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Penggunaan antibiotik untuk neonat yang lahir dengan cecair amniotik bertanda mekonium.

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Referencias

References to studies included in this review

Basu 2007 {published data only}

Basu S, Kumar A, Bhatia BD. Role of antibiotics in meconium aspiration syndrome. Annals of Tropical Pediatrics 2007;27:107‐13. CENTRAL

Goel 2015 {published data only}

Goel A, Nangia S, Saili A, Garg A, Sharma S, Randhawa VS. Role of prophylactic antibiotics in neonates born through meconium‐stained amniotic fluid (MSAF) ‐ a randomized controlled trial. European Journal of Pediatrics 2015;174:237‐43. CENTRAL

Lin 2005 {published data only}

Lin HC, Su BH, Tsai CH, Lin TW, Yeh TF. Role of antibiotics in management of non‐ventilated cases of meconium aspiration syndrome without risk factors for infection. Biology of the Neonate 2005;87:51‐5. CENTRAL

Shankar 1995 {published data only}

Shankar V, Paul VK, Deorari AK, Singh M. Do neonates with meconium aspiration syndrome require antibiotics?. Indian Journal of Pediatrics 1995;62:327‐31. CENTRAL

References to studies excluded from this review

Adair 1996 {published data only}

Adair CD, Ernest JM, Sanchez‐Ramos L, Burrus DR, Boles ML, Veille JC. Meconium‐stained amniotic fluid‐associated infectious morbidity: a randomized, double‐blind trial of ampicillin‐sulbactam prophylaxis. Obstetrics and Gynecology 1996;88:216‐20. CENTRAL

de Graff 1994 {published data only}

de Graaf MY, Verhagen E, Brand PL. Meconium‐containing amniotic fluid and what actions to take in newborn infants. Nederlands Tijdschrift voor Geneeskunde 1994;138(20):993‐5. CENTRAL

Edwards 1999 {published data only}

Edwards RK, Duff P. Prophylactic cefazolin in amnioinfusions administered for meconium‐stained amniotic fluid. Infectious Diseases in Obstetrics and Gynecology 1999;7:153‐7. CENTRAL

Krishnan 1995 {published data only}

Krishnan L, Nasruddin, Prabhakar P, Bhaskaranand N. Routine antibiotic cover for newborns intubated for aspirating meconium: is it necessary?. Indian Pediatrics 1995;32:529‐31. CENTRAL

Pongmee 2015 {published data only}

Pongmee P, Nagar G, Campbell S, Kumar M. Antibiotic administration for prevention or treatment of meconium aspiration syndrome in neonates: a systematic review. Jounral of Clinical Neonatology 2015;4:221‐6. CENTRAL

Siriwachirachai 2014 {published data only}

Siriwachirachai T, Sangkomkamhang US, Lumbiganon P, Laopaiboon M. Antibiotics for meconium‐stained amniotic fluid in labour for preventing maternal and neonatal infections. The Cochrane Database of Systematic Reviews 2014;11:CD007772. [DOI: 10.1002/14651858.CD007772.pub3]CENTRAL

Vidyasagar 2013 {published data only}

Vidyasagar D. The management of a neonate born with meconium stained amniotic fluid. Conference: 11th World Congress of Perinatal Medicine; Journal of Perinatal Medicine. 2013. CENTRAL

Additional references

Ahanya 2005

Ahanya SN, Lakshmanan J, Morgan BL, Ross MG. Meconium passage in utero: mechanisms, consequences, and management. Obstetrics and Gynecology Survey 2005;60:45‐56.

Blot 1983

Blot P, Milliez J, Breart G, Vige P, Nessmann C, Onufryk JP, et al. Fetal tachycardia and meconium staining: a sign of fetal infection. International Journal of Gynaecology and Obstetrics 1983;21:189‐94.

Bortolucci 1990

Bortolucci R, Seeliger HPR. Listeriosis. In: Remington JS, Klie JO editor(s). Infectious Diseases of the Fetus and Newborn Infant. 3rd Edition. Philadelphia: WB Saunders, 1990:812‐33.

Burgess 1996

Burgess AM, Hutchins GM. Inflammation of the lungs, umbilical cord and placenta associated with meconium passage in utero. Review of 123 autopsied cases. Pathology, Research and Practice 1996;192:1121‐8.

CDC 2004

CDC guidelines. Campaign to prevent antimicrobial resistance in health care settings. 12 steps to prevent antimicrobial resistance among long term care residents. http://www.cdc.gov/drugresistance/healthcare/ltc/12steps_ltc.htm (accessed 5 June 2006).. Atlanta: Centers for Disease Control and Prevention, Atlanta: Centers for Disease Control and Prevention, 2004.

Cleary 1998

Cleary GM, Wiswell TE. Meconium‐stained amniotic fluid and the meconium aspiration syndrome: an update. Pediatric Clinics of North America 1998;45:511‐29.

Craig 2005

Craig S, Lopez A, Hoskin D, Markham F. Meconium inhibits phagocytosis and stimulates respiratory burst in alveolar macrophages. Pediatric Research 2005;57:813‐8.

Fanos 1999

Fanos V, Citaldi L. Antibacterial‐induced nephrotoxicity in the newborn. Drug Safety 1999;20:245‐67.

Florman 1969

Florman AL, Teubner D. Enhancement of bacterial growth in amniotic fluid by meconium. Journal of Pediatrics 1969;74:111‐4.

Gelfand 2004

Gelfand SL, Fanaroff JM, Walsh MC. Controversies in the treatment of meconium aspiration syndrome. Clinics in Perinatology 2004;31:445‐52.

Jiménez 2008

Jiménez E, Marín ML, Martín R, Odriozola JM, Olivares M, Xaus J, et al. Is meconium from healthy newborns actually sterile?. Research in Microbiology 2008;159:187–93.

Lee 2004

Lee JS, Stark AR. Meconium aspiration. In: Cloherty JP, Eichenwald EC, Stark AR editor(s). Manual of Neonatal Care. 5th Edition. Philadelphia: Lippincott Williams and Wilkins, 2004:402‐6.

Lembet 2003

Lembet A, Gaddipati S, Holzman IR, Berkowitz RL, Bottone EJ. Meconium enhances the growth of perinatal bacterial pathogens. Mount Sinai Journal of Medicine 2003;70:126‐9.

Madan 2012

Madan JC, Salari RC, Saxena D, Davidson L, O'Toole GA, Moore JH, et al. Gut microbial colonisation in premature neonates predicts neonatal sepsis. Archives of Disease in Childhood. Fetal & Neonatal Edition 2012;97:F456–62.

Mazor 1995

Mazor M, Furman B, Wiznitzer A, Shoham‐Vardi I, Cohen J, Ghezzi F. Maternal and perinatal outcome of patients with preterm labor and meconium‐stained amniotic fluid. Obstetrics and Gynecology 1995;86:830‐3.

McCracken 1986

McCracken GH. Aminoglycoside toxicity in infants and children. The American Journal of Medicine 1986;80:172‐8.

Mshvildadze 2010

Mshvildadze M, Neu J, Schuster J, Theriaque D, Li N. Intestinal microbial ecology in premature infants assessed with non‐culture‐based techniques. Journal of Pediatrics 2010;156:20‐5.

Natarajan 2016

Natarajan CK, Sankar MJ, Jain K, Agarwal R, Paul VK. Surfactat therapy and antibiotics in neonates with meconium aspiration syndrome: a systematic review and meta‐analysis. Journal of Perinatology 2016;36:548‐53.

Rao 2001

Rao S, Pavlova Z, Incerpi MH, Ramanathan R. Meconium‐stained amniotic fluid and neonatal morbidity in near‐term and term deliveries with acute histologic chorioamnionitis and/or funisitis. Journal of Perinatology 2001;21:537‐40.

Romero 1991

Romero R, Hanaoka S, Mazor M, Athanassiadis AP, Callahan R, Hsu YC, et al. Meconium‐stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity. American Journal of Obstetrics and Gynecology 1991;164:859‐62.

Speer 1998

Speer CP, Groneck P. Oxygen radicals, cytokines, adhesion molecules and lung injury in neonates. Seminars in Neonatology 1998;3:219‐28.

Tom‐Revzon 2004

Tom‐Revzon C. Strategic use of antibiotics in the neonatal intensive care unit. The Journal of Perinatal and Neonatal Nursing 2004;18:241‐58.

Usta 1995

Usta IM, Mercer BM, Sibai BM. Risk factors for meconium aspiration syndrome. Obstetrics and Gynecology 1995;86:230‐4.

Wan 2014

Wan X, Wang W, Lui J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Medical Research Methodology 2014;14:135.

Warrier 2006

Warrier I, Du W, Nataranjan G, Salari V, Aranda J. Patterns of drug utilization in a neonatal intensive care unit. The Journal of Clinical Pharmacology 2006;46(4):449‐55.

Wiswell 1990

Wiswell TE, Tuggle JM, Turner BS. Meconium aspiration syndrome: have we made a difference?. Pediatrics 1990;85:715‐21.

Wiswell 1992

Wiswell TE, Henley MA. Intratracheal suctioning, systemic infection, and the meconium aspiration syndrome. Pediatrics 1992;89:203‐6.

Wiswell 1993

Wiswell TE, Bent RC. Meconium staining and the meconium aspiration syndrome. Unresolved issues. Pediatric Clinics of North America 1993;40:955‐81.

Wiswell 2000

Wiswell TE, Gannon CM, Jacob J, Goldsmith L, Szlyd E, Weiss K, et al. Delivery room management of the apparently vigorous meconium‐stained neonate: results of the multicenter, international collaborative trial. Pediatrics 2000;105:1‐7.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Basu 2007

Methods

Randomised controlled trial

1. Masking of randomisation: yes

2. Masking of intervention: yes

3. Completeness of follow‐up: yes

4. Masking of outcome assessment: partial

Participants

Location: India

Inclusion criteria: diagnosis of MAS, must meet all 5 criteria: (1) delivery through MSAF; (2) retrieval of meconium from below the larynx on endotracheal tube suction; (3) development of respiratory distress within 4 hours of birth and persisting beyond 24 hours; (4) chest radiograph showing features of infiltration with or without hyperinflation and/or atelectasis; and (5) absence of any other explanation for respiratory distress

Antibiotics group (N = 72)

Male = 39/72

Median (IQR) BW (grams) = 2450 (2190‐2900)

Median (IQR) GA (weeks) = 39.0 (37.0‐42.0)

Control group (N = 74)

Male = 39/74

Median (IQR) BW (grams) = 2450 (2170‐2700)

Median (IQR) GA (weeks) = 39.0 (37.0‐41.52)

Exclusion criteria: (1) sepsis; any maternal or fetal risk factor for sepsis (e.g. intrapartum fever > 37.5°C, chorioamnionitis and prolonged rupture of membrane, < 35 weeks' gestation, low birth weight ‐ < 2000 g); development of clinical signs of sepsis after birth (e.g. poor feeding, lethargy, temperature instability, sclerema, delayed capillary filling time (> 3 seconds) with a positive blood culture and/or any 2 laboratory criteria suggestive of sepsis (i.e. total leucocyte count < 5000/109 cells/L or > 30,000/109 cells/L; band/segmented neutrophils ratio above 0.2; raised micro‐ESR > 5 mm in 1st hour on 1st day of life or > 15 mm at any time; and raised C‐reactive protein (> 1000 pg/L)); (2) settling of respiratory distress within 24 hours of birth; and

(3) presence of any congenital malformation

Interventions

Antibiotics:

100 mg/kg/d ampicillin divided into 2 doses and 15 mg/kg/d amikacin divided into 2 doses for 7 days

Control:

No antibiotics

Outcomes

Primary outcome:

Sepsis; clinical signs suggestive of sepsis along with a positive blood culture or any 2 laboratory criteria suggestive of sepsis

Secondary outcomes:

Duration of respiratory distress

Duration of oxygen requirement

Duration of hospital stay

Requirement of IV fluids

Commencement and achievement of full feeds

Clearing of chest radiograph

Notes

No clinical trials registration number or funding source reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation sequence

Allocation concealment (selection bias)

Low risk

Allocation concealed

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Parents/attendants, radiologists, and statisticians were blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Radiologists were blinded. Clinicians could not be blinded, as 1 group received no treatment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for and the number of participants lost to follow‐up was similar in both groups (N = 4 in the antibiotics group; N = 5 in the control group). Two participants died ‐ 1 in each group ‐ and were removed from analysis following randomisation

Selective reporting (reporting bias)

Unclear risk

No access to protocol

Other bias

Low risk

Goel 2015

Methods

Open‐label randomised controlled trial

1. Masking of randomisation: yes

2. Masking of intervention: yes

3. Completeness of follow‐up: yes

4. Masking of outcome assessment: yes

Participants

Location: India

Inclusion criteria: all full‐term infants born as singleton cephalic presentation through MSAF

Antibiotics group (N = 121)

Male = 81/121

Mean (SD) BW (grams) = 2784.35 (447.19)

Median (IQR) GA (weeks) = 39 (38‐40)

Control group (N = 129)

Male = 74/129

Mean (SD) BW = 2640.90 (427.5)

Median (IQR) GA = 39 (38‐40)

Exclusion criteria: major congenital malformation or refusal of consent by parents

Interventions

Antibiotics:

Prophylactic IV antibiotics, piperacillin‐tazobactam 100 mg/kd/d, and amikacin 15 mg/kg/d for 3 days

Control:

No antibiotics

Outcomes

Primary outcome:

Incidence of sepsis

Secondary outcomes:

Incidence of MAS

Severity of MAS

MAS complications

HIE

Duration of stay in hospital

Mortality

Notes

Registered with clinical trial registry (NCT01290003). This research received no specific grant from any funding agency in public, commercial, or not‐for‐profit sectors

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Block‐randomised, computer‐generated

Allocation concealment (selection bias)

Low risk

Allocation concealed

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treating clinician and nursery personnel were described as blinded; on‐duty physician completed randomisation assignment

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Treating clinician and nursery personnel were described as blinded. Unclear how treating clinician could be blinded, as control group received no intervention

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants accounted for in analysis

Selective reporting (reporting bias)

Low risk

Reported outcomes match those prospectively registered with clinicaltrials.gov

Other bias

Low risk

Lin 2005

Methods

Randomised controlled trial

1. Masking of randomisation: unclear

2. Masking of intervention: unclear

3. Completeness of follow‐up: no

4. Masking of outcome assessment: unclear

Participants

Location: Taiwan

Inclusion criteria: MAS; diagnosed by presence of meconium below the vocal cord, accompanied by respiratory distress with tachypnoea, retraction, or cyanosis of the babies and an abnormal chest X‐ray (atelectasis, linear or patchy infiltration)

Antibiotics group (N =132)

Male = 72/132

Mean (SD) BW (grams) = 3280 (395)

Mean (SD) GA (weeks) = 37.3 (3.9)

Control group (N = 127)

Male = 69/127

Mean (SD) BW (grams) = 3450 (320)

Mean (SD) GA (weeks) = 38.5 (3.3)

Exclusion criteria: congential malformation, obvious congential infection (signs or symptoms of TORCHS), cyanotic congenital heart disease, maternal fever, amnionitis, foetal tachycardia, prolonged rupture of membrane > 24 hours, respiratory failure requiring ventilation

Interventions

Antibiotics:

100 mg/kg/d ampicillin and 5.0 mg/kg/d gentamicin for 3 days

Control:

No antibiotics

Outcomes

Blood cultures for infection

Mortality

Tachypnoea

Duration of oxygen therapy

Duration of CPAP

Incidence of nasal CPAP

Incidence of pulmonary air leaks

Notes

No clinical trial registration number or funding source reported. Corresponding study author contacted for comment but could not be reached

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No data provided

Allocation concealment (selection bias)

Unclear risk

No data provided

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

No data provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No data provided

Incomplete outcome data (attrition bias)
All outcomes

High risk

N = 158 (antibiotics), N = 148 (control) recruited, but only 132/158 and 127/148 followed until 2 months of age. Significant post‐randomisation exclusions

Selective reporting (reporting bias)

Unclear risk

No data provided on which outcomes were predesignated as primary or secondary. No access to protocol

Shankar 1995

Methods

Randomised controlled trial

1. Masking of randomisation: unclear

2. Masking of intervention: unclear

3. Completeness of follow‐up: yes

4. Masking of outcome assessment: no

Participants

Location: India

Inclusion criteria: MAS diagnosis if (1) born with meconium‐stained liquor, (2) born with respiratory distress lasting beyond 4 hours of age, and (3) documented presence of meconium in trachea at the time of tracheal suction or suggestive radiographic findings

Antibiotics group (N = 20)

Male = 12/20

Mean (SD) BW (grams) = 2650 (640)

Mean (SD) GA (weeks) = 39.0 (1.95)

Control group (N = 20)

Male = 11/20

Mean (SD) BW (grams) = 3060 (600)

Mean (SD) GA (weeks) = 38.8 (1.71)

Exclusion criteria: maternal fever within 2 weeks before delivery, rupture of membranes of over 12 hours' duration, positive sepsis screen at time of enrolment

Interventions

Antibiotics:

IV gentamicin 6 mg/kg/d q 8 hours for 7 days

Control:

No antibiotics

Outcomes

Duration of respiratory distress

RDS score at 24 hours

RDS score at 48 hours

Incidence of mechanical ventilation

Incidence of secondary infection

Incidence of pulmonary air leaks

Mortality

Notes

Unclear which outcome was designated as primary. No sample size calculation or trial registration number or funding support reported. Corresponding study author contacted for comment but could not be reached

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No data provided

Allocation concealment (selection bias)

Unclear risk

No data provided

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Nursery staff was not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No data provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Outcome data were reported for all 42 randomised neonates

Selective reporting (reporting bias)

Unclear risk

No data provided on which outcomes were predesignated as primary or secondary

Other bias

Unclear risk

No data provided

BW: birth weight

CPAP: continuous positive airway pressure

ESR: erythrocyte sedimentation rate

GA: gestational age

HIE: hypoxic‐ischaemic encephalopathy

IQR: interquartile ratio

MAS: meconium aspiration syndrome

MSAF: meconium‐stained amniotic fluid

RDS: respiratory distress syndrome

SD: standard deviation

TORCHS: acronym for a group of in utero infections that may induce major foetal malformations

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Adair 1996

Antibiotics not administered to neonates

de Graff 1994

Article not available in English

Edwards 1999

Antibiotics not administered to neonates

Krishnan 1995

Not a randomised controlled trial

Pongmee 2015

Review; not a randomised controlled trial

Siriwachirachai 2014

Review; not a randomised controlled trial

Vidyasagar 2013

Not a randomised controlled trial

Data and analyses

Open in table viewer
Comparison 1. Antibiotics versus control (no antibiotics) in symptomatic neonates

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of confirmed sepsis in first 28 days Show forest plot

3

445

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.02, 0.03]

Analysis 1.1

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

2 Mortality (before discharge) Show forest plot

3

445

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.01, 0.02]

Analysis 1.2

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 2 Mortality (before discharge).

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 2 Mortality (before discharge).

3 Duration of oxygen therapy, days Show forest plot

2

405

Mean Difference (IV, Fixed, 95% CI)

‐0.85 [‐1.19, ‐0.52]

Analysis 1.3

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 3 Duration of oxygen therapy, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 3 Duration of oxygen therapy, days.

4 Duration of hospital stay, days Show forest plot

1

146

Mean Difference (IV, Fixed, 95% CI)

0.16 [‐1.15, 1.47]

Analysis 1.4

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 4 Duration of hospital stay, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 4 Duration of hospital stay, days.

5 Incidence of pulmonary air leak syndrome Show forest plot

3

445

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [0.62, 3.67]

Analysis 1.5

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 5 Incidence of pulmonary air leak syndrome.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 5 Incidence of pulmonary air leak syndrome.

6 Incidence of mechanical ventilation Show forest plot

3

445

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.52, 2.67]

Analysis 1.6

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 6 Incidence of mechanical ventilation.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 6 Incidence of mechanical ventilation.

7 Time to clear chest radiograph, days Show forest plot

1

146

Mean Difference (IV, Fixed, 95% CI)

‐1.31 [‐3.04, 0.42]

Analysis 1.7

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 7 Time to clear chest radiograph, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 7 Time to clear chest radiograph, days.

8 Incidence of respiratory failure Show forest plot

2

405

Risk Difference (M‐H, Fixed, 95% CI)

0.01 [‐0.03, 0.05]

Analysis 1.8

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 8 Incidence of respiratory failure.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 8 Incidence of respiratory failure.

9 Duration of respiratory distress, hours Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐25.59, 23.19]

Analysis 1.9

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 9 Duration of respiratory distress, hours.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 9 Duration of respiratory distress, hours.

Open in table viewer
Comparison 2. Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of confirmed sepsis in first 28 days Show forest plot

1

250

Risk Difference (M‐H, Fixed, 95% CI)

‐0.01 [‐0.07, 0.04]

Analysis 2.1

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

2 Mortality (before discharge) Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.22, 5.18]

Analysis 2.2

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 2 Mortality (before discharge).

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 2 Mortality (before discharge).

3 Duration of mechanical ventilation, days Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

0.26 [0.15, 0.37]

Analysis 2.3

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 3 Duration of mechanical ventilation, days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 3 Duration of mechanical ventilation, days.

4 Duration of oxygen therapy, days Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

0.43 [0.13, 0.73]

Analysis 2.4

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 4 Duration of oxygen therapy, days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 4 Duration of oxygen therapy, days.

5 Incidence of suspected sepsis Show forest plot

1

250

Risk Difference (M‐H, Fixed, 95% CI)

‐0.03 [‐0.10, 0.05]

Analysis 2.5

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 5 Incidence of suspected sepsis.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 5 Incidence of suspected sepsis.

6 Incidence of intracranial haemorrhage Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 8.64]

Analysis 2.6

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 6 Incidence of intracranial haemorrhage.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 6 Incidence of intracranial haemorrhage.

7 Incidence of azotaemia Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

3.20 [0.13, 77.73]

Analysis 2.7

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 7 Incidence of azotaemia.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 7 Incidence of azotaemia.

8 Incidence of oliguria Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

3.20 [0.13, 77.73]

Analysis 2.8

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 8 Incidence of oliguria.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 8 Incidence of oliguria.

9 Incidence of diarrhoea Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

0.12 [0.01, 2.18]

Analysis 2.9

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 9 Incidence of diarrhoea.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 9 Incidence of diarrhoea.

10 Incidence of mechanical ventilation Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

2.13 [0.55, 8.34]

Analysis 2.10

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 10 Incidence of mechanical ventilation.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 10 Incidence of mechanical ventilation.

11 Incidence of respiratory distress (Downe's score) Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.81, 1.72]

Analysis 2.11

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 11 Incidence of respiratory distress (Downe's score).

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 11 Incidence of respiratory distress (Downe's score).

12 Duration of respiratory distress, hours Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

6.87 [4.22, 9.52]

Analysis 2.12

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 12 Duration of respiratory distress, hours.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 12 Duration of respiratory distress, hours.

13 Incidence of MAS Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.67, 2.04]

Analysis 2.13

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 13 Incidence of MAS.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 13 Incidence of MAS.

Figure 1. Study flow diagram.
Figuras y tablas -
Figure 1

Figure 1. Study flow diagram.

Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 2

Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Forest plot of comparison: Incidence of confirmed sepsis in symptomatic neonates within the first 28 days.
Figuras y tablas -
Figure 3

Forest plot of comparison: Incidence of confirmed sepsis in symptomatic neonates within the first 28 days.

Forest plot of comparison: Mortality in symptomatic neonates (before discharge).
Figuras y tablas -
Figure 4

Forest plot of comparison: Mortality in symptomatic neonates (before discharge).

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.
Figuras y tablas -
Analysis 1.1

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 2 Mortality (before discharge).
Figuras y tablas -
Analysis 1.2

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 2 Mortality (before discharge).

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 3 Duration of oxygen therapy, days.
Figuras y tablas -
Analysis 1.3

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 3 Duration of oxygen therapy, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 4 Duration of hospital stay, days.
Figuras y tablas -
Analysis 1.4

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 4 Duration of hospital stay, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 5 Incidence of pulmonary air leak syndrome.
Figuras y tablas -
Analysis 1.5

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 5 Incidence of pulmonary air leak syndrome.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 6 Incidence of mechanical ventilation.
Figuras y tablas -
Analysis 1.6

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 6 Incidence of mechanical ventilation.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 7 Time to clear chest radiograph, days.
Figuras y tablas -
Analysis 1.7

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 7 Time to clear chest radiograph, days.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 8 Incidence of respiratory failure.
Figuras y tablas -
Analysis 1.8

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 8 Incidence of respiratory failure.

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 9 Duration of respiratory distress, hours.
Figuras y tablas -
Analysis 1.9

Comparison 1 Antibiotics versus control (no antibiotics) in symptomatic neonates, Outcome 9 Duration of respiratory distress, hours.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.
Figuras y tablas -
Analysis 2.1

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 1 Incidence of confirmed sepsis in first 28 days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 2 Mortality (before discharge).
Figuras y tablas -
Analysis 2.2

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 2 Mortality (before discharge).

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 3 Duration of mechanical ventilation, days.
Figuras y tablas -
Analysis 2.3

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 3 Duration of mechanical ventilation, days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 4 Duration of oxygen therapy, days.
Figuras y tablas -
Analysis 2.4

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 4 Duration of oxygen therapy, days.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 5 Incidence of suspected sepsis.
Figuras y tablas -
Analysis 2.5

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 5 Incidence of suspected sepsis.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 6 Incidence of intracranial haemorrhage.
Figuras y tablas -
Analysis 2.6

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 6 Incidence of intracranial haemorrhage.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 7 Incidence of azotaemia.
Figuras y tablas -
Analysis 2.7

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 7 Incidence of azotaemia.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 8 Incidence of oliguria.
Figuras y tablas -
Analysis 2.8

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 8 Incidence of oliguria.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 9 Incidence of diarrhoea.
Figuras y tablas -
Analysis 2.9

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 9 Incidence of diarrhoea.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 10 Incidence of mechanical ventilation.
Figuras y tablas -
Analysis 2.10

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 10 Incidence of mechanical ventilation.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 11 Incidence of respiratory distress (Downe's score).
Figuras y tablas -
Analysis 2.11

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 11 Incidence of respiratory distress (Downe's score).

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 12 Duration of respiratory distress, hours.
Figuras y tablas -
Analysis 2.12

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 12 Duration of respiratory distress, hours.

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 13 Incidence of MAS.
Figuras y tablas -
Analysis 2.13

Comparison 2 Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates, Outcome 13 Incidence of MAS.

Summary of findings for the main comparison. Antibiotics compared with control (no antibiotics) in symptomatic neonates born through meconium‐stained amniotic fluid

Antibiotics compared with control (no antibiotics) in symptomatic neonates born through meconium‐stained amniotic fluid

Patient or population: symptomatic neonates born through meconium‐stained amniotic fluid
Setting: neonatal intensive care unit
Intervention: antibiotics
Comparison: control (no antibiotics)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with control (no antibiotics)

Risk with antibiotics

Incidence of confirmed sepsis in first 28 days

Study population

Not estimable

445
(3 RCTs)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to unclear risk of bias due to methodological limitations, including a large number of dropouts; and imprecision resulting from a small sample size

9 per 1000

0 per 1000
(0 to 0)

Mortality (before discharge)

Study population

RR 1.69
(0.23 to 12.53)

445
(3 RCTs)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to unclear risk of bias due to methodological limitations, including a large number of dropouts; and imprecision resulting from a small sample size

5 per 1000

8 per 1000
(1 to 57)

Duration of oxygen therapy, days

Mean duration of oxygen therapy (days) was 0

MD 0.85 days lower
(1.19 lower to 0.52 lower)

405
(2 RCTs)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to unclear risk of bias due to methodological limitations, including a large number of dropouts; and imprecision resulting from a small sample size

Duration of hospital stay, days

Mean duration of hospital stay (days) was 0

MD 0.16 days higher
(1.15 lower to 1.47 higher)

146
(1 RCT)

⊕⊕⊕⊝
MODERATE

Evidence was downgraded owing to imprecision resulting from a small sample size

Incidence of mechanical ventilation

Study population

RR 1.18
(0.52 to 2.67)

445
(3 RCTs)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to unclear risk of bias due to methodological limitations, including a large number of dropouts; and imprecision resulting from a small sample size

45 per 1000

53 per 1000
(24 to 121)

Incidence of respiratory failure

Study population

RR 1.20
(0.51 to 2.83)

405
(2 RCTs)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to unclear risk of bias due to methodological limitations, including a large number of dropouts; and imprecision resulting from a small sample size

41 per 1000

47 per 1000
(20 to 113)

*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and relative effect of the intervention (and its 95% CI)

CI: confidence interval; OR: odds ratio; RR: risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to the estimate of effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Figuras y tablas -
Summary of findings for the main comparison. Antibiotics compared with control (no antibiotics) in symptomatic neonates born through meconium‐stained amniotic fluid
Summary of findings 2. Antibiotics compared with control (no antibiotics) in asymptomatic neonates born through meconium‐stained amniotic fluid

Antibiotics compared with control (no antibiotics) in asymptomatic neonates born through meconium‐stained amniotic fluid

Patient or population: asymptomatic neonates born through meconium‐stained amniotic fluid
Setting: neonatal intensive care unit
Intervention: antibiotics
Comparison: control (no antibiotics)

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with control (no antibiotics)

Risk with antibiotics

Incidence of confirmed sepsis in first 28 days

Study population

Not estimable

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

54 per 1000

0 per 1000
(0 to 0)

Mortality (before discharge)

Study population

RR 1.07
(0.22 to 5.18)

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

23 per 1000

25 per 1000
(5 to 120)

Duration of oxygen therapy, days

Mean duration of oxygen therapy (days) was 0

MD 0.43 days higher
(0.13 higher to 0.73 higher)

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

Incidence of suspected sepsis

Study population

Not estimable

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

109 per 1000

0 per 1000
(0 to 0)

Incidence of mechanical ventilation

Study population

RR 2.13
(0.55 to 8.34)

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

23 per 1000

50 per 1000
(13 to 194)

Duration of respiratory distress, hours

Mean duration of respiratory distress (hours) was 0

MD 6.87 higher
(4.22 higher to 9.52 higher)

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

Incidence of MAS

Study population

RR 1.17
(0.67 to 2.04)

250
(1 RCT)

⊕⊕⊝⊝
LOW

Evidence was downgraded owing to very serious imprecision, as the results from this study have not been replicated

155 per 1000

181 per 1000
(104 to 316)

*The risk in the intervention group (and its 95% confidence interval) is based on assumed risk in the comparison group and relative effect of the intervention (and its 95% CI)

CI: confidence interval; OR: odds ratio; RR: risk ratio

GRADE Working Group grades of evidence
High quality: We are very confident that the true effect lies close to the estimate of effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Figuras y tablas -
Summary of findings 2. Antibiotics compared with control (no antibiotics) in asymptomatic neonates born through meconium‐stained amniotic fluid
Comparison 1. Antibiotics versus control (no antibiotics) in symptomatic neonates

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of confirmed sepsis in first 28 days Show forest plot

3

445

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.02, 0.03]

2 Mortality (before discharge) Show forest plot

3

445

Risk Difference (M‐H, Fixed, 95% CI)

0.00 [‐0.01, 0.02]

3 Duration of oxygen therapy, days Show forest plot

2

405

Mean Difference (IV, Fixed, 95% CI)

‐0.85 [‐1.19, ‐0.52]

4 Duration of hospital stay, days Show forest plot

1

146

Mean Difference (IV, Fixed, 95% CI)

0.16 [‐1.15, 1.47]

5 Incidence of pulmonary air leak syndrome Show forest plot

3

445

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [0.62, 3.67]

6 Incidence of mechanical ventilation Show forest plot

3

445

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.52, 2.67]

7 Time to clear chest radiograph, days Show forest plot

1

146

Mean Difference (IV, Fixed, 95% CI)

‐1.31 [‐3.04, 0.42]

8 Incidence of respiratory failure Show forest plot

2

405

Risk Difference (M‐H, Fixed, 95% CI)

0.01 [‐0.03, 0.05]

9 Duration of respiratory distress, hours Show forest plot

1

40

Mean Difference (IV, Random, 95% CI)

‐1.20 [‐25.59, 23.19]

Figuras y tablas -
Comparison 1. Antibiotics versus control (no antibiotics) in symptomatic neonates
Comparison 2. Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Incidence of confirmed sepsis in first 28 days Show forest plot

1

250

Risk Difference (M‐H, Fixed, 95% CI)

‐0.01 [‐0.07, 0.04]

2 Mortality (before discharge) Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.22, 5.18]

3 Duration of mechanical ventilation, days Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

0.26 [0.15, 0.37]

4 Duration of oxygen therapy, days Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

0.43 [0.13, 0.73]

5 Incidence of suspected sepsis Show forest plot

1

250

Risk Difference (M‐H, Fixed, 95% CI)

‐0.03 [‐0.10, 0.05]

6 Incidence of intracranial haemorrhage Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

0.36 [0.01, 8.64]

7 Incidence of azotaemia Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

3.20 [0.13, 77.73]

8 Incidence of oliguria Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

3.20 [0.13, 77.73]

9 Incidence of diarrhoea Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

0.12 [0.01, 2.18]

10 Incidence of mechanical ventilation Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

2.13 [0.55, 8.34]

11 Incidence of respiratory distress (Downe's score) Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.81, 1.72]

12 Duration of respiratory distress, hours Show forest plot

1

250

Mean Difference (IV, Fixed, 95% CI)

6.87 [4.22, 9.52]

13 Incidence of MAS Show forest plot

1

250

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.67, 2.04]

Figuras y tablas -
Comparison 2. Antibiotics versus control (no antibiotics) for prevention in asymptomatic neonates