Risk of infection in neonates born in accidental out-of-hospital deliveries.

Accidental out-of-hospital deliveries (OHDs) are known to have a higher incidence of maternal and neonatal complications. However, neonatal infection related to OHDs has not been studied. The aim of this study was to determine the infection risk of OHDs. This retrospective cohort study enrolled neonates admitted at a children's hospital in an urban setting from January 2004 to December 2017. Accidental OHDs were compared with in-hospital births, and neonatal infection was assessed. This study also investigated both maternal and neonatal risk factors associated with OHDs. A cohort of 158 OHD neonates was enrolled, of whom 29 (23.2%) were preterm. Prematurity and low birth weight were significantly associated with OHD. Eight neonates in the OHD cohort had a documented infection within the first 72 hours of life, which was 11-fold higher than infections documented for the in-hospital births. Multivariate analysis identified low birth weight as the only factor independently associated with increased risk of infection in OHD neonates. Several specific characteristics of mothers with OHDs were identified. Forty-nine (31%) OHD mothers lacked antenatal care, and 10 (6.3%) were unaware of their pregnancies. The OHD group comprised of more teenage mothers compared to the in-hospital deliveries category. Neonatal infection was more prevalent among OHDs than for in-hospital deliveries, and the infection rate was associated with low birth weight. Hospitalization for further care and observation is suggested for the OHD neonates. Social support should be provided for populations with an increased risk of OHD, such as teenage mothers.

Introduction

Accidental out-of-hospital deliveries (OHDs) constitute <1% of all live births in most developed countries [1-8]. These emergency births differ from planned home births and in-hospital births because OHDs usually happen accidentally at home or en route to the hospital [3, 4]. These neonates might be delivered in relatively harsh conditions, and an increase in adverse outcomes has been reported for both mothers and neonates involved in OHD. Neonates born in an unplanned setting have high rates of respiratory distress, hypoglycemia, and hypothermia, contributing to a considerably greater chance of requiring admission to special care nurseries or intensive care units (ICUs) than do neonates from similar in-hospital births [1–3, 7, 8]. In comparison with in-hospital deliveries, OHDs are associated with a higher rate of maternal complications, including extensive lacerations of the birth canal, uterine rupture, and post-partum hemorrhage [9-12]. Khupakonke et al. also demonstrated LBW to be a predicting factor of OHD [11]. Since the maternal and neonatal outcomes of OHDs are substantially different from those of in-hospital births, studying the risk factors in this specific group of patients is worthwhile.

The unpredictable characteristics of OHDs mean that neonates are born in inappropriate locations without midwives or medical professionals on standby [1, 2, 4]. These adverse circumstances and poor perinatal care, such as being born in contaminated places and suboptimal cord practices, may increase the risk of infection from OHDs, which can also result in neonatal sepsis. Neonatal infection is the most common cause of neonatal mortality in developing countries [13, 14]. However, previous studies of OHDs have not clearly proposed the risk factors associated with infection among these neonates. Therefore, the aim of this study was to investigate the risk of infection in neonates born outside hospitals. Furthermore, the maternal characteristics associated with OHDs can be identified antenatally.

Materials and methods

Design and setting

This retrospective cohort study was conducted at MacKay Children’s Hospital, an urban setting in the capital of Taiwan. We enrolled all neonates with birth records in our hospital from January 2004 to December 2017. Stillbirths were excluded. This study was approved by the Institutional Review Board of MacKay Children’s Hospital (IRB No. 18MMHIS112). The information we obtained were lists of fully anonymized data without chart number or patient’s name.

Case definition

In this study, the inclusion criteria for OHDs were neonates who were born accidentally in places other than hospitals and without assistance from health care providers. In-hospital deliveries were defined as neonates born in the delivery room, operation room, or other health facilities. To evaluate the prevalence and compare the variables of OHDs, the obstetrics records and neonatal data during the study period were retrieved from the medical record database of MacKay Children’s Hospital. Fig 1 presents the flowchart of patient enrollment.

Fig 1

Flowchart of the included neonates born in out-of-hospital deliveries.

Study variables

Gestational age (GA), gender, birth weight, duration of hospitalization, ICU stay, maternal medical history, place of labor, laboratory tests, and microbiological studies were reviewed. We recorded the duration of antimicrobial therapy in the first 72 hours of neonatal life for early-onset infections. Cutting of the umbilical cord with unsterilized scissors was considered a suboptimal cord practice. Prematurity was defined as a GA of <37 weeks. Low birth weight (LBW) was defined as weight at birth of <2500g. Teenage mothers were regarded as those aged <20 years in accordance with the World Health Organization definition [15]. Complete blood counts (CBC), C-reactive protein levels (CRP), and blood cultures were routinely taken for all OHD neonates. Cerebrospinal fluid (CSF) and gastric juice (GJ) cultures were collected when patients exhibited signs or symptoms of sepsis, including fever, respiratory distress with desaturation, seizure, apnea, tachycardia or bradycardia [16, 17].

Outcome measures

The primary outcome was the infection rate in the OHD group in comparison with that of the in-hospital deliveries. The criteria for neonatal infection were (1) positive culture from a sterile site, such as blood or CSF, and (2) positive GJ culture accompanied by clinical signs of sepsis. We limited the study to pathogens proven within 72 hours after birth since neonatal infection occurring in the first 72 hours of life is typically caused by organisms transmitted vertically from the mother before or during delivery [17-19], indicating that the pathogens are related to early-onset infections. In the OHD group, factors associated with infection were investigated by dividing the OHD neonates into infection group and non-infection group. We also analyzed the effect of gender, birth weight, GA, places of birth, suboptimal cord practices, and lack of antenatal care.

Statistical analysis

Continuous variables were expressed as means ± standard deviations and compared using Student’s t test. Categorical variables were expressed as numbers and percentages and compared using a chi-square or Fisher’s exact test. A P-value of < 0.05 was considered statistically significant. All probabilities were two tailed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Variables with a P-value of < 0.2 in the univariate analysis were included in the multivariate logistic regression models. All analyses were performed using Microsoft Excel version 14.6.4 (Redmond, WA, USA) and IBM SPSS Statistics for Macintosh version 23.0 (Armonk, NY, USA).

Results

Characteristics of OHD neonates

A total of 158 OHD neonates were identified; all were singletons. The study accounted for 0.22% of the 71,459 live births during the study period. The male:female ratio was 0.98, and the GA ranged from 27 to 41 weeks with a mean age of 37.5 ± 2.8 weeks. Among the 125 neonates with an obtainable GA, 29 (23.2%) were preterm; this rate of preterm delivery was higher than the 12.9% in the control group. The mean birth weight of the OHD neonates was 2768.7 ± 549.8 g, and 43 (27.2%) of them had LBW. Their median hospital stay was 7 days, and 25 neonates (15.8%) were admitted to the ICU. A total of eight neonates (5.1%) received cardiopulmonary resuscitation (CPR), and 10 (6.3%) required endotracheal intubation. No mortality cases were recorded.

Comparison of neonates with OHDs and in-hospital deliveries

Table 1 displays the characteristics of the neonates from OHDs and those from in-hospital deliveries. The OHD neonates had significantly younger mothers, higher rates of prematurity and LBW, and an increased risk of infection (5.1% vs. 0.5%; OR, 11.00; 95% CI, 5.36–22.58; P < 0.001). No significant difference in gender was noted. The maternal age in the OHD group ranged from 14 to 44 years with a mean of 29.4 ± 6.8 years. Twenty mothers (12.7%) were teenagers, 109 mothers (69%) were multiparous, 49 (31%) did not receive any prenatal care, and 10 (6.3%) claimed to be unaware of their pregnancies. Fig 2 shows the distribution of maternal age. Most mothers in both the OHD and in-hospital birth groups were between 20 and 39 years old, which is the usual childbearing age. The percentage of OHD mothers younger than 20 years (12.7%) was higher than that among the mothers without OHDs (1.2%; OR, 18.80; 95% CI, 11.15–30.61; P < 0.001), indicating that teenage mothers had an increased risk of OHD.

Table 1

The characteristics and infection rates of neonates in out-of-hospital deliveries and those in in-hospital deliveries.

Variable	OHDs	In-hospital deliveries	OHDs	P-value
	(N = 158)	(N = 71301)	OR (95% CI)
Maternal mean age ± SD (years)	29.4 ± 6.8	32.1 ± 4.6	Not applicable	<0.001
Male:female ratio	0.98	1.08	0.9 (0.66–1.23)	0.524
Teenage mother	20 (12.7%)	886 (1.2%)	18.80 (11.15–30.61)	<0.001
Prematurity	29 (23.2%)	9179 (12.9%)	2.04 (1.35–3.10)	<0.001
Low birth weight (<2500)(g)	43 (27.2%)	7409 (10.4%)	3.22 (2.27–4.58)	<0.001
Neonatal infection	8 (5.1%)	344 (0.5%)	11.00 (5.36–22.58)	<0.001

OHDs, out-of-hospital deliveries; SD, standard deviation; OR, odds ratio; CI, confidence interval.

Fig 2

Maternal age for neonates born in out-of-hospital deliveries and in-hospital deliveries.

Risk of infection in OHD neonates

In total, eight (5.1%) of the 158 OHD neonates had culture-confirmed infection by the age of 72 hours. As shown in Table 2, the neonates with infection had a younger GA, higher rate of prematurity and LBW, longer duration of antibiotic use, and a more complicated clinical course than did those without infection, as confirmed by the univariate analysis. Three neonates in the infection group and 30 neonates in the non-infection group had unknown GA. No significant differences in gender, birth weight, use of antibiotics, suboptimal umbilical cord practices, CBC values, or CRP levels were observed in the OHD neonates with and without infection. Primipara and lack of prenatal care were more noticeable in the neonates with infection. In the multivariate analysis of the OHD neonates, LBW (OR, 0.16; 95% CI, 0.03–0.96; P = 0.044) was the only independent factor of neonatal infection.

Table 2

Univariate analysis of variables in neonates born outside hospitals with and without infection in the first 72 hours of life.

Variables	Infection	Non-infection	OR (95% CI)	P-value
	(N = 8)	(N = 150)
Gestational age (weeks)	33.3 ± 3.5	37.8 ± 2.7	NA (-8.83– -0.17)	0.045
Prematurity	4 (80.0%)	25 (21.0%)	3.95 (0.68–22.85)	0.011
Unknown gestational age	3 (37.5%)	30 (20%)	2.30(0.54–10.61)	0.235
Male	4 (50.0%)	74 (49.3%)	1.03 (0.25–4.26)	0.971
Birth weight (g)	2224.6 ± 712.9	2797.8 ± 527.2	NA (-1171.06–24.79)	0.058
Low birth weight (<2500)(g)	6 (75.0%)	37 (24.7%)	9.16 (1.77–47.37)	0.005
Maternal age (years)	30.1 ± 8.6	29.4 ± 6.8	NA (-6.49–7.98)	0.818
Teenage mother	2 (25%)	18 (12%)	2.00 (0.22–17.89)	0.281
Lack of antenatal care	5 (62.5%)	44 (29.3%)	4.00 (0.92–17.53)	0.048
Primipara	5 (62.5%)	44 (29.3%)	4.00 (0.92–17.53)	0.048
Suboptimal cord practices	2 (40%)	27 (22.0%)	2.37 (0.38–14.92)	0.317
ICU	6 (75.0%)	19 (12.7%)	20.68 (3.89–109.99)	<0.001
CPR	2 (25.0%)	6 (4.0%)	8.00 (1.33–48.24)	0.054
Endotracheal intubation	3 (37.5%)	7 (4.7%)	12.26 (2.43–61.94)	0.009
Use of antibiotics	8 (100%)	144 (96.0%)	0.96 (0.93–0.99)	0.564
Days of antibiotic use	7.0 ± 2.6	4.1± 2.1	NA (0.71–5.10)	0.016
Toilet or bathroom	4 (50%)	33 (22.0%)	3.55 (0.84–14.95)	0.088
Laboratory data
Hemoglobin (g/dL)	18.9 ± 2.2	18.6 ± 3.8	NA (-1.48–2.28)	0.643
WBC count (/μL)	24425 ± 21929	16528 ± 5866	NA (-10444.16–26237.21)	0.343
Platelet (103/μL)	230.6 ± 66.2	286.2 ± 79.7	NA (-111.38–0.31)	0.051
CRP (mg/dL)	0.4 ± 0.9	0.1 ± 0.6	NA (-0.51–0.95)	0.494

ICU, intensive care unit; CPR, cardiopulmonary resuscitation; WBC, white blood cells; CRP, C-reactive protein; OR, odds ratio; CI, confidence interval; NA, not applicable.

The most frequent place of birth was at home (76, 48.1%), followed by in toilet bowls (22, 13.9%), in ambulances (16, 10.1%), in bathrooms (15, 9.5%), in private cars (14, 8.9%), in taxis (9, 5.7%), on sidewalks (3, 1.9%), and in other places (3, 1.9%). The places of birth in the infection and the non-infection groups were not significantly different.

Etiology in OHD neonates with infection

Table 3 displays the characteristics and etiologies of the eight neonates with infection. Neonatal infections were confirmed by positive blood cultures in one neonate (Enterococcus faecium) and GJ cultures in seven neonates. The most common pathogens were Escherichia coli (three GJ isolates) and Klebsiella spp. (three GJ isolates). Twelve OHD neonates were performed spinal tapping, and all the CSF cultures were negative findings.

Table 3

Characteristics of neonates born outside hospitals with infection within 72 hours after birth.

Case	GA (weeks)	BW (g)	Maternal age (years)	Place of birth	Culture
1	37+4	2890	28	Ambulance	Escherichia coli (GJ), Klebsiella pneumoniae (GJ),
					Staphylococcus aureus (MSSA) (GJ)
2	30	2076	18	Toilet bowl	Escherichia coli (GJ), Klebsiella oxytoca (GJ),
					Morganella morganii (GJ), Viridans streptococci (GJ)
3	36+3	2350	35	Home	Enterococcus faecium (blood)
4	unknown	3600	34	Home	fungi (GJ)
5	unknown	2032	16	Toilet bowl	Klebsiella oxytoca (GJ)
6	31+6	1704	38	Home	Neisseria gonorrhoeae (GJ)
7	30+3	1690	36	Toilet bowl	Candida albicans (GJ)
8	unknown	1455	36	Bathroom	Escherichia coli (GJ)

GA, gestational age; BW, birth weight; GJ, gastric juice; MSSA, methicillin-susceptible Staphylococcus aureus.

In OHD neonates, 152 (96.2%) neonates were administered antibiotics because of signs or symptoms of infection after birth, contaminated places of birth or suboptimal cord cutting. Ninety-seven patients (61.4%) received ampicillin and gentamicin, 27 patients (17.1%) received penicillin and gentamicin, and 11 (7.0%) received oxacillin and gentamicin. The mean duration of antibiotic use was 4.2 ± 2.2 days. Twenty-nine OHD neonates (22.7%) experienced suboptimal umbilical cord separation. One neonate with a congenital anomaly and unsterile cord cutting was administered prophylactic tetanus immune globulin.

Discussion

In this study, neonatal infection in OHDs was 11-fold higher than that in in-hospital deliveries, and LBW was the only factor independently associated with infection risk in OHDs. The infection rate of OHD neonates has not been previously documented. Contaminated places of birth, suboptimal cord cutting and poor perinatal care may be associated with the infection risk of neonates. The umbilical cord can serve as an entry point for bacteria [20, 21]. Pathogens can directly access the bloodstream via the patent vessels of the newly cut cord. Such infections are preventable and can be reduced by hygienic delivery and sterile cord care. However, suboptimal cord practices did not contribute to the risk of infection in this study, possibly because of cleaning of the cord stump soon after hospitalization as well as antibiotic administration [22]. The occurrence of infection did not differ among places of birth, even for toilet bowls or bathrooms, which are generally considered to be unhygienic. The practice of antibiotic administration in the majority of the OHD neonates may have reduced the incidence of infection and conceal the adverse factors of the place where labor occurred. On account of the characteristics of poor prenatal care among the OHD mothers, missing information on GA (20.9%) was common in our study. As birth weight and GA were confounding factors, LBW may more precisely represent factors associated with infection in OHD neonates instead of GA. In addition, preterm neonates and neonates with LBW are at increased risk of infection, neonatal morbidity and mortality compared with normal-weight full-term infants [23, 24]. Consequently, complete postnatal care and subsequent follow-up are crucial for OHD neonates, especially those with LBW.

Over the study period, the incidence of OHD in this study was 0.22%, which is similar to that reported in other studies (Table 4), and our findings were in line with previous studies of accidental OHDs [1–8, 11]. OHDs have been reported to be associated with the risk of prematurity [1–3, 25]. In our study, prematurity was significantly higher for the OHDs than for the in-hospital births. Compared with in-hospital deliveries, previous studies have indicated that ICU admission is more prevalent for OHDs, indicating a more complicated clinical course [1, 2, 4–6]. Teenage mothers and preterm deliveries were found to pose a risk of OHDs. The soft birth canal in young women and small preterm infants may cause rapid delivery [25]. Multiparous mothers and lack of prenatal care were also related to OHDs in previous reports [1–5, 9]. Furthermore, OHDs may cause high neonatal mortality and morbidity, especially in developing countries and areas short of medical assistance [11]. Prompt intervention and care may be required for all OHD neonates to improve outcomes.

Table 4

Comparative variables of neonates born in out-of-hospital deliveries in other studies.

First author	Country	Interval	Cases	Incidence	Maternal age (years)	Multiparous mother	Lack of antenatal care	GA	BW (g)	Preterm	ICU
								(weeks)
This study	Taiwan	2004–2017	158	0.22%	29.4 ± 6.8	69%	31%	37.5 ± 2.8 (27–41)	2768	23.2%	15.8%
					(14–44)
McLelland G	Australia	2000–2010	313	0.45%	29.9 ± 5.8	90.5%	3.7%	38.4 ± 3.6 (20–42)		11%
					(16–44)
Rodie VA	United Kingdom	1995–1999	121	0.6%	26	88.7%	24.3%	39.3	3000		54.3%
					(15–44)			(23–42)
Lazic Z	Slovenia	1997–2005	58	0.32%		79.3%	30%			22%
Unterscheider J	Ireland	2005–2009	143	0.36%	30	92.3%		38.4	3138	12.5%	8.1%
					(18–43)
Ramsewak S	West Indies	1987–1993	326	0.81%			29.7%
L Renesme	France	2007–2009	76	0.42%	30	90.7%	27.4%	40	3130	7.4%	14.5%
					(16–41)			(25–42)
Katja Ovaskainen	Finland	1996–2011	67	0.1%	29		12%	39.7	3460		19%
					(15–47)
François Javaudin	France	2011–2018	1670	<1%	30 ± 5.5	87%	6.5%	38	3008	8.1%	6.3%
					(15–48)
Sikhulile Khupakonke	South Africa	2015–2016	201	4.6%	27	89.8%	16.7%		2689	35.2%	6.4%

GA, gestational age; BW, birth weight; ICU, intensive care unit.

A consensus has not yet been reached on empirical antibiotic use and the pathogens associated with OHDs. The antibiotic combination of ampicillin/penicillin/oxacillin and gentamicin were used for the majority of the OHD neonates in the present study. We attempted to identify pathogens related to OHDs by collecting blood cultures, CSF and GJ cultures before antibiotic use. Several studies have proposed that gastric aspirates are related to amniotic fluid leaks and neonatal infection [26-29]. The neonatal gastrointestinal tract is considered sterile, but diverse microbiota flora is present soon after birth [30, 31]. Preterm neonates are more susceptible to colonization by potentially pathogenic bacteria, resulting in an increased risk of necrotizing enterocolitis [32-34]. The mechanism of the gastric pathogens in neonatal infection was inconclusive. The isolation of pathogens from neonatal gastric contents has been reported to be a source of systemic infection [35]. Consequently, gastric aspirates may be helpful for detecting bacterial infection, especially when neonates exhibit signs of sepsis. Consistent with our study, Stewart et al. and Sawardekar et al. identified Escherichia coli, Klebsiella spp., and Staphylococcus aureus as the most common pathogens isolated in umbilical cord cultures in infants born at home with omphalitis [20, 36]. Although no umbilical cultures were collected in our study, the pathogens isolated from the blood and GJ cultures were similar to those in the OHD infants with omphalitis. Such pathogens might be considered if infection is suspected in clinical practice.

Limitations

Limitations of this study included the unavailability of Apgar scores due to OHDs, which made birth status unclear. Second, in this retrospective study, confounding factors were a concern. Several of the variables were not independent of each other, such as GA and birth weight. In the statistical analysis, we attempted to adjust the confounding factors and predict the risk factors in accidental OHDs. Third, the sample size of the OHDs was relatively small, and neonatal infection related to OHDs has not been investigated, as evidenced in previous studies [1–8, 11]. Therefore, additional studies with more cases are required to elucidate the infection risk of OHDs. Finally, empirical antibiotics were administered to the majority of the neonates in our study, meaning the true risk of infection in OHD neonates may have been underestimated. A prospective study can clarify the effectiveness of empirical antibiotics in these neonates and determine the OHD-related pathogens.

Conclusions

We demonstrated that the infection rate was higher for OHDs than for in-hospital deliveries, and infection rate was associated with LBW. Inpatient care might be needed for accidental OHD neonates. Because poor antenatal care, prematurity, and teenage pregnancy were relatively common in the OHDs, social support services should be provided for vulnerable populations, such as teenage mothers.

(XLSX)

Click here for additional data file.

11 Aug 2021

PONE-D-21-20144

Risk of infection in neonates born in accidental out-of-hospital deliveries.

PLOS ONE

Dear Dr.  Lung Chang

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please attend to the concerns of the reviewers and re-submit should you wish to.

Please submit your revised manuscript by 25 September. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see:  http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at  https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Lloyd J. Tooke, MBChB, MMed(Paeds)

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study. Specifically, please ensure that you have discussed whether all data/samples were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data/samples from their medical records used in research, please include this information.

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access

4. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for this excellent piece of work. Please could you clarify these issues:

1. Regarding the title, it would be valuable to state where the study took place, and whether it was in an urban, peri urban or rural setting. This helps those of us who have never been to your unit understand the context better.

2. Again, the place of study should be included in the abstract for clarity.

3. The outborn cohort is very small, but this certainly speaks to the excellent care provision in your setting. In your setting, are many babies born electively at home, under the care of a doula or midwife?

4. Please clarify this sentence (on line 57 - 58): " Duration and antimicrobial therapy were recorded."

5. Please define what the local antibiotic policy is, in reference to the statement on line 141 - 142: In accordance with the common practices of the facility, 152 (96.2%) OHD neonates were administered antibiotics".

6. This sentence on line 163 ". Khupakonke et al. also demonstrated LBW to be a predicting factor of OHD [11]." feels out of place, and should probably be kept in the introduction.

7. The rest of the paper does not mention the prognosis of the patients, so the sentence on line 167 "The prognostic outcomes of OHD neonates require further research. " does not need to be included.

Reviewer #2: Abstract:

Page 2 line 14, the sentence “the OHD group was comprised of more teenage mothers than adult mothers” technically is not right. The OHD group comprised of more teenage mothers compared to the in-hospital deliveries category.

Study variables:

Does Neonatal age here refer to Gestational age?

“Cerebrospinal fluid (CSF) and gastric juice (GJ) cultures were collected when patients exhibited signs or symptoms of sepsis, including fever, respiratory distress with desaturation, seizure, apnea, tachycardia or bradycardia” but there is no mention of CSF in the results.

Outcome measures:

Page 6 line 72: “…indicating that pathogens are related to OHD.” Granted, infections associated with OHDs are more likely to be Early Onset infections but sentence should be rephrased since it is ambiguous and gives an impression of causality.

Results:

Characteristics of OHD neonates - Hospital stay would be better expressed as a median

Table 2 – Some of the percentages are not correct both under the infection & non infection columns.

What denominators were used for the Prematurity calculations?

The sub-optimal cord practices percentages for both the infection and non-infection columns are incorrect, should be 25% & 18% respectively.

Hospital stay would be better expressed as a median

Etiology of OHD in neonates with infection:

The text on the various pathogens isolated from the cultures should be rewritten as it contains a fair amount of redundancy. Since there was only one blood isolate with the remainder as GJs, it can be made to reflect that as opposed to the numerous GJ mentions.

Page 12 line 145 – percentage value of neonates with sub-optimal cord separation is supposed to be 18.4% based on a denominator of 158, as opposed to the 22.7% that is reported

General comments:

Percentage values for Prematurity seems to be inconsistent throughout the study, sometimes it is 23.2% (Page 2 line 8, page 8 table 1 etc.) and at other times 18.4% (Page 15 Table 4). It would seem different denominators are used interchangeably? When is the 158 used and when is the 125 used?

Accidental, Unexpected and Unplanned seems to be used interchangeably to qualify OHDs. Can the authors stick to one? Perhaps “accidental” would be most appropriate since that is what is used in the title of the study.

Typographical / Grammatical errors

Page 2 line 6 /7 “This study also investigated risk factors…” should read “This study also investigated both maternal and neonatal risk factors…”

Page 2 line 13 should read “Forty-nine (31%) OHD mothers lacked antenatal care…”

Page 2 line 14 / 15 should read “Neonatal infection was more prevalent among…”

Page 16 line 187 should read “The neonatal gastrointestinal tract is considered sterile, but diverse microbiota flora is present soon after birth”

Page 16 line 188, “colonization” typo error

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Lyndal Gibbs

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

17 Oct 2021

Response to Reviewers

Reviewer #1:

1. Regarding the title, it would be valuable to state where the study took place, and whether it was in an urban, peri urban or rural setting. This helps those of us who have never been to your unit understand the context better.

→ Thanks for your suggestion. This study was conducted in an urban setting of the developed country, and we had added this information in the first paragraph of Materials and Methods. (Design and setting: Page 4, line 45-46)

2. Again, the place of study should be included in the abstract for clarity.

→ Thanks for your comments. We had added this information in the abstract. (Abstract: Page 2, line 4-6)

3. The outborn cohort is very small, but this certainly speaks to the excellent care provision in your setting. In your setting, are many babies born electively at home, under the care of a doula or midwife?

→ During the 14 years of study period, none of the neonates was sent to our hospital after electively born at home. Perhaps due to the sound and prevalent National Health Insurance in Taiwan, most pregnant women prefer delivery at medical facilities for the sake of more medical assistance with mothers and neonates, so planned home birth is not common in our country.

4. Please clarify this sentence (on line 57 - 58): " Duration and antimicrobial therapy were recorded."

→ Thanks for your comments. We had added the clarification: We recorded the duration of antimicrobial therapy in the first 72 hours of neonatal life for early-onset infections.

(Materials and Methods: Study variables, Page 5, line 60-62)

5. Please define what the local antibiotic policy is, in reference to the statement on line 141 - 142: In accordance with the common practices of the facility, 152 (96.2%) OHD neonates were administered antibiotics".

→ Thanks for your kind remarks. It is my mistake of imprecise grammar. I had revised as the following: In OHD neonates, 152 (96.2%) neonates were administered antibiotics because of signs or symptoms of infection after birth, contaminated places of birth or suboptimal cord cutting.

(Results: Etiology in OHD neonates with infection, Page 12, line 145-146)

6. This sentence on line 163 ". Khupakonke et al. also demonstrated LBW to be a predicting factor of OHD [11]." feels out of place, and should probably be kept in the introduction.

→ Thanks for your suggestions. I had shifted this sentence to the part of introduction. (Introduction: Page 3, line 30-31)

7. The rest of the paper does not mention the prognosis of the patients, so the sentence on line 167 "The prognostic outcomes of OHD neonates require further research. " does not need to be included.

→ Thanks for your comments. I had deleted this sentence.

Reviewer #2: Abstract:

Page 2 line 14, the sentence “the OHD group was comprised of more teenage mothers than adult mothers” technically is not right. The OHD group comprised of more teenage mothers compared to the in-hospital deliveries category.

→ Thank you. I had revised as your suggestions. (Abstract: Page 2, line 14-15)

Study variables:

Does Neonatal age here refer to Gestational age?

→ Yes. I had corrected neonatal age to gestational age.

(Materials and Methods: Study variables, Page 5, line 58)

“Cerebrospinal fluid (CSF) and gastric juice (GJ) cultures were collected when patients exhibited signs or symptoms of sepsis, including fever, respiratory distress with desaturation, seizure, apnea, tachycardia or bradycardia” but there is no mention of CSF in the results.

→ Thanks for your comments. Twelve OHD neonates were received spinal tapping, and all CSF cultures were negative findings. I had added in the part of results.

(Results: Etiology in OHD neonates with infection, Page 11, line 138-139)

Outcome measures:

Page 6 line 72: “…indicating that pathogens are related to OHD.” Granted, infections associated with OHDs are more likely to be Early Onset infections but sentence should be rephrased since it is ambiguous and gives an impression of causality.

→ Thanks for your kind remarks. We had made the revisions.

We limited the study to pathogens proven within 72 hours after birth since neonatal infection occurring in the first 72 hours of life is typically caused by organisms transmitted vertically from the mother before or during delivery, indicating that the pathogens are related to early-onset infections.

(Materials and Methods: Outcome measures, Page 6, line 73-76)

Results:

Characteristics of OHD neonates - Hospital stay would be better expressed as a median

→ Thanks for your comments. We changed the mean hospital stay to the median hospital stay which was 7 days.

(Results: Characteristics of OHD neonates, Page 7, line 96)

Table 2 – Some of the percentages are not correct both under the infection & non infection columns.

What denominators were used for the Prematurity calculations?

→ Since the characteristics of poor prenatal care among the OHD mothers, 33 neonates with unknown gestational age (GA) were deducted from denominators. Three neonates in the infection group and 30 neonates in the non-infection group had unknown GA. In the infection group (N=8), 5 neonates with obtainable GA, 4 (4/5, 80%) were preterm. In the non-infection group (N=150), 120 neonates with obtainable GA, 25 (25/120, 21%) were preterm.

→ We had added the variable of unknown GA in Table 2 and illustrations in line 120-121 to avoid misleading.

(Results: Risk of infection in OHD neonates, Page 9, line 120-121)

The sub-optimal cord practices percentages for both the infection and non-infection columns are incorrect, should be 25% & 18% respectively.

→ Thirty neonates with missing information of cord practices were deducted from denominators. Three neonates and 27 neonates had unknown methods of cord practices in the infection group and non-infection group, respectively. In the infection group (N=8), 2 (2/5, 40%) neonates had suboptimal cord practices. In the non-infection group (N=150), 27 (27/123, 22%) neonates received suboptimal cord practices.

Hospital stay would be better expressed as a median

→ We had shifted to the median hospital stay in text. (Results: Characteristics of OHD neonates, Page 7, line 96)

Etiology of OHD in neonates with infection:

The text on the various pathogens isolated from the cultures should be rewritten as it contains a fair amount of redundancy. Since there was only one blood isolate with the remainder as GJs, it can be made to reflect that as opposed to the numerous GJ mentions.

Thanks for your suggestions. I had rewritten this paragraph.

(Results: Etiology in OHD neonates with infection, Page 11, line 134-139)

Page 12 line 145 – percentage value of neonates with sub-optimal cord separation is supposed to be 18.4% based on a denominator of 158, as opposed to the 22.7% that is reported

→ Since 30 neonates with missing information of cord practices had deducted from denominators, percentage value of neonates with sub-optimal cord separation was 22.7% (29/128).

General comments:

Percentage values for Prematurity seems to be inconsistent throughout the study, sometimes it is 23.2% (Page 2 line 8, page 8 table 1 etc.) and at other times 18.4% (Page 15 Table 4). It would seem different denominators are used interchangeably? When is the 158 used and when is the 125 used?

→ 33 neonates with unknown GA were deducted from denominators. In the OHD group, 29 neonates were preterm, so the percentage value for prematurity was 23.2% (29/125).

→ Thanks for your kind remarks. It is my mistake of wrong taping of percentage of prematurity in Page 15 Table 4. I had revised the percentage values for prematurity to 23.2% in Table 4. (Discussion: Page 15, Table 4)

Accidental, Unexpected and Unplanned seems to be used interchangeably to qualify OHDs. Can the authors stick to one? Perhaps “accidental” would be most appropriate since that is what is used in the title of the study.

→ Thanks for your suggestions. We had rewritten the manuscript with consistency of“accidental”.

Typographical / Grammatical errors

Page 2 line 6 /7 “This study also investigated risk factors…” should read “This study also investigated both maternal and neonatal risk factors…”

→ Thanks. We had made the revision. (Abstract: Page 2, line 7)

Page 2 line 13 should read “Forty-nine (31%) OHD mothers lacked antenatal care…”

→ We had corrected this error. (Abstract: Page 2, line 13-14)

Page 2 line 14 / 15 should read “Neonatal infection was more prevalent among…”

→ We had revised as your suggestions. (Abstract: Page 2, line 15-16)

Page 16 line 187 should read “The neonatal gastrointestinal tract is considered sterile, but diverse microbiota flora is present soon after birth”

→ We had made the revision. (Discussion: Page 16, line 191-192)

Page 16 line 188, “colonization” typo error

→ Thanks for your kind remarks. We had corrected this error. (Discussion: Page 16, line 192)

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Jan 2022

Risk of infection in neonates born in accidental out-of-hospital deliveries.

PONE-D-21-20144R1

Dear Dr. Chang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Kazumichi Fujioka

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Abstract

Line 5: Could it be specified where the urban setting is? For example, urban setting in Taiwan?

Statistical analyses

Line 81: Since length of hospital stay has now been expressed as a median, the statistical analyses should be modified to reflect that.

Typographical errors

Line 16: Neonatal infection was more prevalent among OHDs than for in hospital deliveries

Line 25: OHD should be made plural

Line 93: The GA ranged from 27 to 41 weeks with a mean of …. (The word “age” should be deleted)

Line 105: … and 10 (6.3%) claimed to be unaware of their pregnancy. The word “claimed” here seems inappropriate, gives the impression, the authors do not believe the mothers. Merriam-Webster defines the word claim as “to assert in the face of possible contradiction”. Is that the case here?

Line 130: should read “inside toilet bowls” instead of ‘in toilet bowls’

Line 132: should read “other places” instead of ‘in other places’

Line 138: Twelve OHD neonates had a spinal tap done and all CSF cultures were sterile.

Line 164: …conceal the adverse “effects” of the place where labour occurred, instead of conceal the adverse “factors” of the place where labour occurred

Reviewer #3: Review comments on Manuscript Number: ONE-D-21-20144R1. Entitled "Risk of infection in neonates born in accidental out-of-hospital deliveries."

Overall, the idea of research is very interesting, organized and well written reasonable. The authors have done great effort to accomplish this work. They fulfilled all reviewers' comments and made necessary changes throughput the manuscript.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Dr Naana Ayiwa Wireko Brobby

Reviewer #3: No

2 Feb 2022

PONE-D-21-20144R1

Risk of infection in neonates born in accidental out-of-hospital deliveries

Dear Dr. Chang:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Kazumichi Fujioka

Academic Editor

PLOS ONE