Factors associated with development of early and late pulmonary hypertension in preterm infants with bronchopulmonary dysplasia

June 12, 2020

MANUSCRIPT CITATION

Sheth, S., Goto, L., Bhandari, V. et al. Factors associated with development of early and late pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. J Perinatol 40, 138–148 (2020) doi:10.1038/s41372-019-0549-9. PMID: 31723236

REVIEWED BY

Sharada Gowda, MD, FAAP,
Asst Professor of Pediatrics
Baylor College of Medicine

Monika Patil, MD, FAAP
Asst Professor of Pediatrics
Baylor College of Medicine

TYPE OF INVESTIGATION

Clinical prediction guides

QUESTION

Do preterm infants with bronchopulmonary dysplasia (BPD) have independent risk factors that could predict their development of early and late pulmonary hypertension (PH)?

METHODS

  • Design: Retrospective case-control observational study
  • Allocation: Not applicable
  • Blinding: Not applicable
  • Follow-up period: 5 years
  • Setting: Level IV referral NICU
  • Patients: Infants <32 weeks gestational age (GA) at birth, with a birth weight (BW) of <1500 g, and those who died >28 days secondary to severe respiratory causes were Patients who died before or at 28 days of life, had multiple congenital anomalies including chromosomal aneuploidy, congenital structural lung disease, or major congenital heart disease with the exception of ASD, VSD and PDA were excluded. Authors used the NICHD NRN Bronchopulmonary Dysplasia (BPD)[1, 2] consensus definition for infants with GA <32 weeks to categorize and classify their patient population, i.e., treatment with oxygen for at least 28 days with categorization into the following three subgroups at 36 weeks’ postmenstrual age (PMA): (1) mild (breathing room air); (2) moderate (need for a <0.3 fraction of inspired oxygen (FiO2), and (3) severe (need for ≥0.3 FiO2 and/or positive pressure support). Infants with BPD who died of respiratory causes before the assessment date (i.e., after 28 DOL and before 36 weeks PMA) were included in the analysis and considered to have “severe disease.”
  • Intervention: Observational study of existing protocol based care of the neonate in a level IV NICU
  • Outcomes: Early and late Pulmonary Hypertension.
    • Primary outcome: Late Pulmonary Hypertension (LPH) defined as PH diagnosed by specific echo criteria after 28 days of life.
    • Secondary outcomes: Early Pulmonary Hypertension (EPH) categorised as EPH I: PH diagnosed ≤7 DOL, EPH II: PH diagnosed ≤14 DOL and EPH III: PH diagnosed <28 DOL and relationship of EPH and LPH. Diagnosis was made by specific echo criteria.
  • Analysis and Sample Size: 1404 charts reviewed, 353 identified with BPD, of whom 57 were excluded because of multiple congenital anomalies, chromosomal aneuploidy. Identified 258 with BPD, 38 excluded because of no Echocardiogram done per unit protocol to diagnose PH. Echo Criteria used were (1) RV systolic pressure (SP) >40 mmHg; (2) RVSP/systemic systolic blood pressure ratio >0.5; (3) Any ASD/PFO, VSD or PDA with bidirectional or right-to-left shunting; (4) If no tricuspid regurgitation (TR) jet or shunt present then two out of following three criteria: (a) Any degree of interventricular septal flattening; (b) RV dilatation; (c) RV hypertrophy
  • Patient follow-up: Not applicable

MAIN RESULTS

This study included a total of 220 infants <32 weeks gestation or weighing <1500 g at birth. About 26.8% (59/220) had LPH and 44% (85/193) had EPH. Authors identified the novel association of LPH with factors such as maternal diabetes, EPH II and EPH III, tracheitis, IVH≥3, gastrostomy tube placement, and systemic steroid use for BPD. Authors found no significant association of LPH with antenatal steroid use, delivery room resuscitation, oligohydramnios, PPROM, Apgar scores, IUGR, multiple gestation, or surgical closure of PDA.

On multiple logistic regression, novel factors associated with development of BPD–LPH included presence of maternal diabetes, prolonged antibiotic usage, EPH II and III, severe BPD, tracheostomy, tracheitis, intraventricular hemorrhage (IVH, grade ≥3) and systemic steroid use for BPD> 7 days duration. For EPH II, these were maternal diabetes, IVH grade ≥3, high frequency ventilator use, and maternal antibiotic use.

CONCLUSION

This study confirms role of previously identified risk factors such as LBW, SGA, HFOV, prolonged ventilator days, prolonged exposure to antibiotics and severe BPD in development of BPD associated LPH and EPH. It also identified novel risk factors for LPH such as tracheitis, IVH grade 3 or 4, and maternal diabetes mellitus. Association of maternal diabetes in both EPH and LPH were explained as secondary to endothelial dysfunction and vascular inflammation leading to antenatal insult of placental under perfusion resulting in BPD.

COMMENTARY

Bronchopulmonary dysplasia (BPD) is a major morbidity in ELBW infants despite advances in neonatal care[3]. BPD is associated with pulmonary vascular disease and right ventricular hypertrophy, which can lead to left ventricular hypertrophy, and systemic hypertension[4]. Maternal placental insufficiency, prenatal nutritional deficiency or inefficient utilization, and inflammation (both pre and postnatally) may alter fetal pulmonary vascular development and lead to pulmonary hypertension (PH).  This is compounded by the severity of BPD [5]. However, there are limitations of diagnosing PH by echocardiographic criterion. Gold standard of diagnosing PH by cardiac catheterization is invasive and costly with significant risks. Many centers have adopted protocols incorporating a combination of expert guidelines to use echocardiography to diagnose PH. However, there are significant limitations to its use such as inter and intra-observer variability, inability to detect a tricuspid regurgitant jet velocity in a failing RV or secondary to hyperinflation  [5].

Prior studies by Mourani et al [6, 7] have already shown factors associated with the development of early pulmonary hypertension (EPH), and have delineated the relationship between EPH and late pulmonary hypertension (LPH). Sheth et al identified novel factors associated with development of LPH such as tracheostomy, IVH grade 3 or 4, and postnatal corticosteroid use for BPD greater than 7 days. The diagnosis of tracheitis is ill defined in preterm infants, and while authors used their institutional criteria for the diagnosis of tracheitis, many of these clinical criteria are non-specific. Additionally, the incidence of tracheitis in the study cohort appears relatively high at 40%. Adherence to stringent clinical parameters to diagnose may be necessary.

Existing literature describes maternal diabetes as being associated with EPH and pulmonary vascular malformation[8] , thus this is not a novel factor as stated by the authors. Further research is needed show if PH has a difference in association between preexisting maternal diabetes vs gestational diabetes, which could strengthen their statement. Interestingly, this study did not show PH was associated with many other factors including antenatal corticosteroids, oligohydramnios, prolonged rupture of membranes, resuscitation and respiratory support in the delivery room, multiple gestation, and low Apgar score <5 at 1 and 5 min.

This study has the usual limitations of a retrospective observational review, including the inability to account for confounding variables, and potential sources of bias in the era of new protocol implementation, better nutritional support, and noninvasive ventilator modes. One strength was the large sample size and multiple risk factor analysis. However, authors discuss the large referral base of inner city underprivileged, lower socioeconomic population that may not accurately represent patients from other hospitals. Furthermore, only 69% of patients in this cohort of BPD patients received at least one dose of antenatal steroid whereas the use of antenatal steroids in most major centers in developed countries is generally much higher.  Because of this, reproducibility in other centers may be limited.

Authors conclude, which is also emphasized from the Mourani et al study, that screening for EPH will identify newborns at risk for LPH.  Earlier recognition of EPH in ELBW infants with an ECHO during week 2-3 of life may help neonatologists identify the patients most at risk for LPH. Subsequently, reducing afterload on the right ventricle, using pulmonary vasodilators as required, optimizing ventilator strategy and maximizing nutrition could perhaps mitigate the severity of PH and associated morbidities in these vulnerable infants. However, similar to the wide variation and the risk profiles in screening practices, there is significant variation in the clinical management of infants identified with BPD-associated PH. There is paucity of clinical trials supporting therapy and even less literature on the long term effects of therapy and safety profile of therapeutic agents. We advocate for a tailored approach based on best evidence when a clinically stable premature patient with early PH has worsening echocardiographic findings. Close clinical evaluation of such patients with diligent monitoring for adverse side effects of interventions is warranted. Having clinical guideline protocols prevent variation that is based solely on a health professional’s practice style or preferences, and may promote consistency of care. Care of the patient and family therefore should be customized where appropriate, and standardized when appropriate [9]. The responsibility is still on the teams caring for the neonate to continue to maintain equipoise, exercise caution while interpreting this data in treating such patients.

REFERENCES

  1. Jobe AH, B.E.B.d.A.J.R.C.C.M. and 163:1723-9
  2. Pasquini, L., et al., Left superior caval vein: a powerful indicator of fetal coarctation. Heart, 2005. 91(4): p. 539-40.
  3. Krishnan, U., et al., Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr, 2017. 188: p. 24-34.e1.
  4. Kinsella, J.P., A. Greenough, and S.H. Abman, Bronchopulmonary dysplasia. Lancet, 2006. 367(9520): p. 1421-31.
  5. Berkelhamer, S.K., K.K. Mestan, and R. Steinhorn, An update on the diagnosis and management of bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension. Semin Perinatol, 2018. 42(7): p. 432-443.
  6. Mourani, P.M., et al., Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med, 2015. 191(1): p. 87-95.
  7. Mourani, P.M., et al., Early Pulmonary Vascular Disease in Preterm Infants Is Associated with Late Respiratory Outcomes in Childhood. Am J Respir Crit Care Med, 2019. 199(8): p. 1020-1027.
  8. Shu, L.P., et al., Maternal Diabetes Mellitus and Persistent Pulmonary Hypertension of the Newborn: Accumulated Evidence From Observational Studies. Can J Diabetes, 2019.
  9. Balakrishnan, M., A. Raghavan, and G.K. Suresh, Eliminating Undesirable Variation in Neonatal Practice: Balancing Standardization and Customization. Clin Perinatol, 2017. 44(3): p. 529-540.

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