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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 4  |  Page : 242-248

Risk factor analysis of persistent pulmonary hypertension of the newborn in meconium aspiration syndrome in Thai neonates


Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai Hospital, Hat Yai, Songkhla, Thailand

Date of Submission28-Oct-2019
Date of Decision27-Jul-2020
Date of Acceptance09-Aug-2020
Date of Web Publication01-Oct-2020

Correspondence Address:
Narongsak Nakwan
Department of Pediatrics, Neonatal Intensive Care Unit, Hat Yai Medical Education Center, Hat Yai Hospital, Hat Yai, Songkhla 90110
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_118_19

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  Abstract 


Background: Meconium aspiration syndrome (MAS)-associated persistent pulmonary hypertension of the newborn (PPHN) is a serious respiratory disease in neonates. Objective: The objective was to examine the risk factors and outcomes of MAS-associated PPHN (MAS-PPHN). Patients and Methods: The records of neonates diagnosed with MAS with and without PPHN at Hat Yai Hospital from January 2015 to December 2017 were retrospectively reviewed. Results: During the study period, the cases of 211 MAS neonates were analyzed. The overall incidence of MAS based on born inside hospital was 7.7 per 1000 live births. Of these, 36 (17.1%) developed PPHN with a 2.4% (5/211) mortality rate. The mean gestational age and birth weight of all MAS neonates were 39.2 ± 1.6 weeks and 3043 ± 584 g, respectively. MAS-PPHN neonates had a significantly lower Apgar score at 5 min of <7 (33.3 vs. 18.3%, P = 0.04) compared with those who did not develop PPHN. Severe MAS was found to be a significant predictor of PPHN in the neonates with MAS (adjusted odds ratio [OR] = 96.5). In a multivariate analysis, lowest mean arterial blood pressure (MBP) of <35 mmHg within 12 h of admission, initial positive end expiratory pressure of ≥6 cmH2O (adjusted OR = 15.1), and initial supplemental fraction of inspired oxygen (FiO2) of ≥0.6 (adjusted OR = 22.2) were found to be independent indicators for developing PPHN in MAS. Conclusions: Lower MBP within 12 h of admission was a significant risk indicator for potential PPHN in MAS in this study.

Keywords: Meconium aspiration syndrome, neonatal mortality, newborn infant, persistent pulmonary hypertension of the newborn, risk factor


How to cite this article:
Nakwan N, Chitrapatima C. Risk factor analysis of persistent pulmonary hypertension of the newborn in meconium aspiration syndrome in Thai neonates. J Clin Neonatol 2020;9:242-8

How to cite this URL:
Nakwan N, Chitrapatima C. Risk factor analysis of persistent pulmonary hypertension of the newborn in meconium aspiration syndrome in Thai neonates. J Clin Neonatol [serial online] 2020 [cited 2020 Oct 26];9:242-8. Available from: https://www.jcnonweb.com/text.asp?2020/9/4/242/296998




  Introduction Top


Meconium aspiration syndrome (MAS) is a serious respiratory disease in neonates who are born through meconium-stained amniotic fluid (MSAF), and persistent pulmonary hypertension of the newborn (PPHN) is one of the complications with MAS. About one-fifth of MAS neonates go on to develop PPHN,[1],[2] with a much higher rate (73%) in cases of severe MAS.[3] Several fetal conditions associated with a higher risk of developing PPHN in MAS, such as fetal hypoxemia, acidosis, atelectasis, and pulmonary smooth muscle hyperplasia, resulting in increasing pulmonary vascular resistance (PVR), have been documented.[4] Pneumothorax, change of fetal heart beat pattern, and asphyxia have also been reported as the risk factors for PPHN in MAS.[5] Thus, an improved understanding of the nature of PPHN associated with MAS may improve clinical care for neonates. The objective of this study was to explore the incidence, clinical outcome, and risk factors for PPHN in MAS in neonates admitted to the neonatal care unit in Hat Yai Hospital, a large hospital in Southern Thailand.


  Patients and Methods Top


Study design

The study used a case–control retrospective design that reviewed the records of all any gestational age patients diagnosed with MAS with or without PPHN admitted to the neonatal care unit of Hat Yai Hospital between January 2015 and December 2017. MAS patients who were also diagnosed with a congenital anomaly related to PPHN, such as a chromosomal or musculoskeletal disorder, or cyanotic heart disease, were excluded. The study was approved by the Hat Yai Hospital Ethics Committee.

Hospital setting

Our neonatal care unit, which comprises a 20-bed intensive care unit and 24-bed intermediate care ward, is an important neonatal referral center serving seven provinces in the southern region of Thailand, which have approximately 7000 live births annually. In our hospital, advanced medical equipment, such as high-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO), are available, but extracorporeal membrane oxygenation is not. In delivery room, the neonates born through MSAF are resuscitated based on the 2015 neonatal resuscitation recommendation.[6] Most mild-to-moderate MAS neonates who are admitted to our neonatal unit are initially supported with noninvasive ventilation such as oxygen hood, nasal high-flow cannula (initial 6–8 LPM flow rate), or nasal continuous positive expiratory pressure (initial 5–8 cmH2O), with minimized supplemental oxygen by keeping pulse oximetry oxygen saturation (SaO2) of 90%–95% and partial pressure of oxygen (PaO2) at 60–80 mmHg. For severe MAS or failure of noninvasive ventilation, the patient is ventilated with conventional mechanical ventilation (CMV) with appropriate initial ventilator setting for an individual infant. Some neonates are changed to HFOV if the infant developed refractory hypoxemia, needed a peak inspiratory pressure (PIP) of >25 mmHg, or presented partial pressure of carbon dioxide (Pa CO2) of >55 mmHg. For PPHN treatment, iNO is normally initiated as the first-line treatment followed by sildenafil, iloprost, milrinone, or bosentan in case of nonresponse to iNO as an adjunctive therapy in MAS-associated PPHN (MAS-PPHN) neonates.

Definitions

MAS was defined by clinical criteria including (1) neonates born through MSAF with respiratory compromise, (2) a need for supplemental oxygen to maintain SaO2 at ≥90%, and (3) confirmed by diagnostic chest radiography (consolidation, air leaks, hyperinflation, hypovascularity, pleural effusion, or relatively normal appearance).[7] The level of severity of MAS was based on the criteria of Cleary and Wiswell (mild: requiring <40% of supplemental oxygen for <48 h, moderate: requiring ≥40% supplemental oxygen for ≥48 h, and severe: requiring assisted mechanical ventilation for >48 h).[8] PPHN was diagnosed based on one or more of the three following conditions: (1) an echocardiographic evidence of elevated pulmonary pressure (right-to-left or bidirectional shunt at patent ductus arteriosus and/or patent foramen ovale level), (2) a pre-to-post-ductal PaO2≥10–20 mmHg, and/or (3) an SaO2 gradient ≥5%–10%.[9],[10]

Data collection

Detailed clinical data from electronic charts were obtained for each patient, including perinatal history (maternal age, resuscitation at delivery room, type of delivery, and Apgar scores), neonatal variables (gestational age, birth weight, sex, and born outside hospital), MAS clinical and treatment data (vital signs within 12 h of admission, central line insertion, mode and parameters of respiratory support, initial laboratory results, medications, and blood transfusion), and short-term outcome (mortality, complications during hospital admission, and length of supplemental oxygen and hospital stay).

Statistical analysis

Descriptive statistics are presented as mean (±standard deviation) or median (interquartile range [IQR]). Categorical data are presented as frequency and percentage. Data were compared using either the Chi-square test or Fisher's exact test for categorical data as appropriate. Student's t-test or Mann–Whitney U-test was used to compare continuous variables as appropriate. Binary logistic regression analysis was used to identify the risk factors for PPHN in MAS. A univariate model was used to analyze the ventilation variables. Variables with a P < 0.2 in univariate analysis were included in the multivariate model. A univariate model based on the Firth's logistic regression analysis was constructed to assess the risk factors and MAS severity. Multicollinearity was checked by calculating the variance inflation factors (of <5). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated to quantify the associations between risk factors and outcomes (PPHN or non-PPHN). A P < 0.05 was considered statistically significant. All statistical analyses were performed using R version 3.3.1 (The R Foundation for Statistical Computing, Vienna, Austria).


  Results Top


Patient characteristics

From January 2015 to December 2017, 20,479 neonates were born in our hospital, and 214 MAS neonates were identified from the medical database. The overall incidence of MAS based on born inside hospital was 7.7/1000 live births. After chart reviews, three MAS neonates were excluded because of congenital cyanotic heart disease. Finally, 211 MAS neonates with or without PPHN were analyzed. The basic characteristics of the study population are shown in [Table 1]. The mean gestational age and birth weight of all MAS neonates were 39.2 ± 1.6 weeks and 3043 ± 584 g, respectively, 53.1% were male, and 26.5% were born outside the hospital. Of the 211 MAS neonates, 36 (17.1%) were complicated with PPHN. The basic characteristics of the two groups were similar, except for a significantly higher PPHN rate in neonates with MAS who had an Apgar score at 5 min of <7 (33.3% vs. 18.3%, P = 0.04) compared with those who did not develop PPHN. Furthermore, we did additional analysis of the basic characteristic data, clinical cause, and outcome between MAS neonates born outside and inside hospital groups, because born outside status might be effected on the severity of MAS. The result of analysis showed no significant differences between the groups in all clinical parameters.
Table 1: Basic characteristics of meconium aspiration syndrome infants with or without persistent pulmonary hypertension of the newborn

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Clinical course of meconium aspiration syndrome-associated persistent pulmonary hypertension of the newborn

PPHN in MAS was diagnosed at a median age of 9 (IQR: 4.3–16.0) h after birth. The distribution of the levels of severity of MAS is shown in [Table 1]. All severe MAS neonates developed PPHN, while 73.7% (129/175) of mild-to-moderate MAS neonates did not develop PPHN. The initial vital signs, laboratory results, initial treatment of MAS neonates with or without PPHN, and pulmonary vasodilators treated PPHN in MAS-PPHN group are presented in [Table 2]. The MAS-PPHN neonates had a significantly higher rate of mean blood pressure (MBP) <35 mmHg within 12 h of admission (22.2% vs. 7.4%, P < 0.01), higher rate of central line insertion, higher amount of transfused blood components, and required more medications (such as sedation, analgesia, muscle relaxation, inotropic agents, and alkali therapy) compared with those who did not develop PPHN [Table 1]. There were no statistically significant differences in initial laboratory results, except the initial blood pH being found to be significantly lower in the PPHN group compared with the non-PPHN group, based on data from 146 patients [Table 2]. For respiratory support in MAS, 66.8% (141/211) of the patients were initially supported with CMV, while 33% of the MAS neonates received noninvasive ventilation support, of whom 23 cases (10.9%) failed noninvasive ventilation. In the initial CMV support group, MAS neonates with PPHN had significantly higher PIP, higher positive end expiratory pressure (PEEP), and higher supplemental fraction inspired oxygen (FiO2) than those without PPHN [Table 2]. In addition, we found that MAS neonates who received initial PIP of ≥18 cmH2O, PEEP of ≥6 cmH2O, and FiO2 of ≥0.6 had a significantly higher rate of PPHN than those who received PIP of <18 cmH2O, PEEP of <6 H2O, and FiO2 of <0.6, respectively.
Table 2: Clinical variables, laboratory results, and treatment of meconium aspiration syndrome infants with or without persistent pulmonary hypertension of the newborn

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Meconium aspiration syndrome-associated persistent pulmonary hypertension of the newborn outcomes

The overall mortality rate of the neonates with MAS was 2.4% (5/211). The MAS-PPHN neonates had a higher mortality rate than those without PPHN (11.1% vs. 0.6%, respectively, P < 0.01). The MAS-PPHN neonates had a significantly higher rate of severe complications during hospitalization, such as chronic lung disease, acute kidney injury, pneumothorax, bloodstream infection, pulmonary hemorrhage, urinary tract infection, and refractory hypotension, as presented in [Table 1]. The median duration of supplemental oxygen and length of stay in the PPHN group were significantly longer than in the non-PPHN group (18.5 [IQR: 11.3–27.3] days vs. 4.0 [3.0–8.0] days, P < 0.01, and 21.5 [IQR: 13.5–27.8] days vs. 8.0 [IQR: 7.0–12.0], P < 0.01, respectively).

Risk factors for persistent pulmonary hypertension of the newborn in meconium aspiration syndrome patients

In univariate analysis using the Firth method, severe MAS was found to be a significant predictor of PPHN (adjusted OR = 96.5 [95% CI 1.1–8,339.8]). Binary logistic regression analysis was performed to identify risk factors related to MAS-PPHN. Using a multivariate model, only MBP of <35 mmHg was independently associated with an increased risk for PPHN (adjusted OR = 3.92 [95% CI 1.40–10.94]). In subgroup analysis of initial CMV setting, the multivariate model showed that neonates who received initial PEEP of ≥6 cmH2O (adjusted OR = 15.1 [95% CI 0.98–231.1]) and FiO2 of ≥0.6 (adjusted OR = 22.2 [95% CI 2.14–229.9]) had a significantly higher rate of PPHN than neonates with lower CMV setting.


  Discussion Top


MAS is known to be significantly associated with PPHN. Our incidence of MAS was quite high (7.7/1000 live births), with 17% of the MAS neonates (n = 211) developing PPHN. Severe MAS patients had a greater rate of developing PPHN compared to those with mild-to-moderate MAS. The significant difference between the 11.1% mortality rate in the PPHN-MAS neonates compared with 0.6% in the non-PPHN MAS neonates highlights the fact that PPHN is a serious condition, and it is worthwhile to evaluate the factors that put MAS neonates at risk for developing PPHN. Our study found that lower MBP during the first 12 h of hospital admission was independently associated with an increased risk for PPHN in MAS neonates, while an initial using PEEP of ≥6 cmH2O and supplemental FiO2 of >0.6 in the patient who were ventilated by CMV were found to be significant indicators for developing PPHN.

In our study, the incidence of MAS in our region of Southern Thailand was very high over the 3-year study period. Unfortunately, there are few other studies from low-middle income countries reporting on the incidence of MAS to compare our findings with. Panton and Trotman from Jamaica, another middle-income country similar to our setting, reported that the incidence of MAS was 10.0/1000 live births.[11] Another study from India reported an MAS incidence of 8.8/1000 live births.[12] In these studies of MAS from low-middle-income countries, the incidence is much higher than two earlier studies from high-income countries. Dagaville et al. reported an incidence of MAS in Australia and New Zealand of 0.43/1000 live births, while one from Austria by Hofer et al. reported an incidence of 0.66/1000 live births.[13] This large difference of MAS incidence between lower-middle- and high-income countries is probably due to socioeconomic conditions or maternal education directly related with the quality of prenatal care. Identificatiwwon of the risk of MSAF is the key factor to prevent MAS in pregnant women. Intrauterine growth-retarded neonates, older maternal age, multiparty, lack of prenatal care, and low fetal weight have been reported to be the factors associated with MSAF.[14] Early identification of the signs and symptoms of MSAF in pregnant women could be helpful in the early management of pregnant women with a risk of delivering neonates with MAS. In addition, health professionals in hospitals should be alert to ensure early recognition of MSAF by understanding the risk factors associated with the development of severe MAS, such as acute tocolysis, fetal distress, and birth asphyxia with ORs of 18.2, 3.4, and 4.4, respectively.[13]

Our percentage of PPHN in MAS is similar to previous reports by Louis et al.[15] and Hsieh et al.,[5] who had 17.1% and 17.7%, respectively. Other studies have reported lower percentages of PPHN in MAS neonates, i.e., 4.6% from Jamaica[9] or 9.9% from Austria.[13] The varying percentages of PPHN in MAS from different reports may be explained by reasons, such as differences in antenatal and/or intrapartum care, limited numbers of, or access to, healthcare workers, and/or lack of access to modern medical equipment. Our study also found that the neonates who were diagnosed with severe MAS (defined by requiring assisted mechanical ventilation for >48 h) had a high risk for PPHN with an OR of 96.5, by the univariate Firth logistic regression analysis, compared to those with MAS severity classified as mild or moderate MAS. In a previous study, Hofer et al. reported that MAS-associated PPHN had an OR of 36. Although our hospital has advanced medical treatments available such as HFOV or iNO, many MAS neonates still developed PPHN after aggressive management. We believe that the best way to reduce the incidence of PPHN is proactive education provided to all pregnant women during their antenatal care and during the intrapartum period if risk factors have been noted.

Our study found that blood pressure, particularly MBP of <35 mmHg within 12 h of admission, was the only independent risk factor for PPHN in our MAS population, which was also found in a study by Lee et al.[16] from South Korea, in which hypotension within 24 h after birth was significantly associated with the development PPHN in 60 MAS neonates. The reason for hypotensive MAS to be significantly associated with PPHN may be insufficient systemic oxygenation, due to decreased systemic vascular resistance, leading to anaerobic metabolism at the tissue level further leading to metabolic acidosis from higher hydrogen ions (H+) and finally increased PVR.[17]

In this study, we found that an initial PEEP of ≥6 cmH2O and supplemental FiO2 of ≥0.6 in CMV group were significantly more likely to develop PPHN. The optimal PEEP and supplemental oxygen in MAS depend on the lung pathology induced from the amount of aspirated meconium along with hypoinflation or hyperinflation of the lungs of each individual patient. However, PVR may basically be altered by changing lung volume due to the PEEP level. Raising lung volume by increasing PEEP could lead to increased PVR during CMV due to increased alveolar pressure compressing the intra-alveolar vessels.[18],[19] Thus, the increase of lung volume by PEEP should be carefully balanced between overcoming atelectasis while avoiding overdistension of the lungs.[19] Fox et al. found that a PEEP range of 4–7 cmH2O induced the greatest oxygenation in MAS patients, but higher PEEP levels led to lower oxygenation.[20] Moreover, inducing hyperoxemia at initial treatment may lead to increased oxidative stress and reactive oxygen species formation, enhancing pulmonary vasoconstrictive effects, resulting in the development of PPHN.[21],[22],[23] We suggest that early signs and symptoms of PPHN should be monitored in MAS patients who are prescribed an initial high dose of PEEP in CMV and supplemental oxygen.

There are some limitations to our study. First, although the study had a large enough sample size, it was a retrospective study and thus subject to selection bias. Second, the MAS patients were enrolled in our study from only a single center, and thus the results may lack generalizability. However, about one-fifth of the study patients were referred from other provinces in Southern Thailand. Third, the study focused only on the short-term outcomes (dead and surviving) only, and detailed long-term clinical data are needed to clarify the effects of PPHN in the early months of life in MAS patients. At last, some variables such as the severity of MAS could not be subjected to statistical analysis in regard to higher OR and 95% CI numbers because none of the mild or moderate MAS patients developed PPHN.


  Conclusions Top


Our study documents the high incidence of MAS in Southern Thailand and severe MAS is strongly associated with the development of PPHN. Close bedside monitoring of vital signs, particularly blood pressure, for the first 12 h of hospital admission should be standard procedure for MAS neonates to allow early detection and treatment of PPHN.

Acknowledgments

The authors thank Miss. Walailuk Jitpiboon, Department of Epidemiology, Faculty of Medicine, Prince of Songkhla University, Songkhla, Thailand, for statistical analysis and Mr. Dave Patterson for English editing of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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