Natriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome

doi:10.1067/mob.2002.118845

American Journal of Obstetrics and Gynecology

Volume 186, Issue 1, January 2002, Pages 121-127

https://doi.org/10.1067/mob.2002.118845 Get rights and content

Abstract

Objective: Although serial amnioreduction has substantially improved the prognosis of twin-twin transfusion syndrome, the majority of recipient twins develop cardiac dysfunction in utero and some have structural abnormalities in the neonatal period. The mechanism of cardiac dysfunction is unclear. To test the hypothesis that this occurs as a result of preload or pressure overload, we determined atrial natriuretic peptide and brain natriuretic peptide levels and their association with endothelin-1 in monochorionic pregnancies with or without chronic twin-twin transfusion syndrome. Patients And Methods: Matched maternal and fetal blood samples were obtained in utero from monochorial twin pregnancies complicated with (n = 14) and without twin-twin transfusion syndrome (n = 6). Serial fetal echocardiography assessment included cardiac anatomy, chamber size, cardiothoracic ratio, ventricular thickness, and the presence and severity of atrioventricular valve regurgitation. Postnatal echocardiograms were obtained on the surviving twins. The plasma levels of atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 were measured by use of radio-immunoassay. Results: Levels of fetal atrial natriuretic peptide (P <.001), brain natriuretic peptide (P <.001), and endothelin-1 (P <.001) in the recipient fetuses were higher than in donor twins. Fetal concentrations of atrial natriuretic peptide, brain natriuretic peptide, and endothelin-1 in the donor twins were similar to those concentrations in twins that did not have twin-twin transfusion syndrome. Fetal brain natriuretic peptide (P <.01) and endothelin-1 (P <.01) levels were significantly higher in the recipient fetuses when compared to those without severe cardiac dysfunction. A significant positive correlation was present between levels of fetal brain natriuretic peptide and endothelin-1 (y = 230.9 LOG(x) - 264.1, r =.82; P <.01). In contrast, there was no association between levels of fetal atrial natriuretic peptide and the severity of cardiac dysfunction, or with levels of fetal brain natriuretic peptide and endothelin-1. Conclusion: Fetal natriuretic peptide levels were higher in the recipient twins than the co-twins, and the severity of cardiac dysfunction was related to levels of brain natriuretic peptide. These data, thereby, suggest that brain natriuretic peptide is a sensitive surrogate biochemical marker of cardiac dysfunction in the recipient twin. (Am J Obstet Gynecol 2002;186:121–7.)

Section snippets

Patients

This observational study of 14 consecutive cases of monochorionic twins with TTTS and 6 without TTTS, was conducted in a tertiary referral center. Monochorionicity was established ultrasonically by (a) concordant genitalia, (b) interfetal membrane thickness of <2.0 mm, and (c) single placental mass, and was confirmed by use of placental histology after birth. Only those cases in which both fetuses were alive at the time of fetal blood sampling (FBS) were included in this study. The inclusion

Results

Clinical features of the two groups are shown in the Table.

Table. Clinical parameters for monochorionic twins with or without twin-twin transfusion syndrome

Parameter	TTTS (n = 14)	Non-TTTS (n = 6)	P value
Gestational age at diagnosis (wk)	21 (16-28)
Gestational age at FBS (wk)	23 (19-30)	30 (21-34)	NS
Gestational age at delivery (wk)	27 (21-36)	31 (24-36)	NS
Maximum AFL (cm)	58 (35-79)	16 (12-24)	<.001
No. of amnioreductions	2 (1-8)
Total amniotic fluid volume removed (L)	0.7 (.3-20)
Δ Hemoglobin at FBS (g/dL)	3

Comment

This study demonstrates elevated levels of natriuretic peptides ANP and BNP in utero in recipient fetuses of TTTS of midtrimester origin. However, we also found that fetal BNP levels were significantly higher in the recipient fetuses with severe cardiac dysfunction than in those with normal function. In contrast, fetal ANP did not show such an association. Our findings are in keeping with the growing recognition in the human adult subjects that plasma BNP is a sensitive marker in physiologic

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Cited by (78)

Congenital heart disease in monozygotic twins
2020, Developmental and Fetal Origins of Differences in Monozygotic Twins: From Genetics to Environmental Factors
Congenital heart defects (CHDs) represent the most common human birth defect, having a birth prevalence of 7–9 per 1000 singleton live births. CHDs are more common in twin pregnancies with a prevalence of 13 in 1000 total births. Monochorionic (MC) twins are even at higher risk (20 in 1000 total births) compared to dichorionic twins (11 in 1000 total births). In MC twins, all types of congenital heart defects are found. Furthermore, in this specific group of twins the development of acquired structural heart disease can be encountered in association with twin–twin transfusion syndrome.
Cardiomegaly of the larger twin in monochorionic twin pregnancies warrants neonatal intensive care even without twin-to-twin transfusion syndrome
2019, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
Cardiac enlargement is not considered rare among TTTS cases and should be noted even in non-TTTS cases. Increased fetal blood and amniotic fluid levels of BNP are reportedly related to recipient cardiac dysfunction in TTTS [12,27]. Several larger twins in this study did not have TTTS, but were considered to have hemodynamics similar to recipients of TTTS.
Some monochorionic twin pregnancies need intensive cardiac management even in the absence of twin-to-twin transfusion syndrome after birth. The purpose of this study was to investigate risk factors related to persistent hypotension requiring cardiotonic agent use among monochorionic twin pregnancies without twin-to-twin transfusion syndrome.
This was a retrospective study of 316 monochorionic twin pregnancies without twin-to-twin transfusion syndrome (632 babies). All cases were treated in the neonatal intensive care unit. Hypotension was defined as mean arterial blood pressure below the norm for gestational age. Decreased left ventricular ejection fraction was defined as a value <60%. Dopamine, dobutamine and phosphodiesterase III inhibitor were used as cardiotonic agents for hypotension persisting even after adequate infusion.
Among the 632 cases, 33 (5.2%) needed cardiotonic agents for persistent hypotension. The frequency of persistent hypotension with decreased left ventricular ejection fraction was significantly higher among larger twins (4.4%) than among smaller twins (0.6%, p = 0.0038). In larger twins, multivariate analysis showed that Z-score for cardiothoracic area ratio (odds ratio, 2.31; p < 0.001), tricuspid regurgitation (odds ratio, 6.34; p = 0.015) and gestational age at delivery (odds ratio, 0.66; p < 0.001) correlated with persistent hypotension. In smaller twins, univariate analysis showed gestational age at delivery, birth weight, Z-score for birth weight and Z-score for cardiothoracic area ratio of the larger twin were related to persistent hypotension. Concentration of brain natriuretic peptide in the umbilical vein in larger and smaller twins were significantly correlated (coefficient of correlation = 0.792, p < 0.001).
In monochorionic twin pregnancies, attention needs to be given to cardiac size along with amniotic fluid and fetal growth. Both larger and smaller twins carry risks of persistent hypotension after birth. Close observation is needed, especially in cases where the larger twin displays cardiomegaly despite absence of twin-to-twin transfusion syndrome.
Recipient umbilical artery elongation (redundancy) in twin-twin transfusion syndrome
2017, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Myocardial strain and tissue velocities provide a direct reflection of myocardial performance, while the Tei index (which compares the length of time the heart spends in generating relaxation and contraction vs its active state) and cardiac output reflect more global function.5-7 Elevated inactive component N-terminal (NT) pro-brain natriuretic peptide (BNP) levels have been measured in the amniotic fluid (AF), in recipient fetuses with heart failure, or severe disease.8-10 However, the effect of fetal intravascular overload and hypertension on the fetal vascular architecture and its correlation with disease severity remains unknown.
Chronic hypertension in adults causes arterial lengthening in major arteries, but the effects of early fetal hypertension on the twin-twin transfusion syndrome recipient’s vascular architecture remains unknown.
We hypothesize that arterial cord redundancy is related to recipient hypertension and subsequent heart failure. Our objectives were to: (1) establish a 3-dimensional color Doppler ultrasound method of measuring umbilical arterial length relative to its corresponding venous segment in the umbilical cord using artery vein angle; (2) compare recipient artery vein angle to gestational age-matched controls; and (3) test the association of artery vein angle with recipient heart failure.
We compared 3 groups prospectively: twin-twin transfusion syndrome pregnancies undergoing fetoscopic laser surgery (preoperatively) and 2 groups of gestational age-matched controls: uncomplicated monochorionic-diamniotic twin pregnancies and healthy singletons. Using a 3-dimensional color-Doppler volume image of 5 cm of cord near the placental insertion, we traced the umbilical artery and vein producing umbilical artery:vein length, (artery vein index) and measured the artery vein angle between umbilical artery and vein. Correlation of artery vein angle to twin-twin transfusion syndrome stage, maximum vertical pocket, umbilical arterial indices, ductus venosus Doppler, and brain natriuretic peptide were performed. We used pulsed-wave and tissue Doppler to measure tissue Doppler velocities and indexed cardiac output and correlated these with artery vein angle. Comparative statistics, including multivariable linear regression, examined the relationship between umbilical arterial Doppler indices and artery vein angle.
Artery vein angle and artery vein index correlated significantly (R², 0.86; P < .0001), hence, artery vein angle was used for analysis. Mean artery vein angle was 33.1 ± 31.5 degrees in recipients (n = 44), 9.5 ± 6 degrees in monochorionic-diamniotic (n = 11; 22 fetuses), and 8.9 ± 8.3 degrees in singleton controls (n = 16) (P < .001). An artery vein angle ≥26 degrees (>95th percentile for controls) was measured in 52% recipients. Artery vein angle was higher in twin-twin transfusion syndrome stage 3R vs 1 (P = .001). Artery vein angle increased with increasing umbilical arterial pulsatility index (P < .001), and decreased with increasing resistance index (P = .02) after adjusting for gestational age. Interrater agreements to categorize abnormal artery vein angle values was 95% (P < .001). Abnormal ductus venosus Doppler and elevated recipient amniotic fluid N-terminal pro-brain natriuretic peptide/protein levels correlated significantly with artery vein angle. Abnormal artery vein angles were associated with decreased indexed cardiac output, lower tissue Doppler velocities, higher right-sided Tei indices, and severe tricuspid regurgitation.
Umbilical arterial lengthening occurs in 52% of recipients and is associated with abnormal Doppler flows, low systolic tissue Doppler velocities, reduced cardiac output, and elevated markers of cardiac failure. This may reflect chronicity and severity of hypertension in the recipient fetus. Further research is needed to explore the mechanisms of elongation and long-term implications.
Cardiovascular biomarkers in paired maternal and umbilical cord blood samples at term and near term delivery
2016, Early Human Development
Citation Excerpt :
Possibly the fetus has to increase his diuresis by natriuretic peptide elevation in order to maintain an adequate amount of amniotic fluid and to handle maternofetal fluid transfer over the placenta. In discordant twin pregnancies with placental feto-fetal anastomoses could be shown that the acceptor has higher natriuretic peptide levels than the donor, analogous to the distribution of amniotic fluid between donor and acceptor [9]. These literature data support the physiological relevance of natriuretic peptides during fetal development.
Cardiovascular biomarkers might help to identify fetuses or pregnancies at risk.
To examine the umbilical cord neonatal and maternal levels of cardiovascular biomarkers at the time of delivery, and to correlate maternal and fetal biomarker levels to each other, to gestational age and to delivery mode.
In a prospective, observational, cross-sectional, single-center study biomarkers were measured in paired maternal and umbilical venous cord blood samples.
The sample cohort included 66 sets of fetal and maternal blood samples (11 after multiple gestation, 53 after cesarean section, 17 after exposure to labor).
Midregional pro-adrenomedullin (MRproADM), midregional-pro atrial natriuretic peptide (MRproANP), brain natriuretic peptide (BNP), n-terminal-pro brain natriuretic peptide (NTproBNP), copeptin, and high sensitive troponin I (hsTnI) levels were measured.
Mean ± SEM for biomarker levels in umbilical venous/maternal blood were: MRproADM [nmol/L] 1.02 ± 0.04/1.24 ± 0.08, MRproANP [pmol/L] 215.53 ± 12.96/54.65 ± 3.41, BNP [pg/mL] 32.02 ± 3.37/19.76 ± 3.29, NTproBNP [pg/mL] 1228.94 ± 91.73/71.48 ± 8.65, copeptin [pmol/L] 103.42 ± 22.89/10.41 ± 1.71, and hsTnI [pg/mL] 13.54 ± 5.17/4.91 ± 2.37. Fetal MRproANP, NTproBNP, and BNP were inversely correlated with gestational age. Maternal and fetal MRproANP (r = 0.472, p = 0.002) and copeptin (r = 0.572, p < 0.001) levels were correlated, whereas there was no feto-maternal correlation for the other biomarkers. Fetal copeptin was elevated after exposure to labor.
Biomarker levels appear to be regulated independently in mother and fetus. Fetal biomarkers are influenced by gestational age and delivery mode. In this study on term and near term pregnancies without specific fetal pathology, correlation between paired maternal and fetal biomarker levels was weak or not demonstrable.
Consensus protocol for management of early and late twin–twin transfusion syndrome: Delphi study
2024, Ultrasound in Obstetrics and Gynecology
Twin-Twin Transfusion Syndrome: Complications and Management
2023, Practical Guide to Simulation in Delivery Room Emergencies

View all citing articles on Scopus

^☆: Reprint requests: Rekha Bajoria, St Mary's Hospital, Whitworth Park, Manchester M13 OJH, UK. E-mail: [email protected].

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Fetus-Placenta-NewbornNatriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome☆

Abstract

Section snippets

Patients

Results

Comment

Eur J Obstet Gynecol Reprod Biol

Obstet Gynecol

J Biol Chem

Lancet

Obstet Gynecol

Am J Obstet Gynecol

Placenta

A case for routine determination of chorionicity in multiple pregnancies

Prenat Diagn

Clinical and echographic features of in utero cardiac dysfunction in the recipient twin in twin-twin transfusion syndrome

Br Heart J

Vascular anatomy of monochorionic placenta in relation to discordant growth and amniotic fluid volume

Hum Reprod

The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age

Am J Obstet Gynecol

Elevated renin-angiotensin levels in the recipient twin of severe twin-twin transfusion syndrome with neonatal hypertension [abstract]

Placenta

Fetus-Placenta-Newborn
Natriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome☆