The risk factors of meconium aspiration syndrome in newborns: a meta-analysis and systematic review

Introduction

Meconium aspiration syndrome (MAS) is one of the respiratory morbidities that mainly occurs in term and post-term neonate. Additionally, though rare, MAS may also occur in preterm neonates (1). By mechanically obstructing the airways, chemically damaging the epithelium of airway and alveolar, as well as de-activating surfactant and impairing alveoli compliance, MAS can lead to severe adverse outcomes including respiratory distress syndrome, persistent pulmonary hypertension, the use of extracorporeal membrane oxygenation (ECMO) (2), neurological impairment (3), cardiovascular instability and even death (2).

Previous studies have identified several important risk factors for MAS, such as born through meconium-stained amniotic fluid (MSAF) (2,4-8), non-reassuring fetal heart rate tracing (2,4,9-15), cesarean delivery, poor Apgar score (2,11,14-16), advancing gestational age (1,17,18), etc. However, the aforementioned risk factors were from comprehensive studies on the risk factors for MAS done decades before (2). It was demonstrated by studies that the incidence of MAS varied over decades. Yoder et al. reported a reduction of MAS from 1990 to 1998 (15), attributing partially to the medical advancement. Similarly, a population-based study has also reported a declined rate of MAS aligning with the appearance of increase in protective obstetric practice (18). In recent years, there are scattered studies reporting several risk factors related to MAS that were understated previously, such as maternal smoking (4) and maternal obesity (19), and new obstetric strategies that emerged in last decade and were not analyzed in previous clinical settings, such as induction of labor (20). The emerging attention on these factors was a result of changing medial practice and social environment. These factors were not analyzed through meta-analysis. The question raises whether previously overlooked factors have gained significance associating to MAS and the recognized risk factors remained significant with the adding on of new studies done in the era of swift shift of medical practice. The answer to this question may be essential to directing clinical attention.

In this study, we aim to comprehensively review the studies to date and to summarized and meta-analyze, when applicable, the maternal and neonatal risk factors for MAS, to provide a more extended vision on high-risk scenarios related to MAS development for the clinicians and an insight for further research. We present the following article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-23-5/rc).

Methods

This review was performed according to a predefined protocol, which was developed according to recommended for systematic reviews (21,22) and registered in the International Prospective Register of Systematic Reviews (CRD 42022338176).

Sources and search strategy

A comprehensive literature search on published literature for records discussing MAS, infants, and risk factors was performed by a researcher. Search strategies applying a combination of keywords and controlled vocabulary was conducted in PubMed, Ovid MEDLINE, Embase.com, Scopus, Web of science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials from their inception to June 1, 2022. Search terms included “meconium aspiration syndrome”, “meconium aspiration syndrome”, “aspiration syndrome, meconium”, “syndrome, meconium aspiration”, “meconium aspiration”, “aspiration, meconium”, “meconium inhalation”, “newborn”, “infant”, “infant, newborn”, “infants, newborn”, “newborn infant”, “newborn infants”, “newborns”, “neonate”, “neonates”, “infants”, “risk factor”, “risk factors”, “factor, risk”, “social risk factors”, “factor, social risk”, “factors, social risk”, “risk factor, social”, “risk factors, social”, “social risk factor”, “health correlates”, “correlates, health”, “population at risk”, “populations at risk”, “risk scores”, “risk score”, “score, risk”, “risk factor scores”, “risk factor score”, “score, risk factor”. Additional manual search of bibliographies of identified key articles, use of the “related articles” feature in PubMed, and use of the tool in Web of Science was also performed. No language or location limit were set in the searching strategy. Article with available full text in foreign languages to the researchers was translated using online translator.

Study selection

The inclusion criteria were cohort studies that reported on the risk factors for MAS or case-control studies that aimed on analyzing risk factor for the outcome of MAS within any population; using non-MAS population as control group; the sample size and raw data were provided. Studies were excluded if they were an interventional study, review, meta-analysis or cases report; lack control groups; had incomplete data; did not have available full text; included animals; did not report raw data for the included analyzed risk for MAS. Search strategies for each database can be found in the supplemental materials (Appendix 1). Two investigators screened and evaluated for inclusion independently. If any disagreement occurs, it will be resolved by a third investigator.

All search strategies were completed in June 2022, and a total of 2,090 results, published from 1978 to 2022, were exported to Endnote. Notably, 1,202 records were deleted after using the deduplication.

Risk of bias

The assessment of the risk of bias of the included studies was carried out according to Newcastle-Ottawa Scale. Two investigators conducted evaluation independently. If any disagreement occurs, it will be resolved by a third investigator. A score >7 was considered as low risk of bias; a score <3 as very high risk.

Data extraction

Risk factors that impact the incidence of MAS are of interest to this study. The risk factor reported by the eligible studies were recorded, with special attention on the following fifteen factors: six risk factors related to maternal condition: maternal body mass index (BMI) ≥30 kg/m², maternal age >34-year-old, previous cesarean delivery, smoking, nulliparous, as well as maternal fever and chorioamnionitis, which were further combined into maternal inflammatory response according to recent studies (23-25); four peripartum risk factors: oligohydramnios, induction of labor, caesarean section, thick meconium; and five risk factors related to fetal-neonatal factors: abnormal fetal heart rate, male infant, post term, small for gestational age (SGA), and Apgar <7 at 5 min. For each study, when data were available, the raw data and the best estimated effect size of the above factors (the hierarchy being multiple adjusted effect size, and unadjusted effect size) were extracted by one investigator and confirmed by the second. Adjusted effects from subgroups were extracted when adjusted effects were not available in an overall form but detailed in all subgroups, and was dropped when the effect sizes were only provided in selected subgroups. In studies only providing data on rates, manual calculation was performed to convert the rates in the original study into number of cases in the present study.

Statistical analysis

The studies with same extracted risk factors were combined by the factor and meta-analysis was performed using Review Manager (RevMan Version 5.4. The Cochrane Collaboration, 2020). If one or more studies provided data on adjusted effect size of a particular risk factor, the relevant meta-analyses were done by inputting the adjusted effect size from each individual study and combining with Inverse Variance method and other effect sizes from studies only reporting univariate result were displayed in the forest plot but suppressed in the summary estimate. The risk factor of interest with none adjusted effect size available were still analyzed by Mantel-Haenszel method but were marked out in the table to alarm the reader to interpret with caution. Pooled odds ratios (ORs) were calculated as case-control studies were included. In the heterogeneity test, a P value >0.05 and I²<50% was considered no heterogeneity, 0.01<P<0.05 or 50%<I²<70% was considered medium heterogeneity, and 0<P<0.01 or I²>70% was considered large heterogeneity. Random effects models were used in every analysis due to the non-randomize nature of the enrolled studies. Sensitivity analysis was done manually by repeating the meta-analysis when removing the included studies one at a time to testify the stability of the pooled OR. An unchanged significance of pooled OR after removing a study was considered stable; an altered significance yet similar direction of pooled OR was considered fair stability; an altered significance and direction of pooled OR was considered unstable. Publication bias analysis was conducted by the Egger’s test from the metabias add-on program in Stata (Stata Statistical Software: Release 17. StataCorp LLC. College Station, TX, USA) when more than three studies were included. A P value >0.05 in the Egger’s test was considered to be significant. Subgroup analyses were further done for analyses with large heterogeneity. The body of evidence was evaluated by GRADE method.

Results

Literature retrieval result

The search yielded 885 unique records published from 1978 to 2022. Four additional studies were found through reference searches. After excluding 759 records by abstract screening, 129 articles were fully read for eligibility evaluation (Figure 1). A total of 55 studies, including case-control studies (n=17) (4-16,18,24-26) and observational cohort studies (n=38) with single center (19,23,27-36), multicenter (17,37-39), and regional/national studies (1,20,40-59), were selected for this meta-analysis, published from 1985 to 2022. A flow chart of the process was shown in Figure 1. An overview of characteristics of the included studies, including study period, country of objects, study population, number of patients in the reported groups, factors analyzed in the study, are presented in Tables 1,2. The list of the excluded fully read studies is presented in Table S1. The detailed results of quality evaluation of the studies by Newcastle-Ottawa quality scale are presented in Tables S2,S3. The study protocol can be found online (https://www.crd.york.ac.uk/PROSPEROFILES/338176_PROTOCOL_20230111.pdf)

Figure 1 Flow chart of the study. MAS, meconium aspiration syndrome.

Several studies reporting independent risk factors with well-established cohort were not enrolled because of the lack of raw data, including Persson 2014 (60), Björkman 2015 (61), Caughey 2005 (62), Cheng 2006 (63), Darling 2019 (64), Gould 2004 (65) and Gupta 2021 (66).

Risk of bias of included studies

The results of quality evaluation of the studies by Newcastle-Ottawa quality scale are presented in Table 1 and details are presented in Tables S2,S3. The case-control studies were published from 1989 to 2021. The majority of case-control studies were single center studies. All but three [Amitai Komem 2022 (4), Paudel 2020 (16), Vivian-Taylor 2011 (18)] were of small sample size. The majority hit a score of six, with none fell below three. One study was considered as low risk of bias (18) that was determined a score of nine. The main limitation of the case-control studies was that the case definition was extracted from established records, rather than individually validation, that controls were from hospitals, and that adjustment for potential confounders were not performed. The observational cohort studies were published from 1985 to 2022, of which the majority hit a score of nine. In general, the cohort studies were of a higher quality.

Risk factor analysis

Results of the meta-analysis and certainty of evidence body are summarized in Table 3 reviewed below. The forest plots of each analysis, with the presentation with studies providing unadjusted effect size, were provided in the supplementary figures (Figures S1-S15).

Maternal risk factor

Maternal BMI ≥30 kg/m² [5 studies, OR 2.27, 95% confidence interval (CI): 1.53–3.35, P<0.001] was a significant risk factor for MAS with large heterogeneity (I²=74%, P=0.002); there were one unadjusted effect size from Oliveira et al. (12), and was similar to the combined result (Figure S1). Maternal age >34 years old was significant (2 studies, OR 1.46, 95% CI: 1.15–1.85, P=0.002) to MAS with large heterogeneity (I²=83%, P<0.001); there were one unadjusted effect size of maternal age >34 years old from Gurubacharya et al. (10) and was similar in trend with the combined result (Figure S2). Previous cesarean delivery was significant risky to MAS (3 studies, OR 1.27, 95% CI: 1.08–1.50, P=0.004) with no heterogeneity (I²=0%, P=0.52); the unadjusted effect sizes (14,25) were similar to the pooled OR (Figure S3). Maternal inflammatory response (3 studies, OR 2.20, 95% CI: 1.55–3.13, P<0.001) was a significant risk factor with small heterogeneity (I²=54%, P=0.09); the studies with unadjusted effect size (14,15,23) were similar to the summarized effect size of adjusted result (Figure S4). There was only one adjusted effect size for smoking (1 study, OR 1.47, 95% CI: 1.32–1.64) and the unadjusted effect sizes were consistent with this adjusted OR in terms of direction and significance (Figure S5). Nulliparous was a significant risk factor (2 studies, OR 1.42, 95% CI: 1.29–1.56, P<0.001) for MAS with no heterogeneity (I²=0%, P=0.99); the remaining unadjusted ORs were also similar (Figure S6). There was no evidence of publication bias for the maternal risk factors and all conclusions were stable. There was no evidence of publication bias and sensitivity test was stable for all maternal factors.

Maternal fever in the domain of maternal inflammatory response showed to be a risk factor (2 studies, OR 2.37, 95% CI: 1.57–3.58, P<0.001). Chorioamnionitis were reported by three studies with only one adjusted OR available (1 study, OR 1.83, 95% CI: 1.18–2.84); the other three unadjusted OR were consistent to this result (Figure S4) (14,15). The subgroup analysis was not done for maternal age >34 years old, since there were only three publications in the meta-analysis. Subgroup analysis was attempted for maternal BMI ≥30 kg/m², but none of the grouping strategy diminished the heterogeneity.

Peripartum risk factors

Oligohydramnios (2 studies, OR 2.35, 95% CI: 1.09–5.08, P=0.03) and cesarean section (2 studies, OR 2.50, 95% CI: 1.68–3.73, P<0.001) were risk factors for MAS with no heterogeneity; the remaining unadjusted ORs of the two factors were of the same significance to the corresponding summarized effect size (Figures S7,S9). Induction of labor appeared to be a protective factor (6 studies, OR 0.56, 95% CI: 0.47–0.68, P<0.001) with medium heterogeneity (I²=60%, P=0.002). There was no adjusted effect size reported for thick meconium in the enrolled studies, and the pooled OR for the univariate effect sizes showed significant risk for MAS (3 studies, OR 3.96, 95% CI: 2.02–7.77, P<0.001). The stability of the conclusion was true for all. There was no evidence of publication bias for the peripartum risk factors.

Fetal-neonatal risk factors

There was no adjusted effect size reported for fetal-neonatal risk factors in the enrolled studies hence the pooled OR reported below were conducted on the univariate results. The listed fetal-neonatal risk factors, i.e., abnormal fetal heart rate (8 studies, OR 4.70, 95% CI: 3.50–6.32, P<0.001), male infant (10 studies, OR 1.15, 95% CI: 0.98–1.36, P<0.001), post-term (7 studies, OR 4.03, 95% CI: 2.84–5.71, P<0.001), SGA (4 studies, OR 1.97, 95% CI: 1.76–2.20, P<0.001), and Apgar <7 at 5 min (8 studies, OR 14.89, 95% CI: 9.52–23.28, P<0.001), were significant risk of MAS. There was no heterogeneity between studies for male infant (I²=26%, P=0.20), SGA (I²=0%, P=0.76), and post-term (I²=36%, P=0.15), Apgar <7 at 5 min (I²=47%, P=0.07), and abnormal fetal heart rate (I²=0%, P=0.60). There was no evidence of publication bias and the stability of the conclusion was true for all fetal-neonatal risk factors. However, due to the results were from univariate analysis these results should be interpreted with caution.

Certainty of body of evidence

The certainty of evidence were very low for factors including maternal age >34-year-old, previous cesarean delivery, induction of labor, abnormal fetal heart rate, male infant, and SGA, due to the inconsistency from heterogeneity among studies and/or the high risk of bias of included studies (Table 3). The certainty of evidence remained at low level for factors including maternal BMI ≥30 kg/m² and maternal inflammatory response, due to large effect size but inconsistency and for post term and thick meconium due to large effect size but high risk of bias. The certainty of evidence was also low for nulliparous. The certainty for maternal fever, caesarean section and oligohydramnios were moderate due to large effect size (Table 3). The certainty for Apgar <7 at 5 min remained at moderate level due to very large effect size but high risk of bias (Table 3).

Discussion

Though the incidence and mortality of MAS decreased among the decades, MAS is still one of the causes leading to severe adverse outcome and may require advanced therapy of life support. To date, the predictor for MAS remains to be one of the topics for studies in this field. Clarifying the risk factors of MAS is of significance to early notify of the development of MAS which paves the way for early diagnosis and intervention, and may further reduce the use of advanced support caused by delayed intervention. In this study, instead of pre-defining risk factors at the start of the literature searching, we set the risks of interest after reading through the included article for reported factors, with the attempt to capture wider spectrum of information related to the topic. And we have identified a few factors that were understated in previous studies.

We included maternal fever and maternal chorioamnionitis specified by the article in terms of maternal inflammatory response, a concept that gained much attention in recent years (23-25). We did not include premature rupture of membrane (PROM) since PROM does not directly translate to maternal inflammatory response. The role of inflammation on MAS has gained increasing attention (23-25). Ashwal et al. (23) reported a trend, though not significant, of higher rate of MAS in relation to maternal fever (considering the overall incidence of MAS in the cohort, the insignificance might be due to the small sample size). Lee et al. (25) reported that intra-amniotic inflammation was associated to higher rate of MAS. Yokoi et al. (24) found that inflammatory biomarkers at birth of the neonate including C-reactive protein, haptoglobin were all relate to increased risk of MAS. Though the main pathological mechanism was considered to be triggered premature bowel peristalsis by intrauterine hypoxia-ischemia, there are studies proposing intrauterine inflammation as an independent variable for MAS development (25). A potential explanation might be that the elevated proinflammatory mediators such as interleukins and cytokine, transferred into the fetus, by swallowing or passing the cord, trigger bowel peristalsis and thus meconium passage in utero (23-25).

The other maternal factors analyzed in this study are all statistically significant. Smoking is reported to be a risk factor of neonatal morbidities other than MAS (67,68). A higher risk of SGA was reported in off-springs born to mothers smoking during pregnancy (68), which is another risk factor for MAS seen in this study. Maternal obesity, or BMI ≥30 kg/m², was focused more in industrialized countries. Furthermore, apart from a set high BMI, Persson et al. (60) showed that a dynamic increase in the BMI is also associated to higher risk of MAS, based on a nation-wide cohort study. Advanced maternal age was reported to be associated with post-term birth (49), which is also a significant risk factor for MAS demonstrated in this study. However, the limited number of combinable studies the large heterogeneity of studies reporting on maternal factors diminished the certainty of evidence of the reported results, calling for high-quality studies to further investigate into risk factors for MAS surrounding maternal characteristics.

Our data supports the previously identified peripartum and fetal-neonatal risk factors risk factors for MAS, such as oligohydramnios, caesarean section, thick meconium, abnormal fetal heart rate, post-term, SGA, and low Apgar score (2), of which the main pathway leading to MAS is intrauterine hypoxia. Among the aforementioned risk factors, low Apgar score had the largest effect size, which is a straight-forward consequence of intrauterine hypoxia.

Induction of labor seemed to be a protective factor. Paudel et al. (16), reported a different result with comparing different induction method to no induction. However, this study was dropped because of the large heterogeinty among studies and unstable results when including this study. The explanation to this result might be the population and medical strategy in Paudel et al. (16) varied from those from other studies. Further randomized trials can be an option to validate this finding.

Some of the risk factors reported in the study are highly linked to the socioeconomic and demographic characteristics of the study site and the study period. For example, in earlier articles, the aforementioned cesarean section, reported by a series of studies to be a risk factor for MAS, were not categorized as elective and emergency. Vivian-Taylor et al. (18) clarified that it was the emergency cesarean section to be the risk factor for MAS, and the elective cesarean section was seen to be protective. They further pointed out that instrumental delivery was also a risk factor, which was rarely reported by other studies. Industrialized countries tend to conduct more large cohort studies and analyze factors relating to demographic characteristics such as ethnicity, teenage mother and maternal obesity. Additionally, new medical management strategies, i.e., induction of labor, has also gained increasing attention in the latest decade. On the other hand, the developing countries focus more on analyzing direct data from the delivery process, such as Apgar score, meconium-stained amnionic fluids, blood markers. These differences indicated a social-economical and temporal impact on the reported factors. Though a large proportion of the target factors in the large cohort studies are hard to combine due to their uniqueness, we have listed all the analyzed factors in Table 1.

To comply to the inclusion criteria for the analysis, several studies reporting independent risk factors with well-established cohort were not enrolled, including birth trauma (66) and large distance from home birth to emergency obstetric services (64), one unit increase in BMI (60) and born to low-risk mothers at low-cesarean delivery hospitals (65).

The strength of this study includes large sample size of cases and controls as the incidence of MAS was low in general. Additionally, we attempted to control selection bias through a predefined protocol. However, there are several limitations to be pointed out. First, the majority of the included studies were small and at overall high risk of bias, especially those case-control studies. As mentioned above, a lot of factors analyzed by the high-quality cohort studies were too unique to combine, resulting in limited number of pooled analyses with limited quality of studies. Second, the standard for MAS diagnosis varied over time. The enrolled studies did not conduct independent evaluation of MAS, but extracted data through medical records, which may lead to heterogeneity in MAS definition. Third, we could not eliminate language bias as only English databases were searched. Moreover, differences in socioeconomic conditions, lifestyles, and available therapies and medical strategies may introduce large inter-study heterogeneity, undermining the certainty of the conclusion. Also, we were unable to run the sub-analysis according to study era for most of the factor due to the large heterogeneity, hence we were not able to answer whether the effect size of risk factor altered over the decades. Last but not least, the majority of certainty of evidence ranged between very low to low due to the observational nature of the studies. However, since risk factors like maternal, peripartum, and fetal-neonatal characteristics cannot be analyzed by randomized controlled trials, our meta-analysis of observational studies can serve as a source of evidence.

Conclusions

In conclusion, despite the limitations, our study provides evidence reporting the risk factors associating to MAS development. As MAS is a disease with multiple risk factors, all 15 risk factors reported can be considered as potential impacting factors. In clinical practice, maternal smoking and obesity should be controlled and induction of labor can serve as a protective factor. The overall limited quality of relevant case-control studies necessitates further high-quality researches. The limited number of combinable studies focusing on maternal risk factors indicates more attention on the association of maternal characteristics to MAS should be paid in future studies.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-23-5/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-23-5/coif). LQ serves as an unpaid managing editor of Pediatric Medicine. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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