Research Letters
org
respiratory syndrome coronavirus 2 (SARS-CoV-2) test
result at any time during pregnancy were compared 1:2
with randomly selected controls who had a negative SARS-
CoV-2 test result and were matched for race and parity.
COVID-19 was diagnosed with nasopharyngeal reverse
transcription polymerase chain reaction or rapid antigen
testing. HDP was diagnosed using standard criteria. Cox
proportional hazards models with left truncation to
account for the varying gestational age at COVID-19
diagnosis and random effects (frailty) to account for the
matching design and small cluster sizes were used to
examine the association between COVID-19 and HDP.2
Because this was a sensitivity analysis, we also examined
early (before 32 weeks’ gestation) vs late COVID-19
infection and HDP development. The study was deemed
exempt from review by the institutional review board.
RESULTS: Of 1856 births, there were 83 women (4.5%) with
COVID-19 infection. There was no difference in baseline
characteristics between COVID-19 infected women and
controls (Table). Patients with COVID-19 infection had
almost a 2-fold risk of HDP (hazard ratio [HR], 1.93; 95%
confidence interval [CI], 1.13e3.31). However, COVID-19
infection was not associated with severity of HDP, and severity
of COVID-193 was not associated with HDP development.
Among patients with COVID-19 and HDP at delivery, the
median interval from COVID-19 diagnosis to delivery was 3.8
weeks (interquartile range, 0.29e11.5). In additional analysis,
early, but not late, COVID-19 infection was associated with
HDP development (HR for early COVID-19, 2.17 [95% CI,
1.11e4.24]; HR for late COVID-19, 1.68 [95% CI, 0.79e3.57]).
CONCLUSION: Early COVID-19 infections are associated
with HDP, even when accounting for differential exposure
and delivery times, suggesting that COVID-19 infection
may alter pregnancy physiology and increase the risk of
HDP development over time. Infection closer to term is not
associated with HDP, which likely reflects our high
proportion of asymptomatic infections found at the time of
delivery from a universal testing policy4 and insufficient
time to develop HDP in these cases. Furthermore, emerging
evidence suggests that COVID-19 modulates placental
angiotensin-converting enzyme 2 expression, which may be
related to HDP development.5 Our study is limited by
Intracervical balloon catheter for labor induction
after rupture of membranes: a systematic review
and meta-analysis
OBJECTIVE: Although unequivocal benefits to ripening
exist in the setting of intact membranes, ripening remains
controversial in the setting of prelabor rupture of membranes
624 American Journal of Obstetrics & Gynecology JUNE 2021
ajog.
sampling in a single institution with a high HDP incidence.
However, our results suggest that monitoring of patients
with antepartum COVID-19 infection should encompass
precautions for HDP development. -
ACKNOWLEDGMENTS
The authors acknowledge Lori Stevenson, MSN, for performing the data
collection.
Joshua I. Rosenbloom, MD, MPH
Division of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Washington University School of Medicine in St. Louis
660 South Euclid Ave.
St. Louis, MO 63110
Department of Obstetrics and Gynecology
Hadassah Medical Center and Faculty of Medicine
Hebrew University of Jerusalem
Jerusalem, Israel
rosenbloomj@wustl.edu
Nandini Raghuraman, MD, MS
Ebony B. Carter, MD, MPH
Jeannie C. Kelly, MD, MS
Division of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Washington University School of Medicine in St. Louis
St. Louis, MO
The authors report no conflict of interest.
REFERENCES
1. Adhikari EH, Moreno W, Zofkie AC, et al. Pregnancy outcomes among
women with and without severe acute respiratory syndrome coronavirus
2 infection. JAMA Network Open 2020;3:e2029256.
2. O’Quigley J, Stare J. Proportional hazards models with frailties and
random effects. Stat Med 2002;21:3219–33.
3. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med
2020;383:2451–60.
4. Kelly JC, Raghuraman N, Carter EB, Palanisamy A, Stout MJ. Pre-
procedural asymptomatic coronavirus disease 2019 cases in obstetrical
and surgical units. Am J Obstet Gynecol 2021;224:114–6.
5. Jing Y, Run-Qian L, Hao-Ran W, et al. Potential influence of COVID-
19/ACE2 on the female reproductive system. Mol Hum Reprod
2020;26:367–73.
ª 2021 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.
2021.03.001
(PROM). PROM complicates 8% of term pregnancies, which
translates to approximately 270,000 births in the United
States annually.1 We undertook a systematic review and
 ajog.org
TABLE 1
Characteristics of included studies
Amorosa et al,4 Greybush et al,6 Kehl et al,7 Kruit et al,8 Mackeen et al,9 Prager et al,10 Rust et al,11 Sheiker et al,12
Characteristic 2016a El Khouly,5 2017 2001 2011 2016a 2018a 2008a 2001 2009
Participants 127 women with 108 women, 205 women, 122 women, 188 women 201 women with 592 women, 81 women, 90 women,
PROM including 11 including 14% including 22 with PROM PROM including 89 including 10 including 17%
women with with PROM women with women with women with with PROM
PROM PROM PROM PROM
Intervention 1. Foley catheter 1. Foley catheter 1. Foley 1. Double- 1. Foley 1. Foley catheter 1. Foley catheter 1. Foley catheter 1. Foley catheter
arms for plus oxytocin (n¼5) catheter balloon catheter plus oxytocin (n¼28) plus 2. Oral
patients with (n¼62) 2. Foley catheter 2. Foley cath- catheter (n¼101) (n¼93) 2. Intravaginal misoprostol misoprostol
PROM 2. Oxytocin plus oxytocin eter plus plus oral 2. Oral 2. Oxytocin misoprostol 2. Intravaginal 3. Intravaginal
(n¼66) (n¼3) dinoprostone misopros- misopros- (n¼108) (n¼29) misoprostol misoprostol
3. Oxytocin 3. Intravaginal tol (n¼8) tol 3. Intravaginal
(n¼3) misoprostol 2. Oral (n¼101) dinoprostone
misopros- (n¼32)
tol (n¼14)
Primary IOL to delivery Success of IOL IOL to delivery Rate of failure Cesarean IOL to delivery IOL to delivery IOL to delivery Not specified
outcome interval, hours, interval, hours, of IOL delivery rate; interval, hours, interval, hours, interval, hours,
median (IQR) mean (SD) maternal and mean (SD) median (IQR) mean (SD)
neonatal
infections
Defined Cervical dilation Bishop score5 Bishop score5 Bishop Bishop Cervical dilation Bishop score6 Bishop score5 Bishop score5
unfavorable of <3 cm or <3 score<8 score<6 of <2 or 80%
cervix contractions in 10 effaced
mins when initial
JUNE 2021 American Journal of Obstetrics & Gynecology

exam was
deferred
Gestational age 34 >28 N/A 37 37 34 37 N/A 37e42
for inclusion,
wks
Overall risk of Low Low Low High High Low Low Low High
bias
IOL, induction of labor; IQR, interquartile range; N/A, not applicable; PROM, prelabor rupture of membranes; SD, standard deviation.
a
Studies that contributed data.

Research Letters
Mackeen. Balloon catheter use after membrane rupture. Am J Obstet Gynecol 2021.
625
Research Letters ajog.org

TABLE 2
Summary of outcomes for those treated with an intracervical balloon catheter vs pharmacologic agents
Risk ratio (95% confidence
Number of Exposure groups: n/n (%) interval)
studies Intracervical balloon Pharmacologic Observed pooled
Outcomes in the analysis catheter method estimate
All included studies
Intra-amniotic infection 4 21/271 (7.7) 15/334 (4.5) 1.84 (0.91e3.73)
Intra-amniotic infection (sensitivity 3 19/182 (10.4) 13/235 (5.5) 2.07 (0.85e5.03)
analysis)
Cesarean delivery 4 68/271 (25.1) 70/334 (21.0) 1.21 (0.90e1.64)
Indications for cesarean delivery
Nonreassuring fetal heart rate 4 16/68 (23.5) 22/70 (31.4) 0.81 (0.35e1.85)
Arrest of dilation or decent 4 47/68 (69.1) 44/70 (62.9) 1.06 (0.79e1.56)
Other 4 5/68 (7.4) 4/70 (5.7) 1.20 (0.38e3.80)
Postpartum hemorrhage 3 20/178 (11.2) 21/226 (9.3) 1.19 (0.66e2.15)
Endometritis 3 3/243 (1.2) 4/273 (1.5) 0.83 (0.19e1.64)
Suspected neonatal infection 4 37/271 (13.7) 35/334 (10.5) 0.87 (0.31e2.41)
5-min Apgar score <7 4 3/271 (1.1) 1/334 (0.3) 3.35 (0.50e22.54)
Neonatal intensive care unit 4 35/271 (12.9) 40/334 (12.0) 1.07 (0.70e1.62)
admission
Oxytocin studies only
Intraamniotic infection 2 15/154 (9.7) 5/174 (2.9) 3.20 (1.17e8.70)
Cesarean delivery 2 43/154 (27.9) 37/174 (21.6) 1.31 (0.89e1.92)
Indications for cesarean delivery
Nonreassuring fetal heart rate 2 9/43 (20.9) 5/37 (13.5) 1.94 (0.13e28.78)
Arrest of dilation or decent 2 31/43 (72.1) 28/37 (75.7) 0.97 (0.62e1.50)
Other 2 3/43 (7.0) 4/37 (10.8) 0.69 (0.18e2.67)
Endometritis 2 2/154 (1.3) 2/174 (1.2) 1.08 (0.16e7.45)
Suspected neonatal infection 2 36/154 (23.4) 30/174 (17.2) 1.29 (0.66e2.54)
5-min Apgar score<7 2 2/154 (1.3) 1/174 (0.6) 2.32 (0.21e25.21)
Neonatal intensive care unit 2 25/154 (16.2) 28/174 (16.1) 0.96 (0.46e1.99)
admission
Mackeen. Balloon catheter use after membrane rupture. Am J Obstet Gynecol 2021.

meta-analysis (which adhered to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses2
guidelines) of randomized controlled trials (RCT) where an
intracervical balloon catheter (ICBC) was compared with a
pharmacologic agent for the induction of labor (IOL) after
PROM, including preterm PROM.
STUDY DESIGN: This study was exempt from the institu-
tional review board and was registered on the International
Prospective Register of Systematic Reviews on January 28, 2020
(CRD42020166936). MEDLINE (1966 to date), Cochrane, and
ClinicalTrials.gov databases were searched in January 2020 and
May 2020 to identify eligible trials. Randomized trials
comparing balloon catheter with or without pharmacologic
agents with pharmacologic agents for IOL after PROM at or
near term were included. The included articles were assessed
for risk of bias using the Cochrane risk-of-bias tool for RCTs
(RoB 2), of which 3 articles were considered high risk of
bias: 2 articles because of the deviation from intended
intervention and 1 article because of the measurement of the
outcome.3 The primary outcome was intra-amniotic
infection (IAI) as defined by the individual RCTs. Secondary

626 American Journal of Obstetrics & Gynecology JUNE 2021

ajog.org
outcomes included time to vaginal delivery, cesarean delivery
and indication for cesarean delivery, postpartum hemorrhage,
endometritis, and neonatal outcomes (suspected neonatal
infection or culture-proven neonatal sepsis, neonatal intensive
care unit admission, and 5-minute Apgar score of <7).
Random effects meta-analyses were used to report the risk ratio
(RR) and 95% confidence interval (CI). Data were
independently abstracted by multiple authors. Authors of the
included trials were contacted to provide additional
clarifications or data when applicable. Preplanned subgroup
analyses included a sensitivity analysis excluding studies
considered at high risk of bias, comparison of ICBC with or
without pharmacologic agent vs oxytocin, vs misoprostol, and
vs dinoprostone, to be separately analyzed by route of delivery.
In addition, we planned to analyze ICBC without an additional
pharmacologic agent vs individual pharmacologic agents.
RESULTS: A total of 9 studies4e12 assessed patients with
PROM who were randomized to ICBC (with or without
pharmacologic agents) vs pharmacologic agents for IOL
(Table 1): 4 studies contributed data for analysis (605 women).
We were unable to procure data specific to those induced for
PROM in 5 studies,5e7,11,12 and therefore, these studies were
excluded from the analysis. There was an increased risk of IAI
in those treated with ICBC vs pharmacologic agents, although
the CI crossed 1 (RR, 1.84; 95% CI, 0.91e3.73). When
comparing ICBC with oxytocin (without ICBC) for IOL in
PROM, there was a 3.2-fold increased risk of IAI in the ICBC
arm (15 of 154 [9.7%]) compared with the oxytocin arm (5 of
174 [2.9%]; 95% CI, 1.17e8.70) (Table 2). There were no
significant differences in other outcomes, including
endometritis and suspected neonatal infection, nor were there
any differences with respect to preplanned subgroup analyses.
Many of the planned subgroup analyses could not be
conducted as there was no more than 1 trial available for a
given medication, with the exception of oxytocin.
CONCLUSION: The use of intracervical balloon catheter for
IOL in PROM at or near term almost doubles the risk of IAI
compared with the use of pharmacologic methods for IOL.
The increased risk of IAI was most significantly clear when
the intracervical balloon catheter group was compared with
the oxytocin group, as rates of IAI were 3.2-fold higher in
those treated with the intracervical balloon catheter. These
findings support the use of pharmacologic agents, specifically
oxytocin, for IOL in PROM. - 7. Kehl S, Ehard A, Berlit S, Spaich S, Sütterlin M, Siemer J. Combination
ACKNOWLEDGMENTS
We would like to thank Drs Amorosa, Kruit, Marions, and Mackeen for
providing the additional unpublished data that we requested for inclusion
in this meta-analysis.
A. Dhanya Mackeen, MD, MPH
Shantel T. Quinn, MD, MS
Vani C. Movva, MD
Research Letters
Division of Maternal-Fetal Medicine
Women’s Health Service Line
Geisinger
100 N. Academy Ave.
Danville, PA 17822
admackeen@geisinger.edu
Vincenzo Berghella, MD
Division of Maternal-Fetal Medicine
Department of Obstetrics and Gynecology
Sidney Kimmel Medical College
Thomas Jefferson University
Philadelphia, PA
Cande V. Ananth, PhD, MPH
Department of Obstetrics, Gynecology and Reproductive Sciences
Rutgers Robert Wood Johnson Medical School
New Brunswick, NJ
Department of Biostatistics and Epidemiology
Rutgers School of Public Health
Piscataway, NJ
Cardiovascular Institute of New Jersey
Rutgers Robert Wood Johnson Medical School
New Brunswick, NJ
Environmental and Occupational Health Sciences Institute
Rutgers Robert Wood Johnson Medical School
New Brunswick, NJ
The authors report no conflict of interest.
This meta-analysis is registered on the International Prospective Register
of Systematic Reviews (CRD42020166936).
REFERENCES
1. Martin JA, Hamilton BE, Osterman MJK. Births in the united states,
2018. NCHS Data Brief 2019;1e8.
2. Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension
statement for reporting of systematic reviews incorporating network
meta-analyses of health care interventions: checklist and explanations.
Ann Intern Med 2015;162:777–84.
3. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for
assessing risk of bias in randomised trials. BMJ 2019;366:14898.
4. Amorosa JMH, Stone J, Factor SH, Booker W, Newland M, Bianco A.
A randomized trial of Foley bulb for labor induction in premature rupture of
membranes in nulliparas (FLIP). Am J Obstet Gynecol 2017;217:360.
e1–7.
5. El Khouly NI. A prospective randomized trial comparing foley catheter,
oxytocin, and combination foley catheter-oxytocin for labour induction
with unfavourable cervix. J Obstet Gynaecol 2017;37:309–14.
6. Greybush M, Singleton C, Atlas RO, Balducci J, Rust OA. Prein-
duction cervical ripening techniques compared. J Reprod Med
2001;46:11–7.
of misoprostol and mechanical dilation for induction of labour: a ran-
domized controlled trial. Eur J Obstet Gynecol Reprod Biol 2011;159:
315–9.
8. Kruit H, Tihtonen K, Raudaskoski T, et al. Foley catheter or oral miso-
prostol for induction of labor in women with term premature rupture of
membranes: a randomized multicenter trial. Am J Perinatol 2016;33:866–72.
9. Mackeen AD, Durie DE, Lin M, et al. Foley plus oxytocin compared
with oxytocin for induction after membrane rupture: a randomized
controlled trial. Obstet Gynecol 2018;131:4–11.
10. Prager M, Eneroth-Grimfors E, Edlund M, Marions L. A randomised
controlled trial of intravaginal dinoprostone, intravaginal misoprostol and
JUNE 2021 American Journal of Obstetrics & Gynecology 627
Research Letters
transcervical balloon catheter for labour induction. BJOG 2008;115:
1443–50.
11. Rust OA, Greybush M, Atlas RO, Jones KJ, Balducci J. Preinduction
cervical ripening. A randomized trial of intravaginal misoprostol alone vs. a
combination of transcervical foley balloon and intravaginal misoprostol.
J Reprod Med 2001;46:899–904.
Screening for perinatal anxiety
OBJECTIVE: Perinatal mood and anxiety disorders
(PMADs) are some of the most common complications of the
perinatal period.1 The American College of Obstetricians and
Gynecologists recommends screening for both depressive and
anxiety symptoms at least once during the perinatal period
using a standardized, validated tool.2 The Edinburgh
Postnatal Depression Screen (EPDS) is the most commonly
used tool to screen for depression, and although it contains
anxiety-related questions, it has not been validated to screen
for anxiety. In fact, the ideal tool to screen for perinatal
anxiety remains a matter of debate.3e5 The aim of our
study was to evaluate the ability of the EPDS to also screen
for anxiety-related symptoms in comparison with the gold
standard tool, the Generalized Anxiety Disorder-7 (GAD-7)
screening tool.
STUDY DESIGN: Women receiving obstetrical care at 3 of
the University of Alabama at Birmingham obstetrical
clinics were screened simultaneously using the EPDS and
GAD-7 screening tools from October 1, 2017, to May 31,
2018. The screened population included English and
Spanish-speaking women from public and private offices
at varied gestational ages and during the postpartum
period. Only the first screen was included if a woman
was screened more than once. The total score for both
FIGURE
Association between the EPDS anxiety-specific
questions and GAD-7
EPDS, Edinburgh Postnatal Depression Screen; GAD-7, Generalized Anxiety Disorder-7.
Mazzoni. Screening for perinatal anxiety. Am J Obstet Gynecol 2021.
628 American Journal of Obstetrics & Gynecology JUNE 2021
ajog.org
12. Sheiker C, Suri N, Kholi U. Comparative evaluation of oral miso-
prostol, vaginal misoprostol and intracervical Folley’s catheter for induc-
tion of labour at term. J Med Educ 2009;11:75–7.
ª 2021 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.
2021.03.002
the EPDS and GAD-7 tools in addition to the score on 3
anxiety-specific EPDS questions (#4, 5, and 6) were
collected. Demographic data were collected from the
electronic medical records. A positive score was set at 10
for both the GAD-7 and EPDS tools. The data were then
analyzed using standard statistical modeling including a
logistic regression analysis and Pearson correlation
coefficients.
RESULTS: A total of 407 women were screened and
included in the study. Of these, 102 (25%) were screened
during the postpartum period, whereas the average gesta-
tional age for the remaining patients was 22.4 weeks; 178
(44%) patients self-identified as African American and 24
(6%) as Hispanic, and 203 (49%) received care in the
public office (predominantly Medicaid insured). Only 13
(3%) of the screens were completed in Spanish. The
prevalence of a positive GAD-7 score was 17% and that of
a positive EPDS score was 11%. The correlation between a
positive EPDS and GAD-7 screen was 0.83 (P<.001),
whereas the correlation between the anxiety-specific EPDS
questions and GAD-7 was 0.75 (P<.001) (Figure). A score
of 5 or greater on the anxiety-specific EPDS questions had
a sensitivity of 75% and a specificity of 90% for a positive
GAD-7 score. The demographic data were analyzed and
none were found to be significantly associated with a
positive screen for either anxiety or depression.
CONCLUSION: PMADs are common in our obstetrical
population. A positive EPDS score alone was correlated with a
positive GAD-7 score. In the case of a negative EPDS screen,
using a score of 5 or greater on the 3 anxiety-specific EPDS
questions may be helpful in identifying women who could
benefit from further anxiety screening and treatment. -
Sara E. Mazzoni, MD, MPH
Department of Obstetrics and Gynecology
The University of Alabama at Birmingham
Birmingham, AL
Department of Obstetrics and Gynecology
University of Washington
325 9th Ave.
Seattle, WA 35249
Sara.e.mazzoni@gmail.com
mazzoni@uw.edu