Maternal and neonatal outcomes associated with illness severity of maternal COVID-19

Abstract

BACKGROUND:

Several reports demonstrated that perinatal SARS-CoV-2 has significant impact on maternal and neonatal health outcomes. However, the relationship between severity of maternal illness with outcomes remains less clear.

METHODS:

This is a single-center retrospective cohort study of mother/infant dyads with positive maternal test for SARS-CoV-2 between 14 days prior and 3 days after delivery from 3/30/2020 to 12/28/2021.

RESULTS:

Among 538 mothers, those with moderate/severe/critical illness were more likely to undergo induction, receive oxygen, mechanical ventilation or ECMO. Mortality was significantly higher among the mothers with severe illness than asymptomatic and those with mild illness (6% vs 0% and 0%, respectively, P < 0.05). Neonates born to mothers with moderate/severe/critical illness were more likely to be preterm with lower birth weight, and to be admitted to the NICU (P < 0.05) but not to be small for gestational age. Mild maternal illness was only associated with NICU admission for isolation precaution and decreased rate of breastfeeding.

CONCLUSIONS:

Maternal illness severity was significantly associated with prematurity and several adverse maternal and neonatal outcomes.

Keywords

COVID-19 illness severity neonates

1 Introduction

The coronavirus disease 2019 (COVID-19) pandemic, resulting from SARS-CoV-2 infection necessitated that clinicians quickly acquire data and develop guidelines based on best available evidence. Therefore, serial changes occurred in the management of perinatal-neonatal COVID-19 [1 –4]. Reports from multiple centers including The American Academy of Pediatrics (AAP) National Registry for the Surveillance and Epidemiology of Perinatal COVID-19 (NPC-19) provided valuable data on maternal and neonatal characteristics related to perinatal SARS-CoV-2 infection. These reports demonstrated that perinatal SARS-CoV-2 infection has a significant impact on maternal and neonatal health outcomes [5 –7]. Despite the fact that our understanding is expanding, there are still unanswered questions about how infection severity impacts these vulnerable populations as the relationship between severity of maternal illness and outcomes remains less clear.

The rate of SARS-CoV-2 positivity among pregnant women shows significant variability due to changes in testing policy in given hospital systems. Mother-to-infant transmission is uncommon, and congenital infection of SARS-CoV-2 appears to be a rare event [8 –10]. The placenta is capable of being infected, as syncytiotrophoblasts, villous and extravillous trophoblasts could express angiotensin converting enzyme 2 (ACE2) receptors. ACE2 RNA expression is extremely low at 6–14 weeks gestation but is highly expressed at 24 weeks gestation [11, 12].

There is considerably extensive data available on association of SARS-CoV-2 infection during pregnancy with maternal and neonatal outcomes, [6 , 13–17]. However, only limited number of studies have investigated the association between maternal COVID-19 illness severity and risk of developing adverse maternal and neonatal outcomes [18 –21]. Furthermore, only one of these studies [18] focused on the delivery hospitalization whereas other studies included all pregnant women with SARS-CoV-2 infection. Maternal COVID-19 severity can be categorized using the NIH COVID-19 illness severity classification, the categories of which include asymptomatic, mild, moderate, severe, or critical [22]. The primary aim of this retrospective study was to evaluate whether severity of maternal SARS-CoV-2 infection at the time of the delivery was associated with maternal and neonatal outcomes. We hypothesized that severity of maternal COVID-19 at delivery would have a significant impact on neonatal outcomes including neonatal intensive care (NICU) admission, preterm birth, low birthweight, and neonatal SARS-CoV-2 infection.

2 Methods

2.1 Study design and population

This is a retrospective cohort study of 538 mother/infant dyads with positive maternal SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) detection between 14 days prior and 3 days after delivery from 3/30/2020 to 12/28/2021 at Parkland Health. Time frame of 14 days prior and 3 days after to delivery was selected to analyze delivery-associated transmission of SARS-CoV-2 infection [5, 18]. This study was approved by the Institutional Review Board at the University of Texas Southwestern Medical Center and by Parkland Health, and a waiver of informed consent was granted because the research involved minimal risk to the patients. Parkland Health, a high-risk academic acute care hospital with a high-volume prenatal clinical system and public hospital in Dallas, Texas, provides care for approximately 12,000 births annually. It serves predominantly Hispanic and Black population, who are primarily insured by Medicaid.

Testing for SARS-CoV-2 was performed on the basis of symptoms (fever, cough, dyspnea, myalgia, loss of smell or taste, vomiting, diarrhea and sore throat) or specific risk criteria (contact with a confirmed or suspected case, incarceration or group home setting, homelessness, outside hospital transfers) before May 14, 2020. A universal SARS-CoV-2 testing protocol was implemented in the labor and delivery unit on May 14, 2020. Diagnosis was by RT-PCR detection of SARS-CoV-2 nucleic acid using nasal or nasopharyngeal specimens. Both asymptomatic and symptomatic women were managed on the labor and delivery unit if the respiratory status was stable and noncritical. Symptomatic postpartum and nonlaboring antepartum women with respiratory illness were managed in a dedicated COVID unit. COVID-19 vaccines were offered beginning December 2020.

Following delivery, neonatal nasal RT-PCR was performed at 24 and 48 hours for infants born within 4 weeks of maternal diagnosis or when clinically indicated until late 2021, when protocols were reduced to testing at a single time point. Neonatal infection was defined based on at least one positive result of RT-PCR testing at 24 or 48 hours of life. Guidelines for infection prevention practices and maternal newborn separation changed over time in accordance with accumulating evidence and changes in AAP recommendations [2, 3]. All neonates born to mothers with positive SARS-CoV-2 RT-PCR within 14 days prior to delivery were isolated in the NICU in the beginning of the pandemic regardless of their presentation from March 30 to June 30, 2020. After June 2020 newborns delivered to mothers with positive SARS-CoV-2 PCR were allowed to room-in with their asymptomatic mothers if they were >35 wks gestational age (GA). When rooming-in, mothers were encouraged to use face mask and hand hygiene.

2.2 Data collection

Data were collected from the electronic health records of the mothers and neonates. Among patients admitted to the hospital, primary indication for hospitalization was recorded for this study as either obstetric or COVID-19 related. A subset of de-identified data was submitted to the American Academy of Pediatrics (AAP) Section on Neonatal Perinatal Medicine’s National Registry for Surveillance and Epidemiology of Perinatal COVID-19 Infection (NPC-19 Registry) [5].

Maternal variables included maternal age, gravidity, race/ethnicity, SARS-CoV-2 RT-PCR testing results, mothers identified as positive by routine testing on admission, illness severity, number of days from first symptom to delivery, days from admission to delivery, days from test to delivery, maternal condition and symptoms before and at delivery, hospital admission for COVID-19, duration of rupture of membranes, spontaneous versus induced vaginal delivery versus cesarean delivery, indication for delivery, steroids prior to delivery, maternal need for respiratory support (including oxygen, intubation, extracorporeal membrane oxygenation (ECMO), medications, length of hospital stay and mortality. Neonatal variables included NICU admission, GA less than 35 weeks GA or birth weight less than 2100 g (NICU admission criteria), GA, birth weight, sex, small for gestational age (SGA), Apgar score less than 7 at 5 minutes, status at birth, resuscitation in the delivery room, separation, isolation, location, length of stay, mortality, neonatal symptoms during hospitalization, need for respiratory support, additional diagnoses, congenital anomalies, medications, therapeutic hypothermia, ECMO, SARS-CoV-2 PCR testing results at 24 and 48 h, any breastmilk during hospital stay, breastfeeding at discharge.

2.3. Statistical analysis

Descriptive statistics included frequencies, proportions, median, and interquartile ranges (IQR) as appropriate. Continuous data was compared using a Wilcoxon rank-sum test after accessing the normality of the data distribution using Kolmogorov-Smirnov normality test. Categorical data was compared using a Chi-square or Fisher-exact test dependent on the cell count. Pair-wise comparisons were performed with a Bonferroni correction. All statistical test used 0.05 as the significance level. SPSS version 25 (IBM) was used to perform the statisticalanalysis.

Post-hoc power analysis was conducted for prematurity as the primary outcome. A sample size of 543 achieved 100% power to detect an effect size (W) of 0.2365 using a 2 degrees of freedom Chi-Square test with a significance level (alpha) of 0.05. In the primary analysis we compared maternal and neonatal outcomes in three groups classified by maternal symptomatology: asymptomatic, mild, and moderate/severe/critical. A sensitivity analysis was conducted to compare maternal and neonatal outcomes in four groups classified by maternal symptomatology: asymptomatic, mild, moderate and severe/critical.

3 Results

3.1 Maternal characteristics and outcomes

Among 20,134 pregnant women who delivered 20,393 infants in our hospital from 3/30/2020 to 12/28/2021, 538 (2.7%) had a positive SARS-CoV-2 test on their birth admission, up to 14 days prior, or 3 days after birth. There were 543 neonates born to positive PCR mothers, including 5 sets of multiples.

Of these 538 mothers who tested positive for SARS-CoV-2, 345 (64%) were asymptomatic, 161 (30%) had mild symptoms and 32 (6%) had moderate, severe or critical illness (referred to as “severe” in this manuscript). Notably, there were 391 of 538 (72%) mothers recorded as asymptomatic upon admission and of those, 49 (12%) developed mild symptoms and 4 (1%) progressed to severe illness during the delivery hospitalization.

Most asymptomatic mothers (91%) were tested for universal testing policy compared to 45% and 44% respectively for mothers with mild and severe illness (P < 0.01). Mothers who had severe illness were more likely to be symptomatic at home prior to delivery with lower respiratory symptoms and fever (P < 0.01), were more likely to be hospitalized for COVID-19 related reasons (P < 0.05). Of those who developed severe illness; only 8/32 (25%) delivered via spontaneous vaginal delivery, 3/32 (9%) were augmented, 13/32 (41%) were induced, and 14/32 (44%) had cesarean section. The likelihood of induction for COVID-19 increased with maternal COVID-19 severity (P < 0.01). However, we did not identify a significant difference in frequency of cesarean-section delivery among the groups studied. The frequency of cesarean section delivery was 121/345 (36%) in asymptomatic mothers, 51/161 (32%) in mothers with mild illness, and 14/32 (44%) in mothers with severe COVID-19 (P = 0.4). The overall frequency of cesarean delivery in our institution was 1011/3035 (33%) in mothers who tested negative for SARS-CoV-2 infection in a study which was conducted in our hospital during the same time period [23]. Mothers with severe illness were more likely to receive antiviral treatment, oxygen, mechanical ventilation and ECMO (P < 0.01), and had longer hospital stay and higher mortality (P < 0.05). Also, mothers with severe illness were more likely to receive antenatal steroids prior to delivery (P < 0.01) (Table 1).

Table 1
Maternal characteristics and health outcomes for each category of illness severity for maternal COVID-19

Severity of Maternal COVID-19

Asymptomatic (N = 345) Mild(N = 161) Moderate/Severe/Critical (N = 32) P value^*

Maternal age, Median (IQR) years 28 (23, 33) 28 (23, 32) 30 (24, 36) 0.24

Gravida, Median (IQR) 3 (2, 4) 3 (2, 4) 3 (2, 4) 0.38

Race/Ethnicity, n (%)

Hispanic 286 (83) 133 (83) 27 (84) 0.74

Non-Hispanic Black 37 (11) 21 (13) 2 (6)

Non-Hispanic White 11 (3) 5 (3) 1 (3)

Asian 6 (2) 2 (1) 1 (3)

Other/unknown 5 (1) 0 (0) 1 (3)

Admission to delivery Median (IQR) (days) 0 (0,1) 0 (0,1) 1 (0,3) <0.01

Test to delivery Median (IQR) 1 (0,2) 2 (1,7) 3 (1,10) <0.01

Tested for universal screening policy 315 (91)^a 72 (45)^b 14 (44)^c <0.01

Labor, n (%)

Spontaneous 184 (53)^a 71 (44)^ab 8 (25)^b 0.01

Augmented 32 (9) 11 (7) 3 (9)

Induced 67 (19)^a 48 (30)^b 13 (41)^b

No labor 62 (18) 31 (19) 8 (25)

Route of delivery

Vaginal 224 (65) 110 (68) 18 (56) 0.40

C-section 121 (36) 51 (32) 14 (44)

Delivery for worsening COVID-19^** 0 (0)^a 5 (3)^b 15 (47)^c <0.01

Duration of ROM > 18 hours 18 (5) 11 (7) 0 (0) 0.29

Steroids prior to delivery 9 (3)^a 5 (3)^a 7 (22)^b <0.01

Maternal admit condition

Asymptomatic 338 (98)^a 49 (30)^b 4 (13)^c <0.01

Hospital admission for COVID-19 0 (0)^a 1(1)^a 16 (50)^b <0.01

IV fluids 0 (0)^a 1 (1)^a 10 (31)^b <0.01

Oxygen 0 (0)^a 0 (0)^a 16 (50)^b <0.01

CPAP 0 (0)^a 0 (0)^a 3 (9)^b <0.01

Intubated 0 (0)^a 0 (0)^a 4 (13)^b <0.01

ECMO 0 (0)^a 0 (0)^a 1 (3)^b <0.01

SARS-Cov-2 Treated 0 (0)^a 2 (1)^a 20 (63)^b <0.01

Chloroquine 0 (0)^a 0 (0)^a 1 (3)^b <0.01

Remdesevir 0 (0)^a 1 (1)^a 16 (50)^b <0.01

Ritonavir 0 (0) 1 (1) 0 (0) 0.31

Dexamethasone 0 (0)^a 2 (1)^a 19 (59)^b <0.01

Expired 0 (0)^a 0 (0)^a 2 (6)^b <0.01

Length of hospitalization (days) 4 (3,4)^a 4 (3,4)^a 7 (5,14)^b <0.01

	Severity of Maternal COVID-19
Maternal age, Median (IQR) years	28 (23, 33)	28 (23, 32)	30 (24, 36)	0.24
Gravida, Median (IQR)	3 (2, 4)	3 (2, 4)	3 (2, 4)	0.38
Race/Ethnicity, n (%)
Hispanic	286 (83)	133 (83)	27 (84)	0.74
Non-Hispanic Black	37 (11)	21 (13)	2 (6)
Non-Hispanic White	11 (3)	5 (3)	1 (3)
Asian	6 (2)	2 (1)	1 (3)
Other/unknown	5 (1)	0 (0)	1 (3)
Admission to delivery Median (IQR) (days)	0 (0,1)	0 (0,1)	1 (0,3)	<0.01
Test to delivery Median (IQR)	1 (0,2)	2 (1,7)	3 (1,10)	<0.01
Tested for universal screening policy	315 (91)^a	72 (45)^b	14 (44)^c	<0.01
Labor, n (%)
Spontaneous	184 (53)^a	71 (44)^ab	8 (25)^b	0.01
Augmented	32 (9)	11 (7)	3 (9)
Induced	67 (19)^a	48 (30)^b	13 (41)^b
No labor	62 (18)	31 (19)	8 (25)
Route of delivery
Vaginal	224 (65)	110 (68)	18 (56)	0.40
C-section	121 (36)	51 (32)	14 (44)
Delivery for worsening COVID-19^**	0 (0)^a	5 (3)^b	15 (47)^c	<0.01
Duration of ROM > 18 hours	18 (5)	11 (7)	0 (0)	0.29
Steroids prior to delivery	9 (3)^a	5 (3)^a	7 (22)^b	<0.01
Maternal admit condition
Asymptomatic	338 (98)^a	49 (30)^b	4 (13)^c	<0.01
Hospital admission for COVID-19	0 (0)^a	1(1)^a	16 (50)^b	<0.01
IV fluids	0 (0)^a	1 (1)^a	10 (31)^b	<0.01
Oxygen	0 (0)^a	0 (0)^a	16 (50)^b	<0.01
CPAP	0 (0)^a	0 (0)^a	3 (9)^b	<0.01
Intubated	0 (0)^a	0 (0)^a	4 (13)^b	<0.01
ECMO	0 (0)^a	0 (0)^a	1 (3)^b	<0.01
SARS-Cov-2 Treated	0 (0)^a	2 (1)^a	20 (63)^b	<0.01
Chloroquine	0 (0)^a	0 (0)^a	1 (3)^b	<0.01
Remdesevir	0 (0)^a	1 (1)^a	16 (50)^b	<0.01
Ritonavir	0 (0)	1 (1)	0 (0)	0.31
Dexamethasone	0 (0)^a	2 (1)^a	19 (59)^b	<0.01
Expired	0 (0)^a	0 (0)^a	2 (6)^b	<0.01
Length of hospitalization (days)	4 (3,4)^a	4 (3,4)^a	7 (5,14)^b	<0.01

^*n (%) compared with Chi-square or Fisher exact test; Median (IQR) compared with Wilcoxon Rank sum test. Different superscript letters in the same row denote significant pair-wise differences across columns at the.05 level with Bonferroni correction. ^**The frequency of induction for preeclampsia, failure to progress, abruption, chorioamnionitis or other reasons did not increase with severity of maternal COVID-19 infection. Abbreviations: ROM, rupture of membranes; CPAP, continuous positive airway pressure, ECMO, extracorporeal membrane oxygenation.

3.2 Neonatal characteristics and outcomes

Neonates who were born to mothers with severe illness were more likely to be preterm with lower birth weight and to be admitted to the NICU (P < 0.05) (Table 2). These neonates were more likely to require resuscitation in the delivery room. Among neonates born to mothers with severe illness, 31% received positive pressure ventilation (PPV) and 6% were intubated in the delivery room, compared with 6% PPV and 1% intubation in the neonates born to mothers with mild illness, and 7% PPV and 1% intubated in neonates born to asymptomatic mothers (P < 0.05). None of the neonates received chest compressions and/or epinephrine in the delivery room. There was no difference in SGA, sex and multiple gestation among the groups.

Table 2
Neonatal characteristics and health outcomes for each category of illness severity for maternal COVID-19

Severity of Maternal COVID-19

Asymptomatic (N = 349) Mild(N = 162) Moderate/Severe/Critical (N = 32) P value^*

GA < 37 weeks 38 (11)^a 16 (10)^a 14 (44) ^b <0.01

Gestational age, Median (IQR) (weeks) 39 (38, 40)^a 39 (38, 39)^a 37 (35, 39)^b <0.01

Birthweight, Median (IQR) (grams) 3250 (2930, 3610)^a 3258 (2965, 3620)^a 2800 (2368, 3303)^b <0.01

Small for GA 29 (8) 7 (4) 2 (6) 0.26

GA < 35 weeks or BW < 2100 g 15 (4)^a 6 (4)^a 7 (22)^b <0.01

Multiple gestation 4 (1) 1 (1) 0 (0) 0.72

Male 155 (44) 76 (47) 19 (59) 0.26

Apgar < 7 at 5 minutes 3 (1)^a 2 (1)^a 3 (10)^b <0.01

Resuscitation in Delivery Room

Oxygen 29 (8)^a 13 (8)^a 10 (31)^b <0.01

PPV 25 (7)^a 9 (6)^a 10 (31)^b <0.01

Intubation 1 (<1)^a 1 (1)^a,b 2 (6)^b <0.01

Newborn signs

None 309 (89)^a 146 (90)^a 20 (63)^b <0.01

Fever 3 (1) 3 (2) 1 (3) 0.42

Cough 0 (0) 0 (0) 0 (0) N/A

Gastrointestinal 3 (1) 0 (0) 0 (0) 0.43

Respiratory distress 32 (9)^a 10 (6)^a 11 (34)^b <0.01

NICU admission (%) 57 (16)^a 85 (53)^b 26 (81)^c <0.01

Separation at birth 51 (15)^a 74 (46)^b 24 (75)^c <0.01

Maximum respiratory support

None 311 (89)^a 150 (93)^a 21 (66)^b <0.01

Oxygen 16 (5) 5 (3) 1 (3)

CPAP 18 (5) 6 (4) 8 (25)

Intubation 4 (1) 1 (1) 2 (6)

Respiratory distress 0.01

TTN 18 (5)^a 2 (1)^a 4 (13)^b

RDS 10 (3) 3 (2) 3 (9)

PPHN 0 (0) 0 (0) 1 (3)

Hypoglycemia 3 (1) 5 (3) 2 (6) 0.04

RT-PCR test + (1 or 2) 15 (4) 8 (5) 2 (6) 0.86

Any breastmilk 301 (86)^a 117 (72)^b 17 (53)^b <0.01

Breastfeeding at discharge 270 (77)^a 91 (56)^b 9 (28)^c <0.01

Final disposition

Discharged Home 346 (99)^a 161 (99)^a 30 (94)^b <0.01

Transferred 3 (1) 1 (1) 1 (3)

Expired 0 (0) 0 (0) 1 (3)

Length of stay, Median (IQR) (days) 3 (3, 4)^a 3 (3, 4)^a 4 (3, 7)^b <0.01

	Severity of Maternal COVID-19
GA < 37 weeks	38 (11)^a	16 (10)^a	14 (44) ^b	<0.01
Gestational age, Median (IQR) (weeks)	39 (38, 40)^a	39 (38, 39)^a	37 (35, 39)^b	<0.01
Birthweight, Median (IQR) (grams)	3250 (2930, 3610)^a	3258 (2965, 3620)^a	2800 (2368, 3303)^b	<0.01
Small for GA	29 (8)	7 (4)	2 (6)	0.26
GA < 35 weeks or BW < 2100 g	15 (4)^a	6 (4)^a	7 (22)^b	<0.01
Multiple gestation	4 (1)	1 (1)	0 (0)	0.72
Male	155 (44)	76 (47)	19 (59)	0.26
Apgar < 7 at 5 minutes	3 (1)^a	2 (1)^a	3 (10)^b	<0.01
Resuscitation in Delivery Room
Oxygen	29 (8)^a	13 (8)^a	10 (31)^b	<0.01
PPV	25 (7)^a	9 (6)^a	10 (31)^b	<0.01
Intubation	1 (<1)^a	1 (1)^a,b	2 (6)^b	<0.01
Newborn signs
None	309 (89)^a	146 (90)^a	20 (63)^b	<0.01
Fever	3 (1)	3 (2)	1 (3)	0.42
Cough	0 (0)	0 (0)	0 (0)	N/A
Gastrointestinal	3 (1)	0 (0)	0 (0)	0.43
Respiratory distress	32 (9)^a	10 (6)^a	11 (34)^b	<0.01
NICU admission (%)	57 (16)^a	85 (53)^b	26 (81)^c	<0.01
Separation at birth	51 (15)^a	74 (46)^b	24 (75)^c	<0.01
Maximum respiratory support
None	311 (89)^a	150 (93)^a	21 (66)^b	<0.01
Oxygen	16 (5)	5 (3)	1 (3)
CPAP	18 (5)	6 (4)	8 (25)
Intubation	4 (1)	1 (1)	2 (6)
Respiratory distress	0.01
TTN	18 (5)^a	2 (1)^a	4 (13)^b
RDS	10 (3)	3 (2)	3 (9)
PPHN	0 (0)	0 (0)	1 (3)
Hypoglycemia	3 (1)	5 (3)	2 (6)	0.04
RT-PCR test + (1 or 2)	15 (4)	8 (5)	2 (6)	0.86
Any breastmilk	301 (86)^a	117 (72)^b	17 (53)^b	<0.01
Breastfeeding at discharge	270 (77)^a	91 (56)^b	9 (28)^c	<0.01
Final disposition
Discharged Home	346 (99)^a	161 (99)^a	30 (94)^b	<0.01
Transferred	3 (1)	1 (1)	1 (3)
Expired	0 (0)	0 (0)	1 (3)
Length of stay, Median (IQR) (days)	3 (3, 4)^a	3 (3, 4)^a	4 (3, 7)^b	<0.01

^*n (%) compared with Chi-square or Fisher exact test; Median (IQR) compared with Wilcoxon Rank sum test. Different superscript letters in the same row denote significant pair-wise differences across columns at the.05 level with Bonferroni correction. Abbreviations: GA, gestational age; PPV, positive pressure ventilation; NICU, neonatal intensive care unit; CPAP, continuous positive airway pressure; TTN, transient tachypnea of the neonate; RDS, respiratory distress syndrome; PPHN, persistent pulmonary hypertension of the neonate.

Neonates born to mothers with severe illness were more likely to be symptomatic with respiratory distress (34% vs 6% vs 9% for neonates born to severe vs mild vs asymptomatic mothers respectively). The frequency of neonatal hypoglycemia increased with maternal severity (P = 0.04). Other potential signs of COVID-19 (fever, cough, gastrointestinal symptoms, hypotonia, and encephalopathy) did not differ among the groups. Only 4 of the 41 neonates who developed respiratory distress tested positive for SARS-CoV-2, and respiratory distress was attributed to COVID-19 in only one of them. This was a preterm infant with congenital SARS-CoV-2 infection, described in a prior publication by our group [24]. There was only one death in our cohort and this infant was a 29 weeks GA who was born to a mother with severe COVID-19 as well as Klebsiella pneumonia. This baby tested negative for SARS-CoV-2 at 24 hours of life but died from pulmonary hemorrhage before testing at 48 hours.

Neonates born to mothers with severe COVID-19 had longer hospital stay, were less likely to receive breastmilk and less likely to be breastfeeding at discharge (P < 0.05). Neonates born to mothers with mild illness were similar to those asymptomatic ones for all the variables studied except for more frequent NICU admission (53% vs 16%) and less breastfeeding at discharge (56% vs 77%) (Table 2). Among 543 neonates born to mothers with COVID-19, 515/543 (95%) were tested for SARS-CoV-2 at 24 hours and 494/543 (91%) at 48 hours of life. Overall, 532/543 (98%) neonates were tested for SARS-CoV-2. The rate of SARS-CoV-2 transmission was low (4.6%) and did not differ by maternal illness severity (P = 0.86).

3.3 Sensitivity analysis

Sensitivity analysis showed that maternal age, NICU admission, GA, birth weight, and GA < 37 weeks were very similar in those born to mothers with moderate illness severity vs those born to mothers with severe or critical illness (Table 3). None of the maternal or neonatal variables were significantly different in these two groups; however, sample size was small with only 6 mothers with moderate and 26 with severe/critical illness.

Table 3
Sensitivity analyses between asymptomatic, mild, moderate, and severe maternal illness of COVID-19 for maternal and neonatal outcomes

Severity of Maternal COVID-19

Asymptomatic (N = 349) Mild(N = 162) Moderate (N = 6) Severe/Critical (N = 26) P value^*

NICU admission (%) 57 (16)^a 85 (53)^b 5 (83)^c 26 (81)^c <0.01

Gestational age Median (IQR) (weeks) 39 (38, 40)^a 39 (38, 39)^a 37 (35, 38)^b 37 (35, 39)^b <0.01

Birthweight Median (IQR) 3250 (2930, 3610)^a 3257 (2965, 3620)^a 2870 (2463, 3258)^b 2790 (2315, 3363)^b <0.01

GA<35 weeks or BW < 2100 15 (4)^a 6 (4)^a 1 (17)^a,b 6 (23)^b <0.01

GA<37 38 (11)^a 16 (10)^a 3 (50)^b 11 (42)^b <0.01

Respiratory distress 32 (9)^a 10 (6)^a 1 (17)^a,b 10 (39)^b <0.01

Maximum support

None 311 (89)^a 150 (93)^a 5 (83)^a,b 16 (62)^b <0.01

Oxygen 16 (5) 5 (3) 0 (0) 1 (4)

CPAP 18 (5) 6 (4) 1 (17) 7 (27)

Intubation 4 (1) 1 (1) 0 (0) 2 (8)

Maternal characteristics

Asymptomatic (N = 345) Mild(N = 161) Moderate (N = 6) Severe (N = 26) P value^*

Maternal Age Median (IQR) 28 (23, 33) 28 (23, 32) 34 (29, 37) 29 (23, 36) 0.23

Delivery for Worsening COVID-19 0 (0)^a 5 (3)^b 1 (17)^b,c 14 (54)^c <0.01

Hospital admission for COVID-19 0 (0)^a 1(1)^a 1 (17)^b 15 (58)^b <0.01

	Severity of Maternal COVID-19
NICU admission (%)	57 (16)^a	85 (53)^b	5 (83)^c	26 (81)^c	<0.01
Gestational age Median (IQR) (weeks)	39 (38, 40)^a	39 (38, 39)^a	37 (35, 38)^b	37 (35, 39)^b	<0.01
Birthweight Median (IQR)	3250 (2930, 3610)^a	3257 (2965, 3620)^a	2870 (2463, 3258)^b	2790 (2315, 3363)^b	<0.01
GA<35 weeks or BW < 2100	15 (4)^a	6 (4)^a	1 (17)^a,b	6 (23)^b	<0.01
GA<37	38 (11)^a	16 (10)^a	3 (50)^b	11 (42)^b	<0.01
Respiratory distress	32 (9)^a	10 (6)^a	1 (17)^a,b	10 (39)^b	<0.01
Maximum support
None	311 (89)^a	150 (93)^a	5 (83)^a,b	16 (62)^b	<0.01
Oxygen	16 (5)	5 (3)	0 (0)	1 (4)
CPAP	18 (5)	6 (4)	1 (17)	7 (27)
Intubation	4 (1)	1 (1)	0 (0)	2 (8)
Maternal characteristics
	Asymptomatic (N = 345)	Mild(N = 161)	Moderate (N = 6)	Severe (N = 26)	P value^*
Maternal Age Median (IQR)	28 (23, 33)	28 (23, 32)	34 (29, 37)	29 (23, 36)	0.23
Delivery for Worsening COVID-19	0 (0)^a	5 (3)^b	1 (17)^b,c	14 (54)^c	<0.01
Hospital admission for COVID-19	0 (0)^a	1(1)^a	1 (17)^b	15 (58)^b	<0.01

Different superscript letters in the same row denote significant pair-wise differences across columns at the.05 level with Bonferroni correction. Abbreviations: GA, gestational age; NICU, neonatal intensive care; CPAP, continuous positive airway pressure.

4 Discussion

Our study supports that illness severity of maternal COVID-19 is significantly associated with prematurity and multiple adverse maternal and neonatal outcomes. Severe maternal illness was associated with increased likelihood of hospitalization, induction of labor for worsening COVID-19, and preterm delivery. Pregnant women who had severe illness were mostly hospitalized due to worsening COVID-19 in the absence of labor. In contrast, pregnant women with asymptomatic or mild infection were admitted for obstetric indications and were detected by the universal testing policy. Neonates born to mothers with severe illness had increased risk for needing delivery room resuscitation, NICU admission, respiratory distress, and hypoglycemia, but not an increased risk of SARS-CoV-2 infection.

Association of maternal COVID-19 and preterm delivery has been well documented in several studies [5 , 26]. Heterogeneity among the studies makes it difficult to answer whether COVID-19 might be the direct cause of preterm delivery. However, higher rates of cesarean section in pregnant women with COVID-19 was also documented by several comparative and non-comparative reports and systemic reviews [8 , 27–31]. The frequency of spontaneous preterm labor and rupture of membranes in affected pregnant women was similar to those before the pandemic [8, 26] aligned with our study indicating this increase was not associated with spontaneous preterm labor; therefore, the increase in preterm birth that was observed was likely associated with iatrogenic preterm delivery due to induction of labor for worsening symptoms of COVID-19.

Neonates born to mothers with COVID-19 have a minimal risk for contracting SARS-CoV-2 virus [30 , 33]. Previous studies indicate that the rate of neonatal test positivity ranges between 2.2–12.1% likely due to difference in implementation of testing and variability of hospital practices since the beginning of the pandemic [14 , 35]. Interestingly, cohort studies from New York City documented no positivity of SARS-CoV-2 and no clinical signs of infection in neonates despite maintaining high rates of rooming in and breastfeeding practices regardless of maternal infection status [36 –38]. Our rate of SARS-CoV-2 transmission was low (4.6%) and did not differ by maternal illness severity, although our hospital policies regarding maternal-infant separation versus rooming in varied as the pandemic progressed. Nevertheless, our result is consistent with a systematic review that included 49 studies from UK which reported a rate of 4% transmission [35]. We previously reported a case of congenital SARS-CoV-2 infection in a preterm neonate and demonstrated placental histopathology revealing the SARS-CoV-2 infection by electron microscopy and immunohistochemistry [24]. None of the other infected neonates in our cohort developed symptoms due to SARS-CoV-2 infection. A recent multicenter national registry evaluating the maternal and newborn outcomes reported the risk factors associated with transmission of SARS-CoV-2 infection at the time of delivery among 7524 pregnant persons. The transmission rate was 2.2% among 84.3% tested newborns and the ones tested positive for SARS-CoV-2 were more likely to be premature and acquired the infection from their symptomatic mothers. There were no significant differences in delivery mode, mother-infant separation at birth, nor breastmilk feeding [5]. However, association of illness severity of COVID-19 with outcomes was not evaluated in this study.

The significance of adverse neonatal outcomes due maternal COVID-19 might vary with population characteristics, timing of pregnancy, SARS-CoV-2 variant and with isolation and breastfeeding practices [39]. A prospective study from Sweden demonstrated increased risk of NICU admission (11% vs 8.4%), increased risk of any neonatal respiratory disorder (2.8 % vs 2%, OR; 1.42 (95% CI: 1.7–1.9) and mechanical ventilation OR 2.04 (95% CI: 1.22–3.39) in neonates born to SARS-CoV-2 positive mothers [17]. A meta-analysis included 10 international studies pursued to further evaluate the significance of symptomatology among pregnant women with COVID-19 concluded that neonates born to symptomatic pregnant women had lower birth weight OR 1.85 (95% CI: 1.06–3.24) and greater requirement of NICU admission OR 1.96 95% CI: 1.59–2.43) [20]. On the contrary, a prospective observational study from two academic birth hospitals in Philadelphia concluded that outcomes were not significantly different between the neonates born to asymptomatic versus symptomatic mothers, but mothers were not further stratified by illness severity [18]. In our study, we evaluated the neonatal outcomes by the severity of the maternal COVID-19 at the time of the delivery and demonstrated that neonatal adverse outcomes were significantly associated with maternal illness severity of COVID-19. Adverse outcomes of neonates born to mothers with critical illness were related to preterm delivery, rather than consequences of neonatal infection. Additionally, being born to mothers with mild illness was not associated with increased risk of prematurity or prematurity related problems. Mild maternal illness was only associated with NICU admission for isolation precaution and decreased rate of breastfeeding.

Our study has several limitations. This is a retrospective cohort, and thus limited by what is documented in the medical record. We evaluated a cohort from a single center that included higher frequency of Hispanic women than previous reports, which comprised 82% of our study cohort. Although the data are consistent on racial and ethnic disparities in COVID-19 cases reported nationwide, women of Hispanic ethnicity account for the vast majority of our general admission cohort. Therefore, our results may not be generalizable in other settings. Another limitation is that this study did not include determination of SARS-CoV-2 variants, which has been shown to impact maternal disease severity and may also play a role in neonatal outcomes. We did not collect data on maternal medical comorbidities that may have confounded neonatal outcomes, such as diabetes, hypertension, or preeclampsia. Therefore, differences in neonatal outcomes may be due to other medical or obstetric conditions rather than to maternal COVID-19 disease severity.

The major strength of our study is that neonatal outcomes were compared by maternal illness severity as determined during the delivery hospitalization, thus providing valuable insights into understanding the role of maternal illness severity on both maternal and neonatal outcomes. Another strength was that our center was the largest referral center in Dallas where the highest number of dedicated beds were available and highest level of care was provided for COVID-19 patients. Lastly, our screening rate for SARS-CoV-2 infection was excellent. We screened 98% of our neonates born to mothers with COVID-19 in our study at least once at 24 and/or at 48 hours. This provides valuable information in understanding the prevalence of the virus and to identify any patterns of transmission.

5 Conclusions

In our cohort, neonates born to mothers with moderate/severe/critical illness have had adverse outcomes related to being born prematurely due to worsening maternal COVID-19 rather than having consequences of neonatal infection. Mild maternal illness was only associated with NICU admission for isolation precautions and decreased breastfeeding rates.

Footnotes

Acknowledgments

The authors would like to acknowledge Brooke W. Payton, NNP, Maria Craig, RN, BSN, Karina Frias-Esparza, NNP, Erin Trout, NNP for their contribution in data collection and the excellent clinical care and support provided by the Obstetric services and NICU staff at Parkland Health & Hospital System, Dallas, Texas. Authors also would like to acknowledge Rachel Leon, MD for her immense help reviewing the manuscript article.

Funding

None.

Conflict of interest

Authors have no conflict of interest to disclose.

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	Severity of Maternal COVID-19
	Asymptomatic (N = 349)	Mild(N = 162)	Moderate/Severe/Critical (N = 32)	P value^*
GA < 37 weeks	38 (11)^a	16 (10)^a	14 (44) ^b	<0.01
Gestational age, Median (IQR) (weeks)	39 (38, 40)^a	39 (38, 39)^a	37 (35, 39)^b	<0.01
Birthweight, Median (IQR) (grams)	3250 (2930, 3610)^a	3258 (2965, 3620)^a	2800 (2368, 3303)^b	<0.01
Small for GA	29 (8)	7 (4)	2 (6)	0.26
GA < 35 weeks or BW < 2100 g	15 (4)^a	6 (4)^a	7 (22)^b	<0.01
Multiple gestation	4 (1)	1 (1)	0 (0)	0.72
Male	155 (44)	76 (47)	19 (59)	0.26
Apgar < 7 at 5 minutes	3 (1)^a	2 (1)^a	3 (10)^b	<0.01
Resuscitation in Delivery Room
Oxygen	29 (8)^a	13 (8)^a	10 (31)^b	<0.01
PPV	25 (7)^a	9 (6)^a	10 (31)^b	<0.01
Intubation	1 (<1)^a	1 (1)^a,b	2 (6)^b	<0.01
Newborn signs
None	309 (89)^a	146 (90)^a	20 (63)^b	<0.01
Fever	3 (1)	3 (2)	1 (3)	0.42
Cough	0 (0)	0 (0)	0 (0)	N/A
Gastrointestinal	3 (1)	0 (0)	0 (0)	0.43
Respiratory distress	32 (9)^a	10 (6)^a	11 (34)^b	<0.01
NICU admission (%)	57 (16)^a	85 (53)^b	26 (81)^c	<0.01
Separation at birth	51 (15)^a	74 (46)^b	24 (75)^c	<0.01
Maximum respiratory support
None	311 (89)^a	150 (93)^a	21 (66)^b	<0.01
Oxygen	16 (5)	5 (3)	1 (3)
CPAP	18 (5)	6 (4)	8 (25)
Intubation	4 (1)	1 (1)	2 (6)
Respiratory distress	0.01
TTN	18 (5)^a	2 (1)^a	4 (13)^b
RDS	10 (3)	3 (2)	3 (9)
PPHN	0 (0)	0 (0)	1 (3)
Hypoglycemia	3 (1)	5 (3)	2 (6)	0.04
RT-PCR test + (1 or 2)	15 (4)	8 (5)	2 (6)	0.86
Any breastmilk	301 (86)^a	117 (72)^b	17 (53)^b	<0.01
Breastfeeding at discharge	270 (77)^a	91 (56)^b	9 (28)^c	<0.01
Final disposition
Discharged Home	346 (99)^a	161 (99)^a	30 (94)^b	<0.01
Transferred	3 (1)	1 (1)	1 (3)
Expired	0 (0)	0 (0)	1 (3)
Length of stay, Median (IQR) (days)	3 (3, 4)^a	3 (3, 4)^a	4 (3, 7)^b	<0.01