the assessment of fetuses with myocardial dysfunction, particularly in the rapidly expanding field of minimally invasive fetal therapy, since access to the amniotic cavity is part of the procedure. Criteria for case selection, intervention timing, prognosis establishment and treatment evaluation are still being established, and are based exclusively on diagnostic imaging. AF-nt-proBNP analysis and correlation with non-invasive methods of myocardial function assessment may provide further insight into the pathophysiology of fetal cardiac function and mechanisms of myocardial adaptation.
Additionally, serial analyses of AF-nt-proBNP concentrations allow the assessment of myocardial changes after intrauterine procedures. In fetal anemia, serial analyses of circulating nt-proBNP levels revealed myocardial adaptations with potential long-term implications [23].
Limitations
Ideally, reference intervals should be constructed with datasets from healthy cases. Furthermore, a longitudinal rather than a cross-sectional study design should be applied. However, ethical considerations prohibit an intervention with inherent complications purely for research purposes. A general limitation of nt-proBNP analysis is the assay-specificity which makes comparisons of studies performed with different assays difficult [43, 44].
Conclusion
Indications for prenatal invasive therapy are on the rise and diagnosis, intervention timing and treatment evaluation are limited to ultrasound-based methods. AF-nt-proBNP analysis may become an additional diagnostic tool in fetal medicine. Furthermore, serial analyses may permit insight into mechanisms of myocardial adaptation that occur as a result of altered loading conditions. Nevertheless, validiation with an independent dataset is required.
Supporting information
(SAV)
Data Availability
All relevant data are within the paper and its Supporting Information Files.
Funding Statement
The authors received no specific funding for this work.
References
- 1.Donofrio MT, Moon-Grady AJ, Hornberger LK, Copel JA, Sklansky MS, Abuhamad A et al. Diagnosis and treatment of fetal cardiac disease. A scientific statement from the American Heart Association. Circulation. 2014;129:2183–2242. 10.1161/01.cir.0000437597.44550.5d [DOI] [PubMed] [Google Scholar]
- 2.Cruz-Lemini M, Crispi F, van Mieghem T, Pedraza D, Cruz-Martinez R, Acosta-Rojas R et al. Risk of perinatal death in early-onset intrauterine growth restriction according to gestational age and cardiovascular Doppler indices: a multicenter study. Fetal Diagn Ther. 2012;32:116–122. 10.1159/000333001 [DOI] [PubMed] [Google Scholar]
- 3.Van Mieghem T, Hodges R, Jaeggi E, Ryan G. Functional echocardiography in the fetus with non-cardiac disease. Prenat Diagn. 2014;34:23–32. 10.1002/pd.4254 [DOI] [PubMed] [Google Scholar]
- 4.Crispi F, Gratacos E. Fetal cardiac function: Technical considerations and potential research and clinical applications. Fetal Diagn Ther. 2012;32:47–64. 10.1159/000338003 [DOI] [PubMed] [Google Scholar]
- 5.Moon-Grady AJ. Fetal echocardiography in twin-twin transfusion syndrome. Am J Perinatol. 2014;S01:S31–38. [DOI] [PubMed] [Google Scholar]
- 6.Weber R, Kantor P, Chitayat D, Friedberg MK, Golding F, Mertens L et al. Sectrum and outcome of primary cardiomyopathies diagnosed during fetal life. JACC Heart Fail. 2014;2:403–411. 10.1016/j.jchf.2014.02.010 [DOI] [PubMed] [Google Scholar]
- 7.Davis L, Thornburg KL, Giraud GD. The effects of anaemia as a programming agent in the fetal heart. J Physiol. 2005;565:35–41. 10.1113/jphysiol.2004.082388 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zanardini C, Papageorghiou A, Bhide A, Thilaganathan B. Giant placental chorioangioma: natural history and pregnancy outcome. Ultrasound Obstet Gynecol. 2010;35:332–336. 10.1002/uog.7451 [DOI] [PubMed] [Google Scholar]
- 9.Deprest JA, Flake AW, Gratacos E, Ville Y, Hecher K, Nicolaides K et al. The making of fetal surgery. Prenat Diagn. 2010;30:653–667. 10.1002/pd.2571 [DOI] [PubMed] [Google Scholar]
- 10.Diemert A, Diehl W, Glosemeyer P, Deprest J, Hecher K. Intrauterine surgery—choices and limitations. Dtsch Arztebl Int. 2012;109:603–608. 10.3238/arztebl.2012.0603 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Van Mieghem T, Baud D, Devlieger R, Lewi L, Ryan G, de Catte L, et al. Minimally invasive fetal therapy. Best Pract Res Clin Obstet and Gynaecol. 2012;26:711–725. [DOI] [PubMed] [Google Scholar]
- 12.Schidlow DN, Tworetzky W, Wilkins-Haug LE. Percutaneous fetal cardiac interventions for structural heart disease. Am J Perinatol. 2014;31:629–636. 10.1055/s-0034-1383884 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Godfrey ME, Messing B, Cohen SM, Valsky DV, Yagel S. Functional assessment of the fetal heart: a review. Ultrasound Obstet Gynecol. 2012;39:131–144. 10.1002/uog.9064 [DOI] [PubMed] [Google Scholar]
- 14.Gardiner HM. Foetal cardiac function: assessing new technologies. Cardiol Young. 2014;24(S2):26–35. [DOI] [PubMed] [Google Scholar]
- 15.Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure. A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation. 2013;128:e240–e327. 10.1161/CIR.0b013e31829e8776 [DOI] [PubMed] [Google Scholar]
- 16.McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2012;33:1787–1847. 10.1093/eurheartj/ehs104 [DOI] [PubMed] [Google Scholar]
- 17.Januzzi JL, Troughton R. Are serial BNP measurements useful in heart failure management?: Serial natriuretic peptide measurements are useful in heart failure management. Circulation. 2013;127:500–508. 10.1161/CIRCULATIONAHA.112.120485 [DOI] [PubMed] [Google Scholar]
- 18.Desai AS. Are serial BNP measurements useful in heart failure management?: Serial natriuretic peptide measurements are not useful in heart failure management. Circulation. 2013;127:509–516. [DOI] [PubMed] [Google Scholar]
- 19.Troughton RW, Frampton CM, Brunner-La Rocca HP, Pfisterer M, Eurlings LW, Erntell H, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35:1559–1567. 10.1093/eurheartj/ehu090 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Cantinotti M, Walters HL, Crocetti M, Marotta M, Murzi B, Clerico A. BNP in children with congenital cardiac disease: is there now sufficient evidence for its routine use? Cardiol Young. 2015;25:424–437. 10.1017/S1047951114002133 [DOI] [PubMed] [Google Scholar]
- 21.Ogawa T, de Bold AJ. Natriuretic peptides In: Pandey KN, editor. Natriuretic peptides. Physiology, molecular biology, and clinical implications. Nova; New York, 2014. pp. 1–30. [Google Scholar]
- 22.Merz WM, Kübler K, Albers E, Stoffel-Wagner B, Gembruch U. N-terminal pro-B-type natriuretic peptide in the circulation of fetuses with cardiac malformations. Clin Res Cardiol. 2012;101:73–79. 10.1007/s00392-011-0366-4 [DOI] [PubMed] [Google Scholar]
- 23.Merz WM, Kübler K, Fimmers R, Stoffel-Wagner B, Geipel A, Gembruch U. Circulating n-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment. Ped Res. 2012;72:174–178. [DOI] [PubMed] [Google Scholar]
- 24.Merz WM, Kübler K, Fimmers R, Willruth A, Stoffel-Wagner B, Gembruch U. Cardiorenal syndrome is present in human fetuses with severe, isolated urinary tract malformations. PLOS ONE. 2013;8:e63664 10.1371/journal.pone.0063664 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Luterek K, Szymusik I, Bartkowiak R, Koltowski L, Filipiak KJ, Wielgos M. N-terminal pro-B-type natriuretic peptide: a potential marker of fetal heart failure in hemolytic disease. Neuroendocrinol Lett. 2011;32:657–662. [PubMed] [Google Scholar]
- 26.Girsen A, Ala-Kopsala M, Mäkikallio K, Vuolteenaho O, Räsänen J. Cardiovascular hemodynamics and umbilical artery N-terminal peptide of proB-type natriuretic peptide in human fetuses with growth restriction. Ultrasound Obstet Gynecol. 2007;29:296–303. 10.1002/uog.3934 [DOI] [PubMed] [Google Scholar]
- 27.Lechner E, Wiesinger-Eidenberger G, Wagner O, Weissensteiner M, Schreier-Lechner E, Leibetseder D, et al. Amino terminal pro B-type natriuretic peptide levels are elevated in the cord blood of neonates with congenital heart defect. Pediatr Res. 2009;66:466–469. 10.1203/PDR.0b013e3181b3aee4 [DOI] [PubMed] [Google Scholar]
- 28.Kocylowski RD, Dubiel M, Gudmundsson S, Sieg I, Fritzer E, Alkasi O, et al. Biochemical tissue-specific injury markers of the heart and brain in postpartum cord blood. Am J Obstet Gynecol. 2009;273.e1–273.e25. [DOI] [PubMed] [Google Scholar]
- 29.Bahlmann F, Krummenauer F, Spahn S, Gallinat R, Kampmann C. Natriuretic peptide levels in intrauterine growth-restricted fetuses with absent and reversed end-diastolic flow of the umbilical artery in relation to ductus venosus flow velocities. J Perinat Med. 2011;39:529–537. 10.1515/JPM.2011.065 [DOI] [PubMed] [Google Scholar]
- 30.Schmidt W. The amniotic fluid compartment: the fetal habitat. Adv Anat Embryol Cell Biol. 1992;127:1–100. [DOI] [PubMed] [Google Scholar]
- 31.Matsumoto LC, Cheung CY, Brace RA. Effect of esophageal ligation on amniotic fluid volume and urinary flow rate in fetal sheep. Am J Obstet Gynecol. 2000;182:699–705. [DOI] [PubMed] [Google Scholar]
- 32.Ross MG, Brace RA, and the NIH Workshop Participants. National Institute of Child Health and Development conference summary: Amniotic fluid biology—basic and clinical aspects. J Matern Fetal Neonatal Med. 2001;10:2–19. [DOI] [PubMed] [Google Scholar]
- 33.Brace RA, Vermin LM, Huijssoon E. Regulation of amniotic fluid volume: Intramembranous solute and volume fluxes in late gestation fetal sheep. Am J Obstet Gynecol. 2004;191:837–846. 10.1016/j.ajog.2004.01.048 [DOI] [PubMed] [Google Scholar]
- 34.Anderson DF, Jonker SS, Louey S, Cheung CY, Brace RA. Regulation of intramembranous absorption and amniotic fluid volume by constituents in fetal sheep urine. Am J Physiol Regul Integr Comp Physiol. 2013;305:R506–511. 10.1152/ajpregu.00175.2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Merz WM, Leufgen C, Fimmers R, Stoffel-Wagner B, Gembruch U. Reference intervals for n-terminal pro-B-type natriuretic peptide in amniotic fluid between 10 and 34 weeks of gestation. PLOS ONE. 2014;9:e114416 10.1371/journal.pone.0114416 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Merz WM, Kübler K, Albers E, Stoffel-Wagner B, Gembruch U. Reference values for N-terminal pro-B-type natriuretic peptide in fetal circulation between 20 and 34 weeks of gestation. Clin Biochem. 2010;43:519–521. 10.1016/j.clinbiochem.2009.11.012 [DOI] [PubMed] [Google Scholar]
- 37.Royston P, Wright EM. How to construct ‘normal ranges’ for fetal variables. Ultrasound Obstet Gynecol. 1998;11:30–38. 10.1046/j.1469-0705.1998.11010030.x [DOI] [PubMed] [Google Scholar]
- 38.Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med. 2000;342:9–14. [DOI] [PubMed] [Google Scholar]
- 39.Delabaere A, Marceau G, Kemeny S, Sapin V, Ughetto S, Coste K, et al. Intra-amniotic N-terminal pro-brain natriuretic peptide in severe twin-to-twin transfusion syndrome treated by fetoscopic laser coagulation. Ultrasound Obstet Gynecol. 2010;35:620–623. 10.1002/uog.7579 [DOI] [PubMed] [Google Scholar]
- 40.Habli M, Cnota J, Michelfelder E, Salisbury S, Schnell B, Polzi W, et al. The relationship between amniotic fluid levels of brain-type natriuretic peptide and recipient cardiomyopathy in twin-twin transfusion syndrome. Am J Obstet Gynecol. 2010;203:404.e1–7. [DOI] [PubMed] [Google Scholar]
- 41.Van Mieghem T, Done E, Gucciardo L, Klaritsch P, Allegaert K, van Bree R, et al. Amniotic fluid markers of fetal cardiac dysfunction in twin-to-twin transfusion syndrome. Am J Obstet Gynecol. 2010;202:48.e1–7. [DOI] [PubMed] [Google Scholar]
- 42.Moriichi A, Cho K, Furuse Y, Akimoto T, Kaneshi Y, Yamada T, et al. B-type natriuretic peptide levels are correlated with birth-weight discordance in monochorionic-diamniotic twins without twin-twin transfusion syndrome. J Perinatol. 2013;33:182–187. 10.1038/jp.2012.94 [DOI] [PubMed] [Google Scholar]
- 43.Clerico A, Emdin M. Diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides: A review. Clin Chem. 2004;50:33–50. 10.1373/clinchem.2003.024760 [DOI] [PubMed] [Google Scholar]
- 44.Yandle TG, Richards AM. B-type natriuretic peptide circulating forms: analytical and bioactivity issues. Clin Chim Acta. 2015;448:195–205. 10.1016/j.cca.2015.07.004 [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
(SAV)
Data Availability Statement
All relevant data are within the paper and its Supporting Information Files.