Management of non-vigorous newborns born through meconium stained amniotic fluid

MANUSCRIPT CITATION:

Chiruvolu, A., Miklis, K. K., Chen, E., Petrey, B., & Desai, S. (2018). Delivery room management of meconium-stained newborns and respiratory support. Pediatrics, 142(6), e20181485

REVIEWED BY:

Sourabh Verma¹, Tara M. Randis²

1. Division of Neonatology, Department of Pediatrics, New York University School of Medicine, New York
2. Division of Neonatology, Department of Pediatrics and Microbiology, New York University School of Medicine, New York

KEYWORDS: Meconium aspiration syndrome, non-vigorous newborn, tracheal suctioning, Neonatal Resuscitation Program

Corresponding author:

Sourabh Verma, MD, FAAP
Division of Neonatology, Department of Pediatrics
New York University School of Medicine
New York, NY
Phone number: 212-263-5790, Email: [email protected]

TYPE OF INVESTIGATION: Treatment

QUESTION: In non-vigorous neonates born through meconium stained amniotic fluid (MSAF), is implementation of the seventh edition of neonatal resuscitation program (NRP) guidelines, compared to retrospective cohort of those resuscitated according to the sixth edition, associated with an increase in the incidence of meconium aspiration syndrome (MAS) and other respiratory morbidities?

METHODS

Design: Multicenter, retrospective and prospective cohort study

Blinding: N/A

Setting: Multicenter community hospitals setting

Patients:

Inclusion criteria: Neonates born at ≥35 weeks gestational age whose delivery was complicated by presence of MSAF and were non-vigorous at birth.

Exclusion criteria: Neonates born at <35 weeks gestational age

Intervention: Change in practice for the management of non-vigorous neonates born through MSAF after implementation of the new NRP guidelines. In retrospective cohort non-vigorous neonates born through MSAF routinely received endotracheal suctioning according to NRP's 6th edition guidelines, while infants in the prospective cohort did not receive routine endotracheal suctioning and were provided positive pressure ventilation following NRP's 7th edition guidelines.

Outcomes

• Primary outcome: To compare the incidence of MAS in non-vigorous neonates born through MSAF before and after the change in policy for management of such neonates.
• Secondary outcome: To compare the incidence of other respiratory outcome data such as admission to neonatal intensive care unit (NICU), duration of oxygen therapy, duration of mechanical ventilation, transient tachypnea of newborn, respiratory distress syndrome, pneumothorax, inhaled nitric oxide therapy (iNO) for persistent pulmonary hypertension of newborn, transfer for extracorporeal membrane oxygenation (ECMO), and therapy for presumed hypoxic-ischemic encephalopathy.

Analysis and Sample Size: A convenience sample size of 100 eligible newborns in each arm was deemed appropriate based upon some previous studies, which was achievable with one-year study period in retrospective and prospective study cohorts each. There were 130 subjects in one-year retrospective study arm and 101 subjects in one-year prospective study arm. Comparison between both study arms was conducted by 2-tailed Student's t-test or Mann-Whitney U test for continuous variables and Pearson's c² test or Fisher's exact test for categorical variables. To determine association between outcomes and changes in delivery room management, logistic regression was used. Odds ratios with 95% confidence interval were used for the data.

Patient follow-up: Patients were followed until the time of NICU discharge. No long-term follow-up is available.

Main results

Table 1: Newborn treatment and outcomes (adapted from Chiruvolu et al.) (1)

There was no significant difference in gestational age (39.9 vs 39.9 weeks), birthweight (3.45 vs 3.39 kg) or 5 min Apgar <7 (18% vs 22%). Fetal distress was more common in prospective group (57% vs 43%). There were more late preterm and late term neonates in the prospective group  (12% vs 2%). The incidence of MSAF was stable across cohorts (~12%). Among those delivered through MSAF, 10% newborns in retrospective and 8% newborns in prospective group were categorized as non-vigorous. Consistent with the policy change, endotracheal suctioning (70% vs 2%) was done predominantly in retrospective group and positive pressure ventilation (19 vs 55%) was used more in prospective group. There was no increase in incidence of MAS after implementation of the NRP's 7^th edition guidelines. Some of the secondary outcomes such as admission to the NICU for respiratory issues, the need for mechanical ventilation, oxygen, and surfactant therapy were increased in the prospective cohort.

Study conclusion

The implementation of new NRP guidelines (7^th edition), against use of endotracheal suctioning for non-vigorous neonates born through MSAF, was not associated with an increased incidence of MAS, but was associated with an increase in incidence of admissions to the NICU for respiratory causes, the need for mechanical ventilation, oxygen therapy, and use of surfactant.

Commentary

Newborns born through MSAF have a significant risk of morbidity and mortality. It is estimated that about 8-15% of all deliveries have MSAF, out of which 10-20% are non-vigorous at birth and approximately 5% develop MAS (2, 3). Guidelines regarding the management of newborns born through MSAF have changed over last two decades, with the NRP recommending less invasive interventions for newborns born through MSAF. There has been a decrease in the incidence of MAS and need for ECMO over last few years (4). The International Liaison Committee on Resuscitation (ILCOR) and the American Heart Association (AHA) NRP steering committee have performed robust systematic reviews to develop evidence-based recommendations regarding the management of these infants. Ideally, these recommendations are based upon data from definitive randomized controlled trials (RCTs).

While making this recommendation against the use of routine endotracheal suctioning for non-vigorous newborns born through MSAF, the NRP steering committee noted that a definite RCT is still needed, but placed value on 'harm avoidance' due to potential delay in starting bag and mask ventilation as well as potential harm of the procedure (5). NRP steering committee further states that there are unknown benefits of endotracheal suctioning of these infants based upon the current available data.

Chirovolu et al. have published the results of their multicenter observational study examining neonatal outcomes before and after the implementation of latest NRP guidelines (1). In this study, the authors found that the guideline change was associated with an increase in incidence of the NICU admissions secondary to respiratory causes, the need for oxygen therapy, and use of surfactant. They found no increase in the incidence of MAS. Results of this important study further reaffirms the need for having a multicenter RCT with rigorous methodology to definitely answer this question of how to manage non-vigorous neonates born through MSAF.

Despite being an observational study, with historical retrospective cohort, and relatively small sample size, this study has multiple strengths. Authors mention that their practice always have an experienced neonatal provider, capable of intubation, at all deliveries with MSAF ensuring consistency in provider expertise at delivery. Both retrospective and prospective group's maternal and neonatal characteristics were compared. Notable differences between these two cohorts include the presence of fetal distress, late preterm or late term deliveries among prospective cohort. The investigators used appropriate statistical methodology to adjust for these potential confounding variables when assessing the odds of the outcome, enhancing the validity of their study. After they implemented new NRP guidelines at their centers, 2% neonates in prospective cohort received endotracheal suctioning as compared to 70% in retrospective cohort, showing compliance with the change in their practice.

Delayed cord clamping is being employed at deliveries in many institutions. It was not practiced at the author's institutions at the time of study. We speculate that some perinatal practice changes such as delayed cord clamping, may impact outcomes of another practice change, such as for non-vigorous neonates born through MSAF. Current evidence for recommendations from NRP comes from a timeframe when delayed cord clamping was not routinely practiced. In coming years, it would be interesting to see impact of change in perinatal practices such as delayed cord clamping, on the outcomes of neonates born through MSAF.

NRP steering committee places the value on harm avoidance in making this recommendation against routinely performing endotracheal suctioning for these patients. At this time we don't know if there should be different set of locally suited, institution-specific guidelines for the management of non-vigorous neonates born through MSAF, based upon if they do, or do not have experienced neonatal providers capable of doing endotracheal intubation at all deliveries. If there are experienced neonatal providers at all deliveries, it is unknown if there may be a subset of non-vigorous neonates born through MSAF who may benefit from endotracheal suctioning that does not delay initiation of resuscitative efforts.

The study by Chiruvolu et al. has already changed how investigators think about managing neonates born through MSAF. Specifically, investigations regarding the management of neonates born through MSAF stand to benefit from more standardized classification of exposed subjects. The NRP steering committee mentions that the definition of the denominator used for calculating the rates of MAS in the entire cohort of neonates born through MSAF is equally important in designing and interpreting studies on neonates born through MSAF, as opposed to including only potentially sicker and non-vigorous neonates in denominator that may possibly increase rate of respiratory diseases (6).

Clearly there is a need for well-designed multicenter RCTs evaluating the best management of non-vigorous neonates born through MSAF, incorporating various perinatal factors and practices in account such as delayed cord clamping. Timing of declaring a newborn non-vigorous after delivery, outlining clear and concise definitions of MAS, and the denominator used for calculating outcomes among neonates born through MSAF are equally important while planning future studies.

In conclusion, findings of the study by Chiruvolu et al. raises valid concerns that require further investigation.  Until we have more conclusive evidence, we should continue to follow NRP guidelines and ensure that we  'do no harm' when  caring for these at-risk neonates.

EBM Lesson: Assessing Validity of Cohort Studies

Cohort study designs are observational in nature and most frequently used to establish both the incidence of disease and temporal associations between exposures and outcomes.  They may be prospective or retrospective, depending on when the subjects are identified relative to the initiation of the study. In some instances, investigators employ a quasi-experimental design using both retrospective and prospective cohorts, as is this case here, to assess clinical outcomes (e.g. respiratory morbidities) following a change in practice (e.g. endotracheal suctioning at delivery).

 A cohort study design offers several advantages. Their longitudinal nature, allows for temporal assessment of exposure and outcome, thereby enabling inferences (though not establishment) of causality.  This is most commonly expressed statistically as the relative risk of an outcome following the exposure. When the outcome of interest is rare, the odds ratio may be used to approximate the relative risk. Another advantage to a cohort study design is that investigators may examine multiple outcomes following a single exposure. Retrospective cohorts have the added advantage of being relatively inexpensive and efficient, as subjects do not need to be followed longitudinally (7).

The major disadvantage of a cohort studies is the inability to control for all other factors that might differ between the two groups. When these factors are associated with both the exposure and outcome, they are known as confounding variables. Consideration of such confounders is paramount in determining whether a cohort study is valid.  Internal validity refers to whether observed changes can be correctly attributed to the exposure (rather than confounders). Internal validity may be compromised when the unexposed group is not comparable to the exposed group due to bias in selection factors, subject dropout rate, or when differences between groups are not adequately controlled for by statistical methods. External validity is the degree to which the conclusions of a study are generalizable (i.e. relevant for other people, in other places and times). Internal validity is essential for external validity (8-10).

Acknowledgement

The Journal Club is a collaboration between the American Academy of Pediatrics - Section of Neonatal Perinatal Medicine and the International Society for Evidence-Based Neonatology (EBNEO.org)

References

1. Chiruvolu A, Miklis KK, Chen E, Petrey B, Desai S. Delivery Room Management of Meconium-Stained Newborns and Respiratory Support. Pediatrics. 2018;142(6).
2. Dargaville PA, Copnell B, Australian, New Zealand Neonatal N. The epidemiology of meconium aspiration syndrome: incidence, risk factors, therapies, and outcome. Pediatrics. 2006;117(5):1712-21.
3. Fischer C, Rybakowski C, Ferdynus C, Sagot P, Gouyon JB. A Population-Based Study of Meconium Aspiration Syndrome in Neonates Born between 37 and 43 Weeks of Gestation. Int J Pediatr. 2012;2012:321545.
4. Mahmood B, Newton D, Pallotto EK. Current trends in neonatal ECMO. Semin Perinatol. 2018;42(2):80-8.
5. Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (Reprint). Pediatrics. 2015;136 Suppl 2:S120-66.
6. Neonatal Resuscitation Program Steering C. Response From the Neonatal Resuscitation Program (NRP) Steering Committee. Pediatrics. 2019;143(3).
7. Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emerg Med J. 2003;20(1):54-60.
8. Carlson MD, Morrison RS. Study design, precision, and validity in observational studies. J Palliat Med. 2009;12(1):77-82.
9. Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet. 2002;359(9302):248-52.
10. Rochon PA, Gurwitz JH, Sykora K, Mamdani M, Streiner DL, Garfinkel S, et al. Reader's guide to critical appraisal of cohort studies: 1. Role and design. BMJ. 2005;330(7496):895-7.