Impact of SARS-CoV-2 on pregnancy and neonatal outcomes: An open prospective study of pregnant women in Brazil

Gomez, Ursula Trovato; Francisco, Rossana Pulcineli Vieira; Baptista, Fernanda Spadotto; Gibelli, Maria Augusta B.C.; Ibidi, Silvia Maria; Carvalho, Werther Brunow de; Paganoti, Cristiane de Freitas; Sabino, Ester Cerdeira; Silva, Lea Campos de Oliveira da; Jaenisch, Thomas; Mayaud, Philippe; Brizot, Maria de Lourdes; ,

doi:10.1016/j.clinsp.2022.100073

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Original articles • Clinics 77 • 2022 • https://doi.org/10.1016/j.clinsp.2022.100073 copy

Impact of SARS-CoV-2 on pregnancy and neonatal outcomes: An open prospective study of pregnant women in Brazil

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objectives:

To determine the incidence and risk of adverse obstetric and neonatal outcomes according to SARS-CoV-2 infection severity in pregnant women.

Method:

Open prospective study of pregnant women tested for SARS-CoV-2 by serological and molecular assays during pregnancy or delivery in two hospitals in Sao Paulo, Brazil from April 12, 2020, to February 28, 2021. Five groups were considered for analysis: C0, negative COVID-19 results and no COVID-19 symptoms; C1, positive COVID-19 results, and no symptoms; C2, positive COVID-19 results with mild symptoms; C3, positive COVID-19 results with moderate symptoms; and C4, positive COVID-19 results with severe symptoms. The association between obstetric and neonatal outcomes and COVID-19 severity was determined using multivariate analysis.

Results:

734 eligible pregnant women were enrolled as follows: C0 (n = 357), C1 (n = 127), C2 (n = 174), C3 (n = 37), and C4 (n = 39). The following pregnancy and neonatal outcomes were associated with severe COVID-19: oligohydramnios (adjusted Odds Ratio [aOR] = 6.18; 95% CI 1.87‒20.39), fetal distress (aOR = 4.01; 95% Confidence Interval [CI] 1.84‒8.75), preterm birth (aOR = 5.51; 95% CI 1.47‒20.61), longer hospital stay (aOR = 1.66; 95% CI 1.36‒2.02), and admission to the neonatal intensive care unit (aOR = 19.36; 95% CI, 5.86‒63.99). All maternal (n = 6, 15.4%, p < 0.001) and neonatal (n = 5, 12.5%, p < 0.001) deaths and most fetal deaths (n = 4, 9.8%, p < 0.001) occurred in C4 group. Moderate COVID-19 was associated with oligohydramnios (aOR = 6.23; 95% CI 1.93‒20.13) and preterm birth (aOR = 3.60; 95% CI 1.45‒9.27). Mild COVID-19 was associated with oligohydramnios (aOR=3.77; 95% CI 1.56‒9.07).

Conclusion:

Adverse pregnancy and neonatal outcomes were associated with maternal symptomatic COVID-19 status, and risk increased with disease severity.

HIGHLIGHTS

COVID-19 increases the rates of adverse pregnancy and neonatal outcomes.
Serious cases are associated with oligohydramnios, fetal distress, prematurity, neonatal ICU admission, maternal and neonatal deaths.
The maternal clinical status dictates obstetric and neonatal outcomes.

Characteristics	COVID-19 Positive, n = 377	COVID-19 Negative, n = 357	p-value
Characteristics	n (%) or median (IQR)		p-value
Maternal age (years)	28 (24‒33)	29 (24‒35)	0.3^a a Mann-Whitney Non-Parametric Test.
BMI (kg/m²)	31 (28‒35), n = 370	30.48 (26.9‒35.02), n = 351	0.09^a a Mann-Whitney Non-Parametric Test.
Years of schooling	12 (10‒12), n = 291	12 (10‒12), n = 356	0.21^a a Mann-Whitney Non-Parametric Test.
Smoking during pregnancy	32/374 (9.3)	33/356 (9.3)	0.73^b b Chi-Square Test.
Obstetric history
Nulliparous	140 (37.0)	145/356 (40.7)	0.30^b b Chi-Square Test.
Multiple pregnancy	15 (4.0)	7 (2.0)	0.11^b b Chi-Square Test.
Comorbidities
Diabetes mellitus	18 (4.8)	5 (1.4)	0.009^b b Chi-Square Test.
Chronic hypertension	36 (9.5)	21 (5.9)	0.06^b b Chi-Square Test.
Cardiac disease	16 (4.2)	9 (2.5)	0.20^b b Chi-Square Test.
Lung disease	40 (10.6)	24 (6.7)	0.06^b b Chi-Square Test.
Rheumatic disease	7 (1.9)	5 (1.4)	0.63^b b Chi-Square Test.
Thromboembolic disease	3 (0.8)	5 (1.4)	0.49^c c Fisheŕs Exact Test.
Gestational age at COVID-19 Symptoms (weeks)	30 (22‒34), n = 187	NA	NA

Characteristics	C0, n = 357	C1, n = 127	C2, n = 174	C3, n = 37	C4, n = 39	p-value
Characteristics	n (%) or median (IQR)					p-value
Demographics
Maternal age (years)	29 (24‒35)	28 (23‒32)	27 (23.75‒33.25)	31 (26.5‒34)	30 (26‒36)	0.044^a a Kruskal-Wallis Non-Parametric Test.
BMI (kg/m²)	30 (27‒35), n = 351	32 (28‒35), n = 122	30 (27‒34)	33 (29‒38), n = 36	33 (29.75‒35.75), n = 38	0.012^a a Kruskal-Wallis Non-Parametric Test.
Years of schooling	12 (10‒12), n = 356	12 (10‒12), n = 125	12 (10‒12), n = 128	12 (10‒12), n = 20	12 (10‒12), n = 18	0.26^a a Kruskal-Wallis Non-Parametric Test.
Smoking during pregnancy	33/356 (9.3)	14 (11.0)	14/171 (8.2)	2 (5.4)	2 (5.1)	0.81^c c Fishers Exact Test.
Obstetrical history
Nulliparous	145/356 (40.7)	52 (40.9)	76 (43.6)	6 (16.2)	6 (15.4)	< 0.001^b b Chi-square Test.
Multiple pregnancy	7 (2.0)	6 (4.7)	6 (3.4)	1 (2.7)	2 (5.1)	0.32^c c Fishers Exact Test.
Comorbidities
Diabetes mellitus	5 (1.4)	3 (2.4)	10 (5.7)	3 (8.1)	2 (5.1)	0.013^c c Fishers Exact Test.
Chronic Hypertension	21 (5.9)	8 (6.3)	10 (5.7)	10 (27.0)	8 (20.5)	< 0.001^c c Fishers Exact Test.
Cardiac disease	9 (2.5)	4 (3.1)	7 (4.0)	2 (5.4)	3 (7.7)	0.33^c c Fishers Exact Test.
Lung disease	24 (6.7)	12 (9.4)	18 (10.3)	7 (18.9)	3 (7.7)	0.13^c c Fishers Exact Test.
Rheumatic disease	5 (1,4)	0 (0)	7 (4.0)	0 (0)	0 (0)	0.10^c c Fishers Exact Test.
Thromboembolic disease	5 (1.4)	1 (0.8)	1 (0.6)	1 (2.7)	0 (0)	0.66^c c Fishers Exact Test.
Gestational age at COVID-19 symptoms (weeks)	NA	NA	30 (22‒36), n = 118	30 (27‒34), n = 31	30.5 (23‒33), n = 36	0.95^a a Kruskal-Wallis Non-Parametric Test.

	C1, n = 127	C2, n = 174	C3, n = 37	C4, n = 39
	OR (95%CI)	OR (95%CI)	OR (95%CI)	OR (95%CI)
BMI, (kg/m²)^a a Adjusted for confounding factors: diabetes mellitus, chronic hypertension, and BMI.
Crude OR	1.03 (0.99‒1.06)	0.99 (0.96‒1.02)	1.06 (1.01‒1.12)	1.07 (1.02‒1.13)
Adjusted	1.03 (0.99‒1.06)	0.99 (0.96‒1.02)	1.03 (0.97‒1.09)	1.05 (1.00‒1.11)
Nulliparous
Crude OR	1.01 (0.67‒1.52)	1.12 (0.78‒1.61)	0.28 (0.12‒0.69)	0.27 (0.11‒0.65)
Adjusted	0.89 (0.57‒1.38)	1.05 (0.71‒1.56)	0.29 (0.11‒0.76)	0.28 (0.11‒0.72)
Diabetes mellitus^a a Adjusted for confounding factors: diabetes mellitus, chronic hypertension, and BMI.
Crude OR	1.70 (0.40‒7.23)	4.27 (1.44‒12.68)	6.21 (1.42‒27.13)	3.81 (0.71‒20.31)
Adjusted	1.69 (0.40‒7.18)	4.27 (1.43‒12.71)	6.23 (1.37‒28.34)	3.58 (0.66‒19.57)
Chronic Hypertension^a a Adjusted for confounding factors: diabetes mellitus, chronic hypertension, and BMI.
Crude OR	1.08 (0.46‒2.49)	0.97 (0.45‒2.11)	5.93 (2.54‒13.85)	4.13 (1.69‒10.9)
Adjusted	0.96 (0.40‒2.28)	1.02 (0.46‒2.26)	5.21 (2.09‒13.0)	2.65 (0.99‒7.13)
Gestational age at COVID‒19 symptoms (weeks)	NA	Reference	1.03 (0.98‒1.08)	1.01 (0.97‒1.06)

Outcomes	C0, n = 357	C1, n = 127		C2, n = 174		C3, n = 37		C4, n = 39		p‒value
	Reference	n (%), M (IQR)	Adjusted OR (95% CI)	n (%), M (IQR)	Adjusted OR (95% CI)	n (%), M (IQR)	Adjusted OR (95% CI)	N (%), M (IQR)	Adjusted OR (95%CI)
Preeclampsia	56/343 (16.3)	14/125 (11.2)	NA	24 (13.8)	NA	5/36 (13.9)	NA	5 (12.8)	NA	0.37^ linear-by-linear association.
Gestational Diabetes^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	107/343 (31.2)	31/125 (24.8)	0.75 (0.46‒1.23)	35/173 (20.2)	0.59 (0.37‒0.93)	5/36 (13.9)	0.40 (0.15‒1.08)	3 (7.7)	0.75 (0.46‒1.23)	<0.001^ linear-by-linear association.
Miscarriage	25 (7.0)	7 (5.5)	NA	0	NA	0	NA	0	NA	<0.001^* * Fisheŕs exact test.
Fetal distress#,^b b Adjusted for confounding factors: fetal distress, oligohydramnios, and fetal death.	34/343 (9.9)	14 (11.0)	1.15 (0.59‒2.21)	23/179 (12.8)	1.31 (0.74‒2.31)	4/38 (10.5)	1.04 (0.35‒3.12)	12 (30.7)	4.01 (1.84‒8.75)	0.012^* * Fisheŕs exact test.
PPROM	12/336 (3.6)	9/120 (7.5)	NA	16/173 (9.2)	NA	1/36 (2.8)	NA	3/38 (7.8)	NA	0.063^* * Fisheŕs exact test.
Oligohydramnios^# # The denominator refers to the number of fetuses. ,^b b Adjusted for confounding factors: fetal distress, oligohydramnios, and fetal death.	8/365 (2.7)	4/133 (3.3)	1.37 (0.40‒4.63)	15/181 (8.3)	3.77 (1.56‒9.07)	5/38 (13.2)	6.23 (1.93‒20.13)	5/41 (12.2)	6.18 (1.87‒20.39)	<0.001^* * Fisheŕs exact test.
Fetal death^# # The denominator refers to the number of fetuses. ,^b b Adjusted for confounding factors: fetal distress, oligohydramnios, and fetal death.	2/340 (0.6)	1/126 (0.8)	NA	2/180 (1.1)	0.99 (0.1‒11.01)	0/38	NA	4/41 (9.8)	4.42 (0.36‒54.80)	0.006^* * Fisheŕs exact test.
GAD, weeks^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	39 (38‒40)	39 (38‒40)	0.97 (0.86‒1.09)	39 (37‒40)	0.91 (0.82‒0.99)	39 (36.5‒40)	0.84 (0.73‒0.97)	34 (31‒39)	0.75 (0.64‒0.90)	<0.001^* * Kruskal-Wallis non-parametric test.
PD < 37 weeks^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	23/331 (6.9)	10/118 (8.5)	1.18 (0.54‒2.60)	30/172 (17.4)	1.80 (0.95‒3.44)	9 (24.3)	3.60 (1.45‒9.27)	23/35 (65.7)	5.51 (1.47‒20.61)	<0.001^ linear-by-linear association.
PD < 34 weeks^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	7/331 (2.1)	3/118 (2.5)	1.04 (0.26‒4.19)	11/172 (6.4)	1.54 (0.51‒4.63)	3 (8.1)	2.38 (0.54‒10.57)	20/39 (51.3)	9.06 (1.95‒42.21)	<0.001^* * Fisheŕs exact test.
PD < 32 weeks^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	2/331 (0.6)	3/118 (2.5)	3.94 (0.64‒24.1)	5/172 (2.9)	2.41 (0.39‒14.9)	2 (5.4)	5.67 (0.70‒45.8)	13/39 (33.3)	7.64 (0.72‒81.53)	<0.001^* * Fisheŕs exact test.
PD < 28 weeks^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	0/331	1/118 (0.8)	NA	1/172 (0.6)	NA	0	NA	6/39 (15.4)	NA	<0.001^* * Fisheŕs exact test.
Spontaneous PD	4/23 (17.4)	3/10 (30.0)	NA	8/30 (26.7)	NA	5/9 (55.6)	NA	2/23 (8.7)	NA	0.063^* * Fisheŕs exact test.
Iatrogenic PD	19/23 (82.6)	7/10 (70.0)	NA	22/30 (73.3)	NA	4/9 (44.4)	NA	21/23 (91.3)	NA	0.063^* * Fisheŕs exact test.
Cesarean section^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	181/332 (54.5)	77/120 (64.2)	1.43 (0.91‒2.24)	113/173 (65.3)	1.37 (0.91‒2.05)	27/37 (73.0)	2.08 (0.89‒4.84)	30/39 (76.9)	2.40 (0.48‒11.96)	<0.001^ linear-by-linear association.
Intra or postpartum aton	y 32/357 (9.0)	8/127 (6.3)	NA	17 (9.7)	NA	2/37 (5.4)	NA	7/39 (17.9)	NA	0.27^* * Fisheŕs exact test.
Delivery HD, days^a a Adjusted for confounding factors: gestational diabetes, preterm birth, cesarean section, and days from delivery to discharge.	2.0 (2‒3), n = 338	3.0 (2‒3), n = 117	1.06 (0.87‒1.29)	3.0 (2‒3), n = 157	1.14 (0.97‒1.34)	3.0 (2‒4), n = 34	1.22 (0.99‒1.50)	11.5 (5.25‒19.75) n = 28	1.66 (1.36‒2.02)	<0.001^* * Kruskal-Wallis non-parametric test.
Maternal death	0/357	0/125	NA	0/172	NA	0/37	NA	6/39 (15.4)	NA	<0.001^* * Fisheŕs exact test.

Outcomes	C0, n = 365	C1, n = 133		C2, n = 181		C3, n = 38		C4, n = 41		p‒value
	Reference	n (%), M (IQR)	Adjusted OR (95% CI)	n (%), M (IQR)	Adjusted OR (95% CI)	n (%), M (IQR)	Adjusted OR (95% CI)	n (%), M (IQR)	Adjusted OR (95% CI)
Birth weight, (g)	3260 (2835-3615), n = 340	3155 (2788‒3555), n = 126	NA	3160 (2707‒3447), n =178	NA	3129 (2795-3574), n = 38	NA	2117.5 (1481.25-3167.5), n = 40	NA	<0.001^* * Kruskal-Wallis Non-Parametric Test.
Birth weight < 10th percentile^# # Denominator refers to the number of neonates.	30/338 (8.9)	12/124 (9.7)	NA	15/177 (8.5)	NA	3/38 (7.9)	NA	0/37	NA	0.37^* * Fisheŕs Exact Test.
Birth weight < 3rd percentile^# # Denominator refers to the number of neonates.	14/338 (4.1)	2/124 (1.6)	NA	2/177 (1.1)	NA	0/38	NA	0/37	NA	0.22^* * Fisheŕs Exact Test.
Apgar score at 5th minute < 7^# # Denominator refers to the number of neonates.	5/329 (1.5)	4/118 (3.4)	NA	0/166	NA	1/35 (2.9)	NA	12/34 (35.3)	NA	<0.001^* * Fisheŕs Exact Test.
Supplemental oxygen^# # Denominator refers to the number of neonates. ,^a a Adjusted for confounding factors: Apgar score at 5th min <7, supplemental oxygen, mechanical ventilation, NICU admission, and length of hospital stay.	36/317 (11.4)	19/119 (16.0)	1.38 (0.64‒2.99)	39/171 (22.8)	1.05 (0.51‒2.15)	6/38 (15,8)	0.54 (0.12‒2.38)	24/36 (66.7)	2.76 (0.93‒8.17)	<0.001^ Linear-by-linear association.
Mechanical ventilation^# # Denominator refers to the number of neonates. ,^a a Adjusted for confounding factors: Apgar score at 5th min <7, supplemental oxygen, mechanical ventilation, NICU admission, and length of hospital stay.	2/328 (0.6)	2/123 (1.6)	NA	3/172 (1.7)	NA	3/38 (7.9)	NA	13/36 (36.1)	NA	<0.001^* * Fisheŕs Exact Test.
NICU admission^# # Denominator refers to the number of neonates. ,^a a Adjusted for confounding factors: Apgar score at 5th min <7, supplemental oxygen, mechanical ventilation, NICU admission, and length of hospital stay.	24/338 (7.1)	13/125 (10.4)	1.24 (0.35‒4.39)	39/177 (22.0)	3.68 (1.43‒9.48)	7/38 (18.4)	5.21 (1.15‒23.67)	23/36 (63.9)	19.36 (5.86‒63.99)	<0.001^ Linear-by-linear association.
Length of hospital stay^# # Denominator refers to the number of neonates. ,^a a Adjusted for confounding factors: Apgar score at 5th min <7, supplemental oxygen, mechanical ventilation, NICU admission, and length of hospital stay.	3 (2‒3), n = 326	3 (2‒3), n = 119	0.99 (0.94-1.05)	3 (2‒5), n = 172	1.01 (0.98‒1.04)	3 (2‒5), n = 37	1.01 (0.95-1.06)	15 (4‒34), n = 35	1.02 (0.98‒1.05)	<0.001^* * Kruskal-Wallis Non-Parametric Test.
Neonatal death^# # Denominator refers to the number of neonates.	0/338	0/125	NA	0/177	NA	0/38	NA	5/40 (12.5)	NA	<0.001^* * Fisheŕs Exact Test.

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[1] * Corresponding author. E-mail address: ursula.gomez@hc.fm.usp.br (U.T. Gomez).