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

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

Siwei Luo1^, Junyan Han1, Huanhuan Yin2, Liling Qian3

1Division of Neonatology, Children’s Hospital of Fudan University, Shanghai, China; 2Department of Rehabilitation, Children’s Hospital of Fudan University, Shanghai, China; 3Division of Respiratory Medicine, Children’s Hospital of Fudan University, Shanghai, China

Contributions: (I) Conception and design: S Luo; (II) Administrative support: L Qian; (III) Provision of study materials or patients: S Luo; (IV) Collection and assembly of data: H Yin, J Han; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

^ORCID: 0000-0003-3673-579X.

Correspondence to: Liling Qian. Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China. Email:

Background: Risk factors related to meconium aspiration syndrome (MAS), that were understated or unanalyzed by previous comprehensive studies, have emerged. The aim of the study is to determine the maternal, peripartum and fetal-neonatal risk factors with a meta-analysis method, to provide a more extended vision on high-risk scenarios related to MAS development and an insight for further research.

Methods: Articles were obtained by searching the PubMed, Ovid MEDLINE,, Scopus, Web of science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials databases, yielding 2,090 records from 1978 to 2022. Inclusion criteria of eligible studies were reported on the risk factors for the outcome of MAS within any population; using non-MAS group as control; and providing the sample size and raw data. Risk of bias of the included studies were assessed by Newcastle-Ottawa quality assessment scale. Meta-analysis on pooled odds ratios (ORs) on the extracted risk factors from the literature were calculated by Mantel-Haenszel or Inverse Variance method.

Results: A total of 55 references, including case-control studies (n=17) and observational cohort studies (n=38), were included. The majority of cohort studies, but not case-control studies, were at low risk of bias. Fifteen risk factors were included, of which 6 were related to maternal status, 3 to peripartum status and 5 to fetal-neonatal status. All factors but gender of infant were significant impactor. The factor with the largest valid effect size was Apgar <7 at 5 min [8 studies, OR 14.89, 95% confidence interval (CI): 9.52–23.28, P<0.001]. Induction of labor was a protective factor (6 studies, OR 0.56, 95% CI: 0.47–0.68, P<0.001). Maternal body mass index (BMI) ≥30 kg/m2 (5 studies, OR 2.27, 95% CI: 1.53–3.35, P<0.001) was a risk factor. Smoking was an unneglectable risk factor that was understated with only one adjusted OR available (1 study, OR 1.47, 95% CI: 1.32–1.64).

Conclusions: The reported factors can be considered as impactors for MAS development by clinicians. Maternal smoking and obesity were understated and should be emphasized and controlled in further clinical practice. The limited quality of relevant case-control studies necessitates further high-quality researches (CRD 42022338176).

Keywords: Risk factors; meconium aspiration syndrome (MAS); smoking; maternal obesity

Received: 16 January 2023; Accepted: 25 February 2023; Published online: 28 February 2023.

doi: 10.21037/pm-23-5

Highlight box

Key findings

• Maternal obesity, maternal inflammatory response, maternal smoking are risk factors related to meconium respiratory syndrome (MAS), which are not emphasized enough by previous studies. Thick meconium and low Apgar score are the factors with the largest effect size among peripartum and fetal-neonatal related factors, respectively. Induction of labor is a protective factor.

What is known and what is new?

• Meconium-stained amniotic fluid, non-reassuring fetal heart rate tracing, cesarean delivery, poor Apgar score, advancing gestational age were known to be risk factors for MAS

• Risk factors such as maternal obesity, maternal inflammatory response, maternal smoking, are understated by previous studies.

• Induction of labor, which just gained attention in last decade, can be a protective factor for MAS.

What is the implication, and what should change now?

• Maternal smoking and obesity should be controlled in clinical practice.

• 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.


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


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,, 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.


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 (

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

Table 1

Characteristics and reported analyzed factors of enrolled case-control studies

Author, year Country Study design Population N of MAS N of non-MAS Analyzed factor related to MAS NOS
Alchalabi 1999 (9) Jordan Single center nested case-control study All live-born term and post-term pregnancies with a singleton fetus with cephalic presentation and MSAF in the center between March to September 1997. Exclusion: women with risk factors for fetal distress such as hypertensive disorders, diabetes mellitus, antepartum hemorrhage, intrauterine growth retardation and major fetal anomalies 19 325 Maternal age, gestation, non-reassuring FHR, cesarean delivery, Apgar ≤7 at 5 minutes, PROM 5
Amitai Komem 2022 (4) Israel Single center case-control study All singleton gestations with cephalic presentation, delivered in the presence of MSAF between March 2011 and March 2020. Exclusion: suspected major fetal anomalies or genetic abnormalities as well as planned cesarean deliveries 78 11,778 Previous cesarean delivery, cesarean delivery, delivery <38 weeks, fever >38 °C, nulliparous, smoking, diabetes, hypertensive disorders 7
Avula 2017 (5) Guntur Single center nested case-control study All births with MSAF between October 2015 to February 2016 in the study center. Exclusion: babies born with prematurity and with congenital anomalies and whose parents didn’t give consent 21 139 Post term, SGA, oligohydramnios, Apgar <7 6
Bhat 2008 (6) India Single center nested case-control study All births with MSAF between June 2002 and May 2004 in the study center. Exclusion not stated 45 364 Birthweight <2,500 g, gestation >37 weeks, Caesarean section, meconium in trachea, thick meconium consistency, BMI increase, amniotic fluid index, serum white blood cell, k/ì 6
Gad 2020 (7) Egypt Single center nested case-control study All singleton term neonates with MSAF between January, 2013 through December, 2017 in the study center. Exclusion: neonates with congenital anomalies and those with risk factors or evidence of neonatal sepsis 22 79 Gender, Caesarean section, elevated C-reactive protein level, Apgar <7 at 5 min 6
Gurubacharya 2015 (10) Nepal Single-center cross-sectional study All live babies born though MSAF between April 2010 to June 2010. Exclusion: newborns with gross congenital anomalies 7 108 Maternal age, Apgar <3 at 1 minute, Apgar <3 at 5 minutes, resuscitation, parity, post-term 6
Lee 2016 (25) Korea Single center nested case-control study 1) Singleton pregnancy; 2) term gestation (gestational age ≥38 weeks); 3) amniotic fluid obtained at the time of cesarean delivery; and 4) MSAF identified at delivery. Exclusion: 1) multiple gestation; 2) stillbirth or fetal death; and 3) presence of major congenital malformations in the study site from July 1995 through June 2009 12 106 Maternal age, nulliparity, non-reassuring FHR pattern, Apgar <7 at 5 minutes, positive amniotic fluid culture, MMP-8 >23 ng/mL, acute histologic chorioamnionitis 6
Liu 2002 (8) USA Single center nested case-control study All infants born through MSAF from May 27, 1994 to June 9, 1997 in the study center. Exclusion not stated 24 660 Apgar <7 at 5 minutes, Apgar <7 at 1 minute, thick meconium, need for resuscitation, infant’s stomach suctioned at <5 minutes of age, post-term, Caesarean section, male 6
Mehar 2016 (26) India Single center retrospective cohort study Patients admitted to the neonatal intensive care unit of the center. Study period and exclusion not specified 27 372 Gender, gestation 5
Meydanli 2001 (11) Turkey Single center nested case-control study Term and post-term pregnant women with a singleton vertex-presenting fetus at 37 weeks’ gestation with thick MSAF whose antepartum course were uncomplicated. Study period not specified. Exclusion: multiple gestations, presentation anomalies, previous cesarean section, already ruptured membranes, gestational age <37 weeks, maternal anemia, maternal diabetes mellitus preexisting or gestational, maternal hypertension, intrauterine growth restriction, hydramnios, fetal anomalies and the presence of moderate or light meconium. Study period not stated 15 55 Postdate pregnancy, meconium below vocal cords, non-reassuring FHR tracing, need for endotracheal intubation at delivery room, caesarean section, Apgar score ≤4 at 1 min, Apgar score ≤6 at 5 min, umbilical cord plasma erythropoietin ≥50 mU/mL 5
Oliveira 2019 (12) Portugal Single center case-control study All newborns admitted to the neonatal intensive care unit of the center born through MSAF, with respiratory distress and changes in thoracic radiography compatible with MAS diagnosis between 1 January 2005 and 31 December 2015. Exclusion: newborns with a diagnosis other than MAS that explained the respiratory distress, those with normal thoracic radiography or with no need of oxygen therapy 29 58 Maternal age, maternal education, birthweight, gender, primipara, maternal obesity, smoker, Caesarean section, non-reassuring or abnormal FHR, maternal fever, resuscitation 6
Paudel 2020 (16) Nepal Multi-center nested case-control study All babies born in the study sites between 1 July 2017 to 29 August 2018. Exclusion: out-born, still born and whose parents did not provide consent 122 59,940 Parity, induction of labor, maternal infection, mode of delivery, complications during pregnancy, gestational age, gender, Apgar score <6 at 1 min and 5 min 7
Rossi 1989 (13) USA Single center case-control study Live-born infants delivered through MSAF with birth weight >2300 gm, and gestational age >37 weeks study site June through October, 1986. Exclusion: recognizable congenital anomalies, breech presentation, multiple gestations, prematurity, SGA, or the type of meconium was not recorded 22 216 non-reassuring FHR 5
Usta 1995 (14) USA Single center retrospective case-control study All cases born through thick or moderate MSAF population between January 1990 and April 1993 in the study center. Exclusion: thin or non-specified meconium, abnormal fetal presentation, multi fetal pregnancy, and congenital anomalies 898 39 Cigarette smoking, admitted for non-reassuring FHR tracing, Apgar score ≤4 at 1min, present cesarean delivery, previous cesarean delivery, chorioamnionitis, PROM, SGA, LGA, male 5
Vivian-Taylor 2011 (18) New South Wales, Australia Population-based nested case-control study All liveborn, term (>37 complete weeks of gestation), singleton infants born in study sites during 1 January 1997–31 December 2007. No exclusion stated 2149 877,037 Maternal age, parity, smoking, labor induction, delivery mode, gestational age, gender, birthweight percentile 9
Yoder 2002 (15) USA Single center nested case-control study The study population consisted of all live infants greater than 37 weeks’ completed gestation born through MSAF at the study center from January 1 1990 to December 31 1998. Exclusion not stated 61 1,365 Tracheal meconium, PROM, 5-min Apgar <7, >2 non-reassuring FHR, Cesarean delivery, need for bag mask ventilation, chorioamnionitis 6
Yokoi 2021 (24) Japan Single-center retrospective observational study Term neonates with MSAF between March 2013 and December 2018 in the study center. Exclusion: neonates whose placentae were unavailable, neonates subsequently diagnosed with major congenital anomalies, multiple gestations 88 1,248 Cesarean delivery, PROM >24 h, multipara, elevated C-reactive protein level, elevated haptoglobin level, gender 7

MAS, meconium aspiration syndrome; NOS, Newcastle-Ottawa Scale; MSAF, meconium-stained amniotic fluid; SGA, small for gestational age; FHR, fetal hearty rate; PROM, premature rupture of membrane; BMI, body mass index; MMP, matrix metalloproteinase; LGA, large for gestational age.

Table 2

Characteristics and reported analyzed factors of enrolled cohort studies

Author, year Country/region of subjects Study design Study population MAS in the observed group MAS in the reference group Observed factor of the study NOS
Andersson 2022 (40) Denmark Nationwide cohort study Singleton births without major congenital malformations, with registered GA, and with in-tended vaginal delivery at GA 41+0–42+0weeks between 2009 and 2018 in Denmark 299/55,717 345/79,160 41+0–41+3 week GA (ref) vs. 41+4– 42+0 week GA 9
Ashwal 2014 (27) Canada Single center retrospective cohort study All singleton pregnancies at term who attempted vaginal delivery at the study center between June 1st and December 31st 2012 4/987 38/22,280 Oligohydramnios vs. normal amniotic fluid index (ref) 8
Ashwal 2018 (23) Canada Single center retrospective cohort study All singleton pregnancies at term who attempted vaginal delivery at the study center between 2012–2015 4/309 2/618 Intrapartum fever vs. afebrile (ref) 8
Ashwal 2022 (28) Canada Single center retrospective cohort study All women who underwent unplanned intrapartum cesarean delivery following a trial of labor in study site between 2009 and 2016 3/337 16/1,892 an intrapartum cesarean delivery with a history of a previous cesarean delivery vs. without (ref) 9
Bailey 2021 (29) USA A secondary analysis of a single center prospective cohort Women admitted for labor at ≥37 weeks of gestation within a single institution from 2010 to 2015. Exclusion: fetal anomalies 5/614 9/5,727 Cord blood PH ≥7.20 vs Cord blood PH 7.11–7.19 (ref) 9
Blankenship 2020 (30) USA Retrospective analysis of a single center prospective cohort Women at 37–38 weeks of gestation; had a singleton, cephalic infant; presented either for induction of labor or in spontaneous labor; and reached 10 cm cervical dilation in the study site from 2010 to 2015. Exclusion: congenital anomalies, had placenta pre-via or other contraindication to vaginal delivery, delivered by cesarean before achieving complete cervical dilation, or had a prior cesarean delivery 2/682 9/6,141 Labour duration > 90th percentile vs. <90th percentile (ref) 8
Blomberg 2014 (41) Sweden Nationwide prospective cohort study All singleton primiparous women prospectively registered in the Swedish Medical Birth Register who gave births from 1 January 1992 through 31 December 2010 30/29,816 (17–19 y), 363/185,942 (20–24 y), 563/205,905 (30–34 y), 193/63,193 (35–40y), 42/10,634 (40+ y) 649/300,822 Maternal age (years): 17–29, 20–24, 25–29 (ref), 30–34, 35–39, 40+ 9
Cassidy 1985 (31) Ireland A secondary retrospective analysis of a single center cohort Pregnancies resulting in an infant below the 5th centile for an Irish delivered over a 16-month period. Study date and exclusion not stated 1/100 0/100 SGA 8
Cedergren 2004 (42) Sweden Nationwide prospective population-based cohort study Pregnancies delivered in Sweden January 1, 1992, through December 31, 2001. Exclusion: women with insulin-dependent diabetes mellitus 85/69,143 (BMI 29.1–35 kg/m2), 42/12,402 (BMI 35.1–40 kg/m2), 11/3,386 (BMI >40 kg/m2) 731/526,038 Maternal BMI (kg/m2): 19.8–26 (ref), 29.1–35, 35.1–40, >40 9
Cedergren 2006 (43) Sweden Nationwide prospective population-based cohort study Singletons born in Sweden between January 1, 1992 to December 31, 2001. Exclusions: were made for pre-existing maternal diabetes and pregnancies where the infant had chromosomal anomalies 130/6,346 10,811/770,355 Cardiovascular defects 9
Cederholm 2005 (44) Sweden Nationwide prospective population-based cohort study Women 35 to 49 years old with single births in Sweden during the period 1991–1996 64/21,748 (Amniocentesis), 5/1,984 (chorionic villus sampling) 99/47,854 Amniocentesis or chorionic villus sampling vs. not exposed (ref) 9
Cheng 2012 (45) USA Nationwide
retrospective cohort study
Nulliparous women with singleton, vertex live births delivered at 39–42 weeks’ gestation in 2005 in USA 19/23,963 (39 wk’ GA)a, 61/30,263 (40 wk’ GA)a, 57/17,379 (41 wk’ GA)a 515/177,733 (39 wk’ GA)a, 189/48,518
(40 wk’ GA)a, 11/2,739 (41 wk’ GA)a
Induction vs. expectant (ref) 9
Chiruvolu 2018 (37) USA Multicenter cohort study Nonvigorous newborns born during the retrospective 1-year period before the implementation of new NRP guidelines (October 1, 2015, to September 30, 2016) to infants born during the 1-year prospective period after implementation (October 1, 2016, to September 30, 2017) 7/130 11/101 Born before vs. born after implementation of new NRP guidelines (ref) 9
Clausson 1999 (46) Sweden Nationwide prospective population-based cohort study All recorded birth between 1991–1995. Exclusion: multiple births, preterm births, and LGA infants 32/10,321 (term-SGA), 155/39,415 (post term-AGA), 3/1,558 (post term-SGA) 595/458,744 Term SGA/post term SGA/post term AGA vs. term AGA (ref) 8
De los Santos-Garate 2011 (17) Mexico Multi-center retrospective cohort study All babies born from April 2006 to April 2009 at the study hospitals in NEOSANO’s Perinatal Network in Mexico. Exclusion: Multiple births, babies with congenital malformations or inaccurate gestational age 26/4545 (40 wk’ GA), 26/3,024 (41 wk’ GA), 12/388 (42–44 wk’ GA) 26/5,034 (39 wk’ GA)a GA (weeks): 39 (ref), 40, 41, 42–44 9
Ding 2021 (1) USA Population-based retrospective cohort study Twin births at a gestational age of 34–40 weeks from national database from 1995 to 2000. Exclusion: (I) extreme birthweights (<500 g or >6,000 g); (II) twin births not delivered at the same gestational week 35/48,942 (34 wk’ GA), 56/71,116 (35 wk’ GA), 65/95,086 (36 wk’ GA)b, 55/101,874 (37 wk’ GA)b, 44/45,318 (39 wk’ GA)b, 31/20,858 (40 wk’ GA)b 49/82,844 GA in twin pregnancy (weeks): 34, 35, 36, 37, 38 (ref), 39, 40 9
Greenwood 2003 (32) Ireland Single-center
prospective cohort study
An established cohort in The National Maternity Hospital, Dublin. Included if they had an early amniotomy that showed clear amniotic fluid 8/435 0/7959 Meconium in amniotic fluid vs. clear amniotic fluid (ref) 8
Flemming 2020 (47) Canada A population-based retrospective cohort study All data routinely collected under universal healthcare coverage in Ontario, Canada from 01/01/2000–12/31/2017 11/2,022 57/10,110 Compensated Cirrhosis vs. general population (ref) 7
Johnson 2005 (48) USA State-wide cohort study Women who had singleton births in Washington state between 1993 and 2001 52/579 14/2,384 (US-Black), 7/2,453 (US-White) Somali immigrants vs. US-Black (ref) or US-White (ref) 9
King 2012 (38) USA Multi-center retrospective cohort study All women with singleton, term gestations (≥37 weeks) delivered from August 1995 to February 2004. Exclusion: women with a stillbirth or a prior cesarean delivery 10/198 184/12,942 Birthweight >4,500 g vs. birthweight <4,000 g (ref) 9
Knight 2017 (49) UK National prospective cohort study Nulliparous women aged 35–50 years delivering at 39 weeks of gestation or beyond 6/3,715 (39 wk’ GA), 26/5,908 (40 wk’ GA), 41/7,254 (41 wk’ GA) 414/55,785 (39 wk’ GA), 242/28,190 (40 wk’ GA), 62/6,276 (41 wk’ GA) Induction vs. expectant management (ref) 9
Kortekaas 2020 (50) The Netherland National retrospective cohort study Women with a singleton birth, no known fetal congenital anomalies, ≥37 weeks of gestation and a fetus in cephalic position. Exclusion: women <18 of age, women with both pre-existing and pregnancy induced hypertensive disorder or both pre-existing or gestational diabetes mellitus. Data from 1999 and 2010 in Perined 291/4,778 (35–39 y), 62/884 (>40 y) 1,168/20,629 (18–34 y) Maternal age (years): 18–34 (ref), 35–39, >40 9
Levin 2020 (39) Israel Multi-center retrospective cohort study The study cohort included all nulliparous women who delivered neonates weighing ≥4,500 g between 2007 and 2018 in the study center 9/78, 13/50 0/43, 4/28 Trial of labor vs. no trial of labor (ref), Vaginal delivery vs. failed (ref) 8
Li 2019 (51) Taiwan Regional retrospective cohort study Newly diagnosed with PIH between January 1, 2000 and December 31, 2013 in a regional database 392/29,013 930/116,052 PIH 9
Lindegren 2017 (52) Sweden Nationwide prospective population-based cohort study Singleton cephalic pregnancies from 2001 to 2013 ≥41+3 weeks, delivered at maternity units with more than 500 deliveries per year during the study period 213/35,252 (primipara),
50/31,180 (multipara)
148/34,985 (primipara)
63/33,081 (multipara)
Deliveries in units expectant management vs. deliveries in units with the most active management of prolonged pregnancies (ref), stratified by parity 9
Lindegren 2020 (20) Sweden Nationwide prospective population-based cohort study Singleton prolonged pregnancies (>41+3) and fetus in cephalic presentation among women with one previous birth. The first birth took place after 1998, and the second delivery took place during the study period 1999–2014 18/13,312 63/45,571 Induction vs. spontaneous start of labor (ref) 9
Narchi 2010 (33) UK Single-center
prospective cohort study
Singleton pregnancy, delivered after 24 completed weeks 2/1537 (BMI 25–30 kg/m2),
7/804 (BMI 30–35 kg/m2)
4/3,322 (BMI <25 kg/m2) Maternal BMI (kg/m2) at the first visit: <25, 25–30, 30–35 9
Persson 2016 (53) Sweden Nationwide prospective population-based cohort study Infants of mothers with two consecutive live singleton term births in Sweden between 1992–2012 10/19,608 (weight change <−2)a, 19/36,538 (−2 to <−1)a, 51/86,441 (1 to <2)a, 54/65,060 (2 to <4)a, 38/24,051 (>4)a 117/198,305 (−1 to <1)a Inter-pregnancy weight change (kg/m2): <−2, −2 to <−1, −1 to <1 (ref), 1 to <2, 2 to <4, >4 9
Petrova 2001 (54) USA Nationwide retrospective cohort analysis Singleton live births in USA from a national database between 1995–1997 39/7,800 (preterm, primipara), 278/39,714 (term, primipara), 44/11,000 (preterm, multipara), 1,013/112,556 (term, multipara) 1,074/537,000 (preterm, primipara),
11,452/5,726,000 (term, primipara), 805/402,500 (preterm, multipara), 12,103/4,034,333 (term, multipara)
Maternal fever, stratified by parity and term 9
Polnaszek 2018 (19) USA A secondary analysis of a prospective cohort study from a single center Singleton deliveries at 37 weeks of gestation or beyond from 2010 to 2014 in the center 11/3,311 5/3,147 Maternal obese (BMI >30 kg/m2) 9
Pyykonen 2018 (55) Finland Nationwide prospective population-based cohort study Term, singleton cephalic deliveries between 2006–2012 in Finland 8/6,874 (40+0–40+2 wk’ GA), 10/5,533 (40+3–40+5 wk’ GA), 11/5,104 (40+6–41+1 wk’ GA), 13/5,568 (41+2–41+4 wk’ GA), 40/10,127 (41+5–42+0 wk’ GA) 20/6,862 (40+0–40+2 wk’ GA), 23/5,520 (40+3–40+5 wk’ GA), 28/5,087 (40+6–41+1 wk’ GA), 28/5,553 (41+2–41+4 wk’ GA), 43/10,124 (41+5–42+0 wk’ GA) Labor induction vs. Expectant management (ref) 9
Rietveld 2015 (56) Netherland National cohort study Women who delivered for the second time between 2000–2007 in the Netherlands after one previous cesarean 6/5,246 14/7,614 attempted operative vaginal delivery vs. emergency repeat cesarean in trial of labor after cesarean (ref) 9
Roos 2011 (57) Sweden Nationwide prospective population-based cohort study Women with singleton pregnancies giving birth between 1995–2007 in Sweden 13/3,787 1,738/1,191,336 Polycystic ovary syndrome 9
Salihu 2011 (58) USA State-wide population-based retrospective cohort study Singleton live births macrocosmic infants born within the gestational age range of 34–42 weeks 81/26,954a 180/90,022 Maternal pre-pregnancy obese
(BMI >30 kg/m2)
Stotland 2006 (34) USA Single-center retrospective cohort study All women delivering term, singleton infants in the center between 1980–2001 with information on pre-pregnancy weight and weight gain 28/4,112 (gain below)a, 90/8,860 (gain above)a 38/7,492a Maternal gestational weight gain by Institute of Medicine guidelines 9
Tyrberg 2013 (59) Sweden A national retrospective cohort study All singleton deliveries in Sweden between 1973 and 2010. No exclusion stated 22/29,408 1,287/893,505 Maternal age (years) <16–19 vs. 20–30 (ref) 9
Usher 1988 (35) Canada Single center retrospective cohort study All births included: The date of the last normal menstrual period was recorded; there was a record of an early ultrasound dating examination; gestational age calculated from early ultrasound examination was concordant within 7 days with that calculated from menstrual history; and delivery occurred at or after 273 days from the last normal menstrual period. Study period between Jan. 1, 1978, and March 31, 1986. No exclusion stated 2/1,407 (41 wk’ GA)a, 6/340 (42+ wk’ GA)a 13/5,915 (39–40 wk’ GA)a 41wk, 42+wk vs. 39–40 wk (ref) 9
Ward 2022 (36) USA Single center retrospective cohort study All women with the term and post-term singleton pregnancies (>37 weeks’ gestation) at the study site from 1990 to 2008. No exclusion stated 9/689 (38 wk GA), 29/1,537 (39 wk GA), 73/2,772 (40 wk GA), 77/1,989 (41 wk GA), 55/1,156 (42 wk GA) N/A (observing the rate of MAS with advancing GA) Gestation 9

a, calculated from the rates provided by the study; b, converted in to individual twins from the twin pairs in the original study. MAS, meconium aspiration syndrome; NOS, Newcastle-Ottawa Scale; GA, gestational age; SGA, small for gestational age; LGA, large for gestational age; AGA, appropriate for gestational age; NRP, Neonatal Resuscitation Program; PIH, pregnancy-induced hypertension; N/A, not applicable; BMI, body mass index; ref, reference group.

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).

Table 3

Combined studies of risk factors

Risk factor N of participants [studies] Combined effect Heterogeneity test Publication bias Sensitivity analysis Certainty of the evidence (GRADE)
Pooled OR 95% CI P value I2 P value Heterogeneity P value conclusion Certainty Reason for adjusting grading
Maternal factors
Maternal BMI ≥30 kg/m2 1,202,375 [5] 2.27 1.53–3.35 <0.001 74% 0.002 Large 0.404 None Stable Low Inconsistency but large effect size
Maternal age >34 year 3,645,799 [2] 1.46 1.15–1.85 0.002 83% <0.001 Large 0.210 None Stable Very Low Inconsistency
Previous cesarean delivery 148,962 [3] 1.27 1.08–1.50 0.004 0% 0.52 None 0.470 None Stable Very Low Inconsistency
Maternal inflammatory responsea 86,091 [3] 2.20 1.55–3.13 <0.001 54% 0.09 Small 0.181 None Stable Low Large effect size but inconsistency
   Maternal fever 24,693 [2] 2.37 1.57–3.58 <0.001 41% 0.18 None 0.578 None Stable Moderate Large effect size
   Chorioamnionitis 1,336 [1] 1.83 1.18–2.84 0.007 N/A N/A N/A N/A N/A N/A N/A N/A
Smokingb 874,865 [1] 1.47 1.32–1.64 N/A N/A N/A N/A N/A N/A N/A N/A N/A
Nulliparous 888,893 [2] 1.42 1.29–1.56 <0.001 0% 0.99 None 0.363 None Stable Low N/A
Peripartum factors
Oligohydramnios 36,837 [2] 2.35 1.09–5.08 0.03 0% 0.97 None 0.739 None Stable Moderate Large effect size
Induction of labor 1,946,604 [6] 0.56 0.47–0.68 <0.001 60% 0.002 Small 0.524 None Stable Very low Inconsistency
Caesarean section 13,191 [2] 2.50 1.68–3.73 <0.001 29% 0.24 None 0.729 None Stable Moderate Large effect size
Thick meconiumc 2,020 [3] 3.96 2.02–7.77 <0.001 39% 0.20 None 0.482 None Stable Low Large effect size but high risk of bias
Fetal-neonatal Factors
Abnormal fetal heart ratec 14,893 [8] 4.70 3.50–6.32 <0.001 0% 0.60 Small 0.840 None Stable Very Low Large effect size but large inconsistency and high risk of bias
Male infantc 953,922 [10] 1.15 0.98–1.36 <0.001 26% 0.20 None 0.335 None Fair Very Low High risk of bias and high risk of bias
Post termc 305,786 [7] 4.03 2.84–5.71 <0.001 36% 0.15 None 0.214 None Stable Low Large effect size but high risk of bias
SGAb 878,078 [4] 1.97 1.76–2.20 <0.001 0% 0.76 None 0.475 None Stable Very Low High risk of bias
Apgar <7 at 5 minb 74,548 [8] 14.89 9.52–23.28 <0.001 47% 0.07 None 0.983 None Stable Moderate Very large effect size but high risk of bias

a, combined analysis of identified risk factors: maternal fever, chorioamnionitis, maternal infection; b, only one study provided adjusted effect size; c, only effect sizes from univariate analysis were available. OR, odds ratio; CI, confidence interval; BMI, body mass index; SGA, small for gestational age; N/A, not applicable.

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).


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.


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.


Funding: None.


Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at 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:


  1. Ding G, Vinturache A, Yu J, et al. Optimal delivery timing for twin pregnancies: A population-based retrospective cohort study. Int J Clin Pract 2021;75:e14014. [Crossref] [PubMed]
  2. Dargaville PA, Copnell B. The epidemiology of meconium aspiration syndrome: incidence, risk factors, therapies, and outcome. Pediatrics 2006;117:1712-21. [Crossref] [PubMed]
  3. Beligere N, Rao R. Neurodevelopmental outcome of infants with meconium aspiration syndrome: report of a study and literature review. J Perinatol 2008;28:S93-101. [Crossref] [PubMed]
  4. Amitai Komem D, Meyer R, Yinon Y, et al. Prediction of meconium aspiration syndrome by data available before delivery. Int J Gynaecol Obstet 2022;158:551-6. [Crossref] [PubMed]
  5. Avula TR, Bollipo S, Potharlanka S. Meconium-stained amniotic fluid and meconium aspiration syndrome- a study on risk factors and neonatal outcome. J Med Dent Sci. 2017;6:4971-4.
  6. Bhat RY, Rao A. Meconium-stained amniotic fluid and meconium aspiration syndrome: a prospective study. Ann Trop Paediatr 2008;28:199-203. [Crossref] [PubMed]
  7. Gad S, Alkhalafawi A, Raza S, et al. Value of neutrophil to lymphocyte ratio in early prediction of meconium aspiration syndrome. J Child Sci 2020;10:E207-11.
  8. Liu WF, Harrington T. Delivery room risk factors for meconium aspiration syndrome. Am J Perinatol 2002;19:367-78. [Crossref] [PubMed]
  9. Alchalabi H, Abu-Heija AT, El-Sunna E, et al. Meconium-stained amniotic fluid in term pregnancies-a clinical view. J Obstet Gynaecol 1999;19:262-4. [Crossref] [PubMed]
  10. Gurubacharya SM, Rajbhandari S, Gurung R, et al. Risk factors and outcome of neonates born through meconium stained amniotic fluid in a tertiary hospital of Nepal. J Nepal Paediatr Soc 2015;35:44-8.
  11. Meydanli MM, Dilbaz B, Calişkan E, et al. Risk factors for meconium aspiration syndrome in infants born through thick meconium. Int J Gynaecol Obstet 2001;72:9-15. [Crossref] [PubMed]
  12. Oliveira CPL, Flôr-de-Lima F, Rocha GMD, et al. Meconium aspiration syndrome: risk factors and predictors of severity. J Matern Fetal Neonatal Med 2019;32:1492-8. [Crossref] [PubMed]
  13. Rossi EM, Philipson EH, Williams TG, et al. Meconium aspiration syndrome: intrapartum and neonatal attributes. Am J Obstet Gynecol 1989;161:1106-10. [Crossref] [PubMed]
  14. Usta IM, Mercer BM, Sibai BM. Risk factors for meconium aspiration syndrome. Obstet Gynecol 1995;86:230-4. [Crossref] [PubMed]
  15. Yoder BA, Kirsch EA, Barth WH, et al. Changing obstetric practices associated with decreasing incidence of meconium aspiration syndrome. Obstet Gynecol 2002;99:731-9. [Crossref] [PubMed]
  16. Paudel P, Sunny AK, Poudel PG, et al. Meconium aspiration syndrome: incidence, associated risk factors and outcome-evidence from a multicentric study in low-resource settings in Nepal. J Paediatr Child Health 2020;56:630-5. [Crossref] [PubMed]
  17. De Los Santos-Garate AM, Villa-Guillen M, Villanueva-García D, et al. Perinatal morbidity and mortality in late-term and post-term pregnancy. NEOSANO perinatal network's experience in Mexico. J Perinatol 2011;31:789-93. [Crossref] [PubMed]
  18. Vivian-Taylor J, Sheng J, Hadfield RM, et al. Trends in obstetric practices and meconium aspiration syndrome: a population-based study. BJOG 2011;118:1601-7. [Crossref] [PubMed]
  19. Polnaszek BE, Raghuraman N, Lopez JD, et al. Neonatal Morbidity in the Offspring of Obese Women Without Hypertension or Diabetes. Obstet Gynecol 2018;132:835-41. [Crossref] [PubMed]
  20. Lindegren L, Stuart A, Carlsson Fagerberg M, et al. Retrospective study of maternal and neonatal outcomes after induction compared to spontaneous start of labour in women with one previous birth in uncomplicated pregnancies > 41+3. J Perinat Med 2020;49:23-9. [Crossref] [PubMed]
  21. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-12. [Crossref] [PubMed]
  22. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097. [Crossref] [PubMed]
  23. Ashwal E, Salman L, Tzur Y, et al. Intrapartum fever and the risk for perinatal complications - the effect of fever duration and positive cultures. J Matern Fetal Neonatal Med 2018;31:1418-25. [Crossref] [PubMed]
  24. Yokoi K, Iwata O, Kobayashi S, et al. Evidence of both foetal inflammation and hypoxia-ischaemia is associated with meconium aspiration syndrome. Sci Rep 2021;11:16799. [Crossref] [PubMed]
  25. Lee J, Romero R, Lee KA, et al. Meconium aspiration syndrome: a role for fetal systemic inflammation. Am J Obstet Gynecol 2016;214:366.e1-9. [Crossref] [PubMed]
  26. Mehar V, Agarwal N, Agarwal A, et al. Meconium-stained amniotic fluid as a potential risk factor for perinatal asphyxia: A single-center experience. J Clin Neonatol 2016;5:157-61.
  27. Ashwal E, Hiersch L, Melamed N, et al. The association between isolated oligohydramnios at term and pregnancy outcome. Arch Gynecol Obstet 2014;290:875-81. [Crossref] [PubMed]
  28. Ashwal E, Lavie A, Blecher Y, et al. Intrapartum cesarean delivery and the risk of perinatal complications in women with and without a single prior cesarean delivery. Int J Gynaecol Obstet 2022;157:359-65. [Crossref] [PubMed]
  29. Bailey EJ, Frolova AI, López JD, et al. Mild Neonatal Acidemia is Associated with Neonatal Morbidity at Term. Am J Perinatol 2021;38:e155-61. [Crossref] [PubMed]
  30. Blankenship SA, Raghuraman N, Delhi A, et al. Association of abnormal first stage of labor duration and maternal and neonatal morbidity. Am J Obstet Gynecol 2020;223:445.e1-445.e15. [Crossref] [PubMed]
  31. Cassidy M, Baker S, Stack J, et al. Risk factors and perinatal problems in small for gestational age pregnancies. Ir J Med Sci 1985;154:237-9. [Crossref] [PubMed]
  32. Greenwood C, Lalchandani S, MacQuillan K, et al. Meconium passed in labor: how reassuring is clear amniotic fluid? Obstet Gynecol 2003;102:89-93. [Crossref] [PubMed]
  33. Narchi H, Skinner A. Overweight and obesity in pregnancy do not adversely affect neonatal outcomes: new evidence. J Obstet Gynaecol 2010;30:679-86. [Crossref] [PubMed]
  34. Stotland NE, Cheng YW, Hopkins LM, et al. Gestational weight gain and adverse neonatal outcome among term infants. Obstet Gynecol 2006;108:635-43. [Crossref] [PubMed]
  35. Usher RH, Boyd ME, McLean FH, et al. Assessment of fetal risk in postdate pregnancies. Am J Obstet Gynecol 1988;158:259-64. [Crossref] [PubMed]
  36. Ward C, Caughey AB. The risk of meconium aspiration syndrome (MAS) increases with gestational age at term. J Matern Fetal Neonatal Med 2022;35:155-60. [Crossref] [PubMed]
  37. Chiruvolu A, Miklis KK, Chen E, et al. Delivery Room Management of Meconium-Stained Newborns and Respiratory Support. Pediatrics 2018;142:e20181485. [Crossref] [PubMed]
  38. King JR, Korst LM, Miller DA, et al. Increased composite maternal and neonatal morbidity associated with ultrasonographically suspected fetal macrosomia. J Matern Fetal Neonatal Med 2012;25:1953-9. [Crossref] [PubMed]
  39. Levin G, Meyer R, Yagel S, et al. Which way is better to deliver the very heavy baby: mode of delivery, maternal and neonatal outcome. Arch Gynecol Obstet 2020;301:941-8. [Crossref] [PubMed]
  40. Andersson CB, Petersen JP, Johnsen SP, et al. Risk of complications in the late vs early days of the 42nd week of pregnancy: A nationwide cohort study. Acta Obstet Gynecol Scand 2022;101:200-11. [Crossref] [PubMed]
  41. Blomberg M, Birch Tyrberg R, Kjølhede P. Impact of maternal age on obstetric and neonatal outcome with emphasis on primiparous adolescents and older women: a Swedish Medical Birth Register Study. BMJ Open 2014;4:e005840. [Crossref] [PubMed]
  42. Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol 2004;103:219-24. [Crossref] [PubMed]
  43. Cedergren MI, Källén BA. Obstetric outcome of 6346 pregnancies with infants affected by congenital heart defects. Eur J Obstet Gynecol Reprod Biol 2006;125:211-6. [Crossref] [PubMed]
  44. Cederholm M, Haglund B, Axelsson O. Infant morbidity following amniocentesis and chorionic villus sampling for prenatal karyotyping. BJOG 2005;112:394-402. [Crossref] [PubMed]
  45. Cheng YW, Kaimal AJ, Snowden JM, et al. Induction of labor compared to expectant management in low-risk women and associated perinatal outcomes. Am J Obstet Gynecol 2012;207:502.e1-8. [Crossref] [PubMed]
  46. Clausson B, Cnattingius S, Axelsson O. Outcomes of post-term births: the role of fetal growth restriction and malformations. Obstet Gynecol 1999;94:758-62. [Crossref] [PubMed]
  47. Flemming JA, Mullin M, Lu J, et al. Outcomes of Pregnant Women With Cirrhosis and Their Infants in a Population-Based Study. Gastroenterology 2020;159:1752-1762.e10. [Crossref] [PubMed]
  48. Johnson EB, Reed SD, Hitti J, et al. Increased risk of adverse pregnancy outcome among Somali immigrants in Washington state. Am J Obstet Gynecol 2005;193:475-82. [Crossref] [PubMed]
  49. Knight HE, Cromwell DA, Gurol-Urganci I, et al. Perinatal mortality associated with induction of labour versus expectant management in nulliparous women aged 35 years or over: An English national cohort study. PLoS Med 2017;14:e1002425. [Crossref] [PubMed]
  50. Kortekaas JC, Kazemier BM, Keulen JKJ, et al. Risk of adverse pregnancy outcomes of late- and postterm pregnancies in advanced maternal age: A national cohort study. Acta Obstet Gynecol Scand 2020;99:1022-30. [Crossref] [PubMed]
  51. Li JY, Wang PH, Vitale SG, et al. Pregnancy-induced hypertension is an independent risk factor for meconium aspiration syndrome: A retrospective population based cohort study. Taiwan J Obstet Gynecol 2019;58:396-400. [Crossref] [PubMed]
  52. Lindegren L, Stuart A, Herbst A, et al. Improved neonatal outcome after active management of prolonged pregnancies beyond 41(+2) weeks in nulliparous, but not among multiparous women. Acta Obstet Gynecol Scand 2017;96:1467-74. [Crossref] [PubMed]
  53. Persson M, Johansson S, Cnattingius S. Inter-pregnancy Weight Change and Risks of Severe Birth-Asphyxia-Related Outcomes in Singleton Infants Born at Term: A Nationwide Swedish Cohort Study. PLoS Med 2016;13:e1002033. [Crossref] [PubMed]
  54. Petrova A, Demissie K, Rhoads GG, et al. Association of maternal fever during labor with neonatal and infant morbidity and mortality. Obstet Gynecol 2001;98:20-7.
  55. Pyykönen A, Tapper AM, Gissler M, et al. Propensity score method for analyzing the effect of labor induction in prolonged pregnancy. Acta Obstet Gynecol Scand 2018;97:445-53. [Crossref] [PubMed]
  56. Rietveld AL, Kok N, Kazemier BM, et al. Trial of labor after cesarean: attempted operative vaginal delivery versus emergency repeat cesarean, a prospective national cohort study. J Perinatol 2015;35:258-62. [Crossref] [PubMed]
  57. Roos N, Kieler H, Sahlin L, et al. Risk of adverse pregnancy outcomes in women with polycystic ovary syndrome: population based cohort study. BMJ 2011;343:d6309. [Crossref] [PubMed]
  58. Salihu HM, Weldeselasse HE, Rao K, et al. The impact of obesity on maternal morbidity and feto-infant outcomes among macrosomic infants. J Matern Fetal Neonatal Med 2011;24:1088-94. [Crossref] [PubMed]
  59. Tyrberg RB, Blomberg M, Kjølhede P. Deliveries among teenage women - with emphasis on incidence and mode of delivery: a Swedish national survey from 1973 to 2010. BMC Pregnancy Childbirth 2013;13:204. [Crossref] [PubMed]
  60. Persson M, Johansson S, Villamor E, et al. Maternal overweight and obesity and risks of severe birth-asphyxia-related complications in term infants: a population-based cohort study in Sweden. PLoS Med 2014;11:e1001648. [Crossref] [PubMed]
  61. Björkman K, Wesström J. Risk for girls can be adversely affected post-term due to underestimation of gestational age by ultrasound in the second trimester. Acta Obstet Gynecol Scand 2015;94:1373-9. [Crossref] [PubMed]
  62. Caughey AB, Washington AE, Laros RK Jr. Neonatal complications of term pregnancy: rates by gestational age increase in a continuous, not threshold, fashion. Am J Obstet Gynecol 2005;192:185-90. [Crossref] [PubMed]
  63. Cheng YW, Shaffer BL, Caughey AB. The association between persistent occiput posterior position and neonatal outcomes. Obstet Gynecol 2006;107:837-44. [Crossref] [PubMed]
  64. Darling EK, Lawford KMO, Wilson K, et al. Distance from Home Birth to Emergency Obstetric Services and Neonatal Outcomes: A Cohort Study. J Midwifery Womens Health 2019;64:170-8. [Crossref] [PubMed]
  65. Gould JB, Danielsen B, Korst LM, et al. Cesarean delivery rates and neonatal morbidity in a low-risk population. Obstet Gynecol 2004;104:11-9. [Crossref] [PubMed]
  66. Gupta R, Cabacungan ET. Neonatal Birth Trauma: Analysis of Yearly Trends, Risk Factors, and Outcomes. J Pediatr 2021;238:174-180.e3. [Crossref] [PubMed]
  67. Sturrock S, Williams E, Ambulkar H, et al. Maternal smoking and cannabis use during pregnancy and infant outcomes. J Perinat Med 2020;48:168-72. [Crossref] [PubMed]
  68. Ratnasiri AWG, Gordon L, Dieckmann RA, et al. Smoking during Pregnancy and Adverse Birth and Maternal Outcomes in California, 2007 to 2016. Am J Perinatol 2020;37:1364-76. [Crossref] [PubMed]
doi: 10.21037/pm-23-5
Cite this article as: Luo S, Han J, Yin H, Qian L. The risk factors of meconium aspiration syndrome in newborns: a meta-analysis and systematic review. Pediatr Med 2023;6:3.

Download Citation