Low Birth Weight and Congenital Heart Disease: Current Status and Future Directions

Abstract

See related article, p 161Low birth weight is traditionally defined as a birth weight less than 2.5 kg. Regardless of the presence of congenital heart disease, contributory factors for low birth weight include maternal medical conditions, fetal anatomic abnormalities or genetic syndromes, prematurity, in utero growth restriction, or some combination thereof. We have known for decades that neonates with congenital heart disease are at greater risk for being born at low birth weight, with the notable exception of those with d-transposition of the great arteries. We also know that neonates with congenital heart disease have a 2- to 3-fold greater risk of being born prematurely and have a 2-fold greater risk for being small for gestational age.1Levy R.J. Rosenthal A. Fyler D.C. Nadas A.S. Birth weight of infants with congenital heart disease.Am J Dis Child. 1978; 132: 249-254PubMed Google Scholar,2Tanner K. Sabrine N. Wren C. Cardiovascular malformations among preterm infants.Pediatrics. 2005; 116: e833-e838Crossref PubMed Scopus (189) Google Scholar Conversely, the prevalence of congenital heart disease in premature or growth restricted infants is twice that encountered in those who are full term or born at an appropriate birth weight.3Van den Berg B.J. Yerushalmy J. The relationship of the rate of intrauterine growth of infants of low birth weight to mortality, morbidity, and congenital anomalies.J Pediatr. 1966; 69: 531-545Abstract Full Text PDF PubMed Scopus (113) Google Scholar See related article, p 161 Although these associations are well established, the etiology for them is not well understood. Experts have speculated that the abnormal circulatory physiology that exists in fetuses with congenital heart disease may contribute to poor growth and preterm labor. For example, ultrasound data suggest that fetal placental blood flow is diminished in pregnancies complicated by congenital heart disease.4Ho D.Y. Josowitz R. Katcoff H. Griffis H.M. Tian Z. Gaynor J.W. et al.Mid-gestational fetal placental blood flow is diminished in the fetus with congenital heart disease.Prenat Diagn. 2020; 40: 1432-1438Crossref PubMed Scopus (7) Google Scholar A population-based analysis found that certain types of congenital heart disease were associated with lower placental weight z scores at the time of delivery and that the lower placental weight was in turn associated with lower birth weight.5Matthiesen N.B. Henriksen T.B. Agergaard P. Gaynor J.W. Bach C.C. Hjortdal V.E. et al.Congenital heart defects and indices of placental and fetal growth in a nationwide study of 924 422 liveborn infants.Circulation. 2016; 134: 1546-1556Crossref PubMed Scopus (47) Google Scholar Recent investigations have also focused on the role that an impaired maternal-fetal environment may play on birth weight and outcomes for neonates with congenital heart disease. Factors such as maternal hypertension, preeclampsia, or placental abruption are more common in pregnancies complicated by congenital heart disease and have been linked with adverse outcomes.6Gaynor J.W. Parry S. Moldenhauer J.S. Simmons R.A. Rychik J. Ittenbach R.F. et al.The impact of the maternal-foetal environment on outcomes of surgery for congenital heart disease in neonates.Eur J Cardiothorac Surg. 2018; 54: 348-353Crossref PubMed Scopus (26) Google Scholar,7Steurer M.A. Peyvandi S. Baer R.J. Oltman S.P. Chambers C.D. Norton M.E. et al.Impaired fetal environment and gestational age: what is driving mortality in neonates with critical congenital heart disease?.J Am Heart Assoc. 2019; 8: e013194Crossref PubMed Scopus (12) Google Scholar Further insights into these pathophysiologic conditions may provide targets for therapeutic intervention and prevention. Neonates born with critical congenital heart disease typically require intervention in the first weeks of life to prevent early death. Common examples include hypoplastic left heart syndrome, d-transposition of the great arteries, severe aortic coarctation, and interrupted aortic arch, among others. Even when delivered full term at a normal birth weight, such patients are at risk for substantial morbidity, mortality, and prolonged hospitalization. Those born at low birth weight, with or without underlying prematurity or in utero growth restriction, are at greater risk and are among the most challenging patients in terms of decision making and surgical interventions, even for the most seasoned clinicians. Optimal management is unknown and practice varies widely within and among centers. With this as backdrop, the report in this volume of The Journal from Kim et al is a welcome contribution.8Kim M. Okunowo O. Ades A.M. Fuller S. Rintoul N.E. Nami M.Y. Single-center comparison of outcomes following cardiac surgery in low birth weight and standard birth weight neonates.J Pediatr. 2021; 238: 161-167.e1Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar In this retrospective single center study from the Children's Hospital of Philadelphia, the investigators compared outcomes for low birth weight (<2.5 kg) and standard birth weight neonates who underwent cardiac surgery with cardiopulmonary bypass during a recent 6-year period. Propensity score matching was used to make baseline characteristics similar between the low birth weight and standard birth weight groups; case matching was based on the complexity of the operation (STAT Mortality Category), race/ethnicity, year of surgery, and presence of a genetic diagnosis. The key findings of this study were generally not surprising. When compared with the standard birth weight group, those who were low birth weight were less likely to survive to hospital discharge (88% vs 95%) and tended to have longer hospital length of stay. Those who were born at less than 1.5 kg had the worst survival to hospital discharge (50%), whereas those born at >2 kg tended to have survival similar to their larger counterparts. Interestingly, the incidence of major complications did not differ between the low and standard birth weight groups. In the low birth weight patients, survival to hospital discharge was better in the current series when compared with a report from the same institution from an earlier era (2000-2004; 88% vs 76%), although in the current series, there were fewer patients who had a single ventricle with aortic arch obstruction, likely because such patients are more likely to undergo a hybrid type palliation in the current era. As noted by the authors, the study had several limitations. Differences existed between groups in the operative procedures performed despite matching by STAT Mortality Category, and patients who underwent an initial “feeding and growing” strategy followed by surgery after 30 days of age or those who died prior to surgery were excluded. As would be expected, the types of congenital heart disease and related operations were highly heterogeneous, which limits the ability to develop inferences for individual patient groups. In relatively small retrospective studies like this one, unmeasured confounding is potentially problematic. Other unmeasured factors, such as preoperative mechanical ventilation at the time of surgery, surgeon, and preoperative inotropic support, were not assessed. By design, the outcomes were limited to hospital events, and late outcomes such as neurodevelopmental status or unplanned cardiac reinterventions that occurred after hospital discharge were not reported. Finally, Children's Hospital of Philadelphia has a large and experienced pediatric cardiac program, and its findings may not be generalizable to other centers. The authors chose to analyze low birth weight as their primary exposure variable. It would have been perfectly reasonable had they decided to examine small for gestational age status or prematurity as the primary exposure. We anticipate that approach would have yielded findings that were directionally similar: small and immature babies with complex congenital heart disease are at greater risk compared with their full-term and normal size counterparts. That being said, the interplay between birth weight, gestational age, and in utero growth is quite complex.9Steurer M.A. Baer R.J. Burke E. Peyvandi S. Oltman S. Chambers C.D. et al.Effect of fetal growth on 1-year mortality in neonates with critical congenital heart disease.J Am Heart Assoc. 2018; 7: e009693Crossref PubMed Scopus (7) Google Scholar,10Steurer M.A. Peyvandi S. Costello J.M. Moon-Grady A.J. Habib R. Hill K.D. et al.Association between Z-score for birth weight and postoperative outcomes in neonates and infants with congenital heart disease.Circulation. 2020; 142: A12360Crossref Google Scholar Despite these limitations, the findings of this study offer hope that neonatal operative outcomes are gradually improving for this very fragile patient population. Opportunity for improvement continues to exist, and given the magnitude of the problem, a multifaceted approach is needed. From the clinical perspective, strategies that may be beneficial include early referral of low birth weight patients with critical congenital heart disease to centers with substantial expertise in managing these patients. When growth restriction is identified in utero and/or early birth is anticipated, transfer prior to delivery when feasible seems optimal. Programmatically, better collaboration between clinicians with expertise in cardiac intensive care and neonatology in the day-to-day critical care management of these patients may be beneficial.11Costello J.M. Preze E. Nguyen N. McBride M.E. Collins J.W. Eltayeb O.M. et al.Experience with an acuity adaptable care model for pediatric cardiac surgery.World J Pediatr Congenit Heart Surg. 2017; 8: 665-671Crossref PubMed Scopus (3) Google Scholar,12Levy V.Y. Bhombal S. Villafane J. McBride M.E. Chung S. Figueroa M. et al.Status of multidisciplinary collaboration in neonatal cardiac care in the United States.Pediatr Cardiol. 2021; 42: 1088-1101Crossref PubMed Scopus (2) Google Scholar Optimal management in terms of timing and type of intervention for small babies with critical congenital heart disease is unknown. The decision of whether to undertake early or delayed cardiac intervention in the low weight, premature neonate is complex. A period of growth may increase exposure to complications, without significantly decreasing the overall risk of mortality.13Hickey E.J. Nosikova Y. Zhang H. Caldarone C.A. Benson L. Redington A. et al.Very low-birth-weight infants with congenital cardiac lesions: is there merit in delaying intervention to permit growth and maturation?.J Thorac Cardiovasc Surg. 2012; 143 (136 e121): 126-136Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar,14Reddy V.M. McElhinney D.B. Sagrado T. Parry A.J. Teitel D.F. Hanley F.L. Results of 102 cases of complete repair of congenital heart defects in patients weighing 700 to 2500 grams.J Thorac Cardiovasc Surg. 1999; 117: 324-331Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar More recent approaches to staged management, such as the use of branch pulmonary artery banding or a full hybrid procedure, may well be helpful. However, there is a paucity of high-quality studies in the literature, and the lack of granular multicenter studies is striking. Clearly more research is needed, which will require support from federal, industry, and philanthropic sources. Linkage or harmonization of existing clinical registries for neonatology, cardiac surgery, and cardiac intensive care would facilitate large multicenter analyses that would yield highly generalizable data. Further investigation into the various factors that contribute to growth restriction and premature birth in neonates with congenital heart disease is desperately needed. Multidisciplinary educational programs such as those offered by the Pediatric Cardiac Intensive Care Society and Neonatal Heart Society will help disseminate new knowledge. Finally, efforts are needed to ensure that the current public reporting of congenital heart surgery outcome initiatives do not result in the smallest cardiac neonates not being offered potentially lifesaving surgery. Continued concerted efforts by this research team and others are needed to improve outcomes for this complex and vulnerable patient population. Single-Center Comparison of Outcomes Following Cardiac Surgery in Low Birth Weight and Standard Birth Weight NeonatesThe Journal of PediatricsVol. 238PreviewTo compare outcomes between low birth weight (LBW; <2.5 kg) and standard birth weight neonates undergoing cardiac surgery. Full-Text PDF