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Author Affiliations: Department of Pediatrics, Columbia University Irving
Medical Center, New York, New York.
Corresponding Author: Eva W. Cheung, MD, Divisions of Cardiology and Critical
Care, Department of Pediatrics, Columbia University Irving Medical Center,3959
Broadway,CHN 2 North, New York, NY 10032 (ec2335@cumc.columbia.edu).
Accepted for Publication: May 27, 2020.
Published Online: June 8, 2020.doi:10.1001/jama.2020.10374
Author Contributions: Drs Cheung and Zachariah had full access to all of the
data in the study and take responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Cheung and Zachariah contributed equally to
the authorship of this article.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Cheung, Zachariah, Gorelik,
Boneparth, Orange, Milner.
Drafting of the manuscript: Cheung, Zachariah, Gorelik, Boneparth, Milner.
Critical revision of the manuscript for important intellectual content:All authors.
Statistical analysis: Cheung, Zachariah.
Administrative, technical, or material support: Zachariah, Gorelik, Orange.
Supervision: Kernie, Orange, Milner.
Conflict of Interest Disclosures: Dr Orange reported receiving personal fees
from ADMA Biologics, CSL Bhering, Gigagen, Grifols, and Takeda. No other
disclosures were reported.
Additional Contributions: Candace Johnson, MD, Kara Gross-Margolis, MD,
Irene Lytrivi, MD, AngelaChan, MD, and Brian Jonat, MD, MPH (Department of
Pediatrics, Columbia University Irving Medical Center), contributed to data
collection and analysis and editing assistance for this letter. Eldad A. Hod, MD
(Department of Pathology and Cell Biology, Columbia University Irving Medical
Center), contributed to data collection and writing of the manuscript. None of
these individuals were compensated for their contributions.
1. Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2)infection in children and adolescents: a systematic
review. JAMAPediatr. Published online April 22, 2020. doi:10.1001/
jamapediatrics.2020.1467
2. Tagarro A, Epalza C, Santos M, et al. Screening and severity of coronavirus
disease 2019 (COVID-19) in children in Madrid, Spain.JAMA Pediatr. Published
online April 8, 2020. doi:10.1001/jamapediatrics.2020.1346
3. Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P.
Hyperinflammatory shock in children during COVID-19 pandemic. Lancet.2020;
395(10237):1607-1608.doi:10.1016/S0140-6736(20)31094-1
4. McCrindle BW, Rowley AH, Newburger JW, et al; American Heart Association
Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council
on Cardiovascular Disease in the Young;Council on Cardiovascular and Stroke
Nursing; Council on Cardiovascular Surgery and Anesthesia; and Council on
Epidemiology and Prevention. Diagnosis, treatment, and long-term
management of Kawasaki disease: a scientific statement for health
professionals from the American Heart Association. Circulation. 2017;135(17):
e927-e999.doi:10.1161/CIR.0000000000000484
5. Li Y,Zheng Q, Zou L, et al. Kawasaki disease shock syndrome: clinical
characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early
recognition. Pediatr Rheumatol Online J. 2019;17(1):1. doi:10.1186/s12969-018-
0303-4
6. Chen G, Wu D, Guo W,et al. Clinical and immunological features of severe
and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-2629.
doi:10.1172/JCI137244
Association Between Mode of Delivery Among
Pregnant Women With COVID-19 and Maternal
and Neonatal Outcomes in Spain
Data from China found severe complications in 8% of pregnant
women with coronavirus disease 2019 (COVID-19).
1
However,
the high rate of cesarean deliveries (>90%) in Chinese reports
is concerning,
2
and whether
mode of delivery is associ-
ated with maternal complica-
tions or neonatal transmission is unknown.
3
We assessed births
to women with COVID-19 by mode of delivery.
Methods |Women with singletonpregnanc ies and a positive re-
verse transcriptase–polymerase chain reaction (RT-PCR) test
result for severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) between March 12 and April 6, 2020, and who
delivered within the next 14 days at 96 level 2 or level 3 ma-
ternity hospitals throughout Spain were included.
The study was approved by the national ethics commit-
tee. Oral informed consent was obtained.
Pregnant women were tested if they presentedw ith symp-
toms compatible with COVID-19 or a history of potential ex-
posure; additionally, universal screening was started in some
hospitals in April. Newborns had a nasopharyngeal swab ob-
tained for RT-PCR within 6 hours of life.
Mothers were stratified by symptom severity at admis-
sion as asymptomatic, mild, or severe (need for advanced oxy-
gen support: high-flow nasal cannula, noninvasive ventila-
tion, or mechanical ventilation).
Maternal outcomes were defined as severe if mothers re-
quired advanced oxygen support or admission to the inten-
sive care unit (ICU) or had signs of sepsis with hypoperfusion/
organ dysfunction. Clinical deterioration was defined by an
increased need for oxygen supplementation after delivery.
Neonatal outcomes considered were neonatal ICU (NICU)
admission and rates of SARS-CoV-2 perinatal transmission.
Multivariable logistic regression was performed assess-
ing the association between mode of delivery and maternal and
neonatal outcomes among patients with mild symptoms, ad-
justing for maternal age, body mass index, comorbidities, need
for oxygen supplementationat admission, abnormal chest x-ray
findings at admission, nulliparity, smoking, and prematurity.
Stata version 14 (StataCorp) was used. A 2-tailed P< .05 de-
fined statistical significance.
Results |Of 82 pregnant patients included, 4 presentedw ithse-
vere COVID-19 symptoms, including 1 with concomitant pre-
eclampsia; all 4 underwent cesarean delivery and required ICU
admission.
Seventy-eight patientspresented with no or mild COVID-19
symptoms, including 11 patients requiring oxygen supplemen-
tation. Forty-one (53%) delivered vaginally and 37 (47%) by ce-
sarean delivery, 29 for obstetrical indications and 8 for
COVID-19 symptoms without other obstetrical indications.
Women with cesarean deliveries were more likely to be mul-
tiparous, be obese, require oxygen at admission, and have ab-
normal chest x-ray findings than those delivering vaginally
(Table 1). No patients with a vaginal delivery developed se-
vere adverse outcomes, while 5 (13.5%) with cesarean deliv-
ery required ICU admission. Two patients (4.9%) with a vagi-
nal delivery had clinical deterioration after birth vs 8 (21.6%)
with cesarean delivery. After adjustment for potential con-
founding factors, cesarean birth was significantly associated
with clinical deterioration (adjusted odds ratio, 13.4; 95% CI,
1.5-121.9; P=.02)(Table 2).
Eight newborns (19.5%) delivered vaginally and 11 (29.7%)
born by cesarean delivery were admitted to the NICU. After ad-
justment for confounding factors, cesarean birth was not sig-
nificantly associated with an increased risk of NICU admis-
sion (adjusted odds ratio, 1.2; 95% CI, 0.3-4.5; P= .76).
Related article page 304
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Three (4.2%) of 72 newborns tested within 6 hours after
birth had a positive SARS-CoV-2 RT-PCR result. Repeat test-
ing at 48 hours was negative.None developed COVID-19 symp-
toms within 10 days.
Two other newborns, both cesarean deliveries at term, de-
veloped COVID-19 symptoms within 10 days. Though initial
testing at birth was negative, repeattesting was positive. Both
newborns were in contact with their parents immediately af-
ter birth. Symptoms resolved within 48 hours.
Discussion |In this cohort of pregnant women in Spain,
severe adverse maternal outcomes occurred in 11% (9/82),
4 of whom presented with severe and 5 with mild COVID-19
symptoms.
Table 1. Maternal Characteristics, Clinical Presentation, and Obstetrical Management
Characteristics
Asymptomatic/mild COVID-19 symptoms Severe COVID-19
symptoms and cesarean
delivery (n = 4)
Vaginal delivery
(n = 41)
Cesarean delivery
(n = 37)
Maternal characteristics
Age
Median (range), y 35 (19-43) 33 (19-48) 36 (22-47)
>35, No. (%) 21 (51.2) 18 (48.7) 2 (50.0)
Parity, No. (%)
Nulliparous 16 (39.0) 9 (24.3) 1 (25.0)
Multiparous >3 3 (7.3) 5 (13.5) 0
Comorbidities, No. (%)
Any
a
14 (34.1) 11 (30.6) 1 (25.0)
Gestational diabetes 1 (2.4) 0 0
Preeclampsia 1 (2.4) 2 (5.6) 1 (25.0)
Asthma 3 (7.3) 3 (8.3) 0
Smoking, No. (%) 3 (7.3) 3 (8.3) 0
BMI
Median (range) 23 (17-35) 26 (19-38) 23 (22-30)
>30, No. (%) 3 (8.8) 15 (36.6) 1 (25.0)
COVID-19 history and prepartum clinical presentation
Signs and symptoms at presentation, No. (%)
Asymptomatic 13 (31.7) 9 (25.0) NA
Oxygen supplementation at admission 4 (9.8) 7 (18.9) 4 (100.0)
b
Diagnostic tests, No. (%)
Abnormal chest x-ray 8 (19.5) 12 (32.4) 3 (75.0)
Abnormal ALT/AST 5 (12.2) 0 0
Lymphopenia (<1.0 × 10
9
/L), No. (%) 4 (9.8) 2 (5.6) 1 (25.0)
Delivery management
Time from onset of symptoms to delivery,
median (range), d
2 (0-14) 1 (0-10) 4 (1-6)
Gestational age at delivery
Median (range) 39 wk 1 d (27 wk
3 d–41 wk 3 d)
38 wk 3 d (25 wk
0 d–41 wk 4 d)
29 wk 6 d (28 wk
0 d–34 wk 0 d)
Preterm birth, No. (%)
34 wk to <37 wk 4 (9.8) 10 (27.0) 1 (25.0)
Iatrogenic preterm birth 1 (25)
c
4 (40.0)
c
1 (100.0)
d
<34 wk 3 (7.3) 4 (10.8) 3 (75.0)
Iatrogenic preterm birth 0 3 (75.0)
e
3 (100.0)
d
Premature rupture of membranes, No. (%) 9 (22.0) 9 (24.3) 0
Preterm premature rupture of membranes,
No. (%)
3 (7.3) 4 (10.8) 0
Obstetrical management, No. (%)
Prelabor cesarean delivery NA 13 (35.1) 4 (100.0)
Induction of labor 8 (19.5) 8 (21.6) 0
Spontaneous onset of labor 33 (80.5) 16 (43.2) 0
In-labor cesarean delivery NA 24 (64.9) 0
Instrumental delivery 12 (29.3) NA NA
Anesthesia, No. (%)
Locoregional analgesia 32 (78.0) 32 (86.5) 2 (50.0)
General anesthesia NA 5 (13.5) 2 (50.0)
Abbreviations: ALT, alanine
aminotransferase; AST, aspartate
aminotransferase; BMI, body mass
index (calculated as weight in
kilograms divided by height in meters
squared); COVID-19, coronavirus
disease 2019; NA, not applicable.
a
In the vaginal delivery group, other
maternal complications included
hypothyroidism (n=3), epilepsy
(n=1), Subek muscular dystrophy
(n=1), myopathy (n=1),
heterozygous factor V mutation
(n=1), psychiatric disorders (n=3),
unspecified autoimmune disease
(n=1), hyperprolactinemia (n=1),
gastritis (n=1), vitiligo (n=1), and
chronic hepatitis C infection (n=1). In
the cesarean delivery group, other
maternal complications included
hypothyroidism (n=2),
homocysteine mutation (n=1),
anti-Kell alloimmunization (n=1),
concomitant pyelonephritis (n=1),
myomatosis (n=1), mutation of
methylenetetrahydrofolate
reductase (MTHFR) (n=1), ischemic
cardiomyopathy (n=1), and
depressive disorders (n=1).
b
These patients required advanced
oxygen support (eg, high-flow nasal
cannula or continuous positive
airway pressure).
c
Indications for iatrogenic preterm
birth at ⱖ34 weeks’ gestation
included maternal COVID-19
symptoms without other obstetrical
reasons in 4 (1 vaginal delivery after
induction of labor and 3 prelabor
cesarean deliveries) and
preeclampsia in 1 (cesarean delivery
after failure of induction).
d
All iatrogenic preterm births were
performed in relation to COVID-19 in
the mother without other
obstetrical indications.
e
Indication for iatrogenic preterm
birth at <34 weeks’ gestation
included 2 patients with COVID-19
symptoms without any other
obstetrical indications for delivery
(prelabor cesarean deliveries) and 1
patient with abnormal findings on
fetal cardiac monitoring and
suspected fetal asphyxia leading to
prelabor cesarean delivery.
Letters
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Among patients with mild symptoms at presentation, all
patients with a vaginal birth had excellent outcomes. In con-
trast, 13.5% of women undergoing cesarean delivery had se-
vere maternal outcomes and 21.6% had clinical deteriora-
tion. Women undergoing cesarean delivery may have been at
higher risk of adverse outcomes, but after adjusting for con-
founding factors, cesarean birth remained independently as-
sociated with an increased risk of clinical deterioration. The
physiological stress induced by surgery is known to increase
postpartum maternal complications.
4,5
Limitations include a lack of sufficient information on new-
borns to determine vertical transmission. The lack of associa-
tion between cesarean delivery and risk of NICU admission may
have been related to the lack of statistical power. Also, the 95%
CIs around the odds ratios for cesarean birth and clinical de-
terioration were wide and the estimates fragile.
Oscar Martínez-Perez, MD, PhD
Manon Vouga, MD, PhD
Sara Cruz Melguizo, MD, PhD
Laura Forcen Acebal, MD
Alice Panchaud, PhD
Mar Muñoz-Chápuli, MD
David Baud, MD, PhD
Author Affiliations: Obstetrics and Gynaecology Department, Puerta de Hierro
University Hospital, Madrid, Spain (Martínez-Perez, Cruz Melguizo);
Department Woman-Mother-Child, Lausanne University Hospital, Lausanne,
Switzerland (Vouga, Baud); Obstetrics and Gynaecology Department, 12
Octubre University Hospital, Madrid, Spain (Forcen Acebal); Service of
Pharmacy, Lausanne UniversityHospital, Lausanne, Switzerland (Panchaud);
Obstetrics and Gynaecology Department, Gregorio Marañon University
Hospital, Madrid, Spain (Muñoz-Chápuli).
Corresponding Author: David Baud, MD, PhD,Materno-Fetal and Obstetrics
Research Unit, Department of Obstetrics and Gynecology, Centre Hospitalier
Universitaire Vaudois, 1011 Lausanne, Switzerland (david.baud@chuv.ch).
Accepted for Publication: May 26, 2020.
Published Online: June 8, 2020.doi:10.1001/jama.2020.10125
Correction: This article was corrected on July 21, 2020, for data and statistical
significance changes.
Author Contributions: Drs Martínez-Perez and Vouga had full access to all the
data in the study and take responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Martínez-Perez and Vouga contributed
equally.
Concept and design: Martínez-Perez, Vouga, Cruz Melguizo,Panchaud.
Acquisition, analysis, or interpretation of data: Martínez-Perez, Vouga, Forcen
Acebal, Panchaud, Muñoz-Chápuli, Baud.
Drafting of the manuscript: Vouga, Cruz Melguizo,Forcen Acebal, Panchaud,
Baud.
Critical revision of the manuscript for important intellectual content:
Martínez-Perez, Vouga, Panchaud, Muñoz-Chápuli, Baud.
Statistical analysis: Martínez-Perez, Vouga, Panchaud, Muñoz-Chápuli,Baud.
Obtained funding: Martínez-Perez.
Administrative, technical, or material support: Martínez-Perez, Cruz Melguizo,
Muñoz-Chápuli, Baud.
Supervision: Martínez-Perez, Cruz Melguizo, Panchaud, Muñoz-Chápuli, Baud.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the Emergencia Obstetrica España Group
for participation in the study.We also thank Tirso Perez Medina, MD, PhD,
Obstetrics and Gynaecology Department, Puerta de Hierro University Hospital,
Table 2. Maternal and Neonatal Outcomes
a
Outcomes
Asymptomatic/mild COVID-19 symptoms
Severe COVID-19
symptoms and
cesarean delivery,
No. (%) (n = 4)
Vaginal
delivery,
No. (%)
(n = 41)
Cesarean
delivery,
No. (%)
(n = 37)
Odds ratio
(95% CI)
Adjusted odds
ratio (95% CI)
Maternal outcomes
Severe adverse outcomes 0 5 (13.5) NA NA 4 (100.0)
Severe pneumonia 0 3 (8.1) 2 (50.0)
Sepsis 0 0 1 (25.0)
Postnatal intensive care unit
admission
0 5 (13.5) 4 (100.0)
Length of stay, median
(range), d
NA 10 (2-18) 4 (1-13)
Mechanical ventilation 0 4 (10.8) 2 (50.0)
Clinical deterioration 2 (4.9) 8 (21.6) 5.4 (1.0-54.6) 13.4 (1.5-121.9) 2 (50.0)
Neonatal outcomes
Neonatal intensive care unit
admission
8 (19.5) 11 (29.7) 1.7 (0.5-5.8) 1.2 (0.3-4.5) 3 (75.0)
SARS-CoV-2 perinatal
transmission rates
Total with tests at birth 41 (100) 30 (81.1) 1 (25.0)
Suspected
b
2 (4.9) 1 (3.3) 0.7 (0.0-13.6) NA 0
Confirmed
c
0 2 (5.4) NA NA 0
Secondary outcomes
Apgar score <5 at 5 min 0 3 (8.1) 0
Arterial umbilical pH <7.10 3 (7.3) 3 (8.1) 0
Birth weight, median
(range), g
3060
(940-4750)
3210
(910-4510)
1450
(1110-1580)
<10th percentile 1 (2.4) 0 0
Breastfeeding 23 (56.1) 19 (51.4) 0
Abbreviations: COVID-19, coronavirus
disease 2019; NA, not applicable;
RT-PCR, reverse transcriptase–
polymerase chain reaction;
SARS-CoV-2,severe acute respiratory
syndrome coronavirus 2.
a
Odds ratios and 95% CIs are based
on multivariate logistic regression
analysis assessing risk of severe
maternal outcomes, clinical
deterioration, neonatal intensive
care unit admission, and perinatal
transmission associated with mode
of delivery among patients with
mild symptoms. Estimates were
adjusted for confounding factors
and heterogeneity between the 2
groups (maternal age >35 years,
body mass index >30,maternal
comorbidities, need for oxygen
supplementation at admission,
abnormal chest x-ray findings at
admission, nulliparity,smoking, and
prematurity).
b
Positive RT-PCR result at birth. Two
were preterm births in which testing
was performed after initial
resuscitation; the other newborn
had contact with his mother
immediately after birth.
c
Repeat positive RT-PCR result and
compatible symptoms.
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Autonoma University,Madrid, Spain, for his contribution to the design of the
study and data collection. He received no compensation for his participation.
1. Chen L, Li Q, Zheng D, et al. Clinical characteristics of pregnant women with
Covid-19 in Wuhan, China. N Engl J Med. Published online April 17, 2020. doi:10.
1056/NEJMc2009226
2. Della Gatta AN, Rizzo R, Pilu G, Simonazzi G. Coronavirus disease 2019 during
pregnancy: a systematic review of reported cases. Am J Obstet Gynecol. Published
online April 18, 2020. doi:10.1016/j.ajog.2020.04.013
3. Kimberlin DW, Stagno S. Can SARS-CoV-2 infection be acquired in utero?
more definitive evidence is needed. JAMA. Published online March 26, 2020.
doi:10.1001/jama.2020.4868
4. Middleton PG, Gade EJ, Aguilera C, et al. ERS/TSANZ TaskForce statement
on the management of reproduction and pregnancy in women with airways
diseases. Eur Respir J. 2020;55(2):1901208. doi:10.1183/13993003.01208-2019
5. Sandall J, TribeRM, Avery L, et al. Short-term and long-term effects of
caesarean section on the health of women and children. Lancet. 2018;392
(10155):1349-1357. doi:10.1016/S0140-6736(18)31930-5
Use of Risk Evaluation and Mitigation Strategies
by the US Food and Drug Administration, 2008-2019
The US Food and Drug Administration(FDA) Amendments Act
of 2007 gave the FDA authority to require a Risk Evaluation
and Mitigation Strategy (REMS) to “ensure the benefits of the
medication outweigh its risks.”
1
At its inception, the REMS pro-
gram could require (1) that pharmacies distribute medication
guides; (2) that manufacturers design communication plans
about specific safety issues; and/or (3) that manufacturers pro-
vide “elements to assure safe use” (ETASUs) such as pre-
scriber training, prescriber/dispenser certifications, or pa-
tient registries.
1
Despite several important changes tothe REMS
program, including the 2011 decision to release (or remove) all
medications that required a medication guide alone from the
program,
1
few comprehensive characterizations of the pro-
gram have been performed.
Methods |In April 2019, we used FDA.gov to extract informa-
tion on each medication (ie, unique chemical entity or com-
bination, approved via various pathways)included in the REMS
program, including those that may no longer be subject to a
REMS and thus have been released from the program.
1
We used
descriptive statistics to examine the number and classes of
medications included in the REMS program (based on Lexi-
con Plus/Cerner Multum), the strategies deployed,and the FDA-
designated risks that the program had intended to mitigate.
Results |A total of 222 medications had a REMS designation
since the program’s inception. Of these, all 83 drugs that had
a medication guide alone were released from the program,
most between 2011 and 2012. The Figure depicts trends in
the remaining 139 medications that required a communica-
tion plan or ETASU. The number of medications with an
active REMS designation that required these strategies
increased from 11 in 2008 to 60 in 2010. Since 2010, the
number of medications that required a communication plan
declined and those that required ETASUs increased. As of
2019, 80 medications that required these strategies remained
in the program; 45 medications were added and 59 were
released between 2010 and 2019.
Of the 57 medications that required a communication plan
alone, 87.7% were released since the program’sinception, com-
pared with 11.0% of the 82 medications that required ETASUs
(alone [n = 63] or in combination [n = 19]) (Table). As of 2019,
51.3% of medications that required ETASUs used prescriber
(38.8%) or dispenser (37.5%) certification or patient registries
(28.8%); 13.6% of medications released had any of these re-
quirements. Released medications also differed from those
with an active REMS designation in terms of drug classes and
risks the program was designed to mitigate. For example, 38.8%
of medications with an active REMS designation were opioid
analgesics associated with addiction and overdose, whereas
half of released medications consisted of biologics (31.7%) and
antidiabetics (16.7%), for which a REMS was primarily in-
tended to reduce the risk of life-threatening infections and car-
diovascular events, respectively.
Discussion |The REMS program has evolved, with the less re-
strictive strategies either released from the program (medica-
tion guides) or used less often (communication plans) and the
Figure. Medications That Required a REMS With a Communication Plan and/orElements to Assure Safe Use, 2008-2019
140
80
120
100
60
40
20
0
Medications, No.
Year
Trends in REMS medications
A
20192008 2009 2010 2011 2012 2013 2014 2015 2016 20182017
Total
Active
Active, elements to assure safe use
Active, communication plan alone
40
20
35
30
25
15
10
5
0
Medications, No.
Year
Medications added to or released from the REMS program
B
2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
Released
Added
REMS indicates Risk Evaluation and Mitigation Strategy.
Letters
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