Original Research ajog.

org

OBSTETRICS
Maternal and neonatal outcomes of pregnancies with
COVID-19 after medically assisted reproduction: results
from the prospective COVID-19-Related Obstetrical and
Neonatal Outcome Study
Yvonne Ziert, PhD; Michael Abou-Dakn, MD; Clara Backes, MD; Constanze Banz-Jansen, MD; Nina Bock, MD;
Michael Bohlmann, MD; Charlotte Engelbrecht, MD; Teresa Mia Gruber, MD; Antonella Iannaccone, MD;
Magdalena Jegen, MD; Corinna Keil, MD; Ioannis Kyvernitakis, MD; Katharina Lang, MD; Angela Lihs, MD; Jula Manz, MD;
Christine Morfeld, MD; Manuela Richter, MD; Gregor Seliger, MD; Marina Sourouni, MD;
Constantin Sylvius von Kaisenberg, MD; Silke Wegener, MD; Ulrich Pecks, MD;
Frauke von Versen-Höynck, MD, MSc; On behalf of the COVID-19-Related Obstetric and Neonatal Outcome Study (CRONOS)
Network

BACKGROUND: Severe acute respiratory syndrome coronavirus type assisted reproduction pregnancies. Yet, the risk of obstetrical and neonatal
2 infections in pregnancy have been associated with maternal morbidity, complications was higher in pregnancies achieved through medically
admission to intensive care, and adverse perinatal outcomes such as assisted reproduction. However, medically assisted reproduction was not
preterm birth, stillbirth, and hypertensive disorders of pregnancy. It is the primary risk factor for adverse maternal and neonatal outcomes
unclear whether medically assisted reproduction additionally affects including pregnancy-related hypertensive disorders, gestational diabetes
maternal and neonatal outcomes in women with COVID-19. mellitus, cervical insufficiency, peripartum hemorrhage, cesarean de-
OBJECTIVE: To evaluate the effect of medically assisted reproduction livery, preterm birth, or admission to neonatal intensive care. Maternal
on maternal and neonatal outcomes in women with COVID-19 in age, multiple pregnancies, nulliparity, body mass index >30 (before
pregnancy. pregnancy) and multiple gestation contributed differently to the increased
STUDY DESIGN: A total of 1485 women with COVID-19 registered in risks of adverse pregnancy outcomes in women with COVID-19 inde-
the COVID-19 Related Obstetric and Neonatal Outcome Study (a multi- pendent of medically assisted reproduction.
centric, prospective, observational cohort study) were included. The CONCLUSION: Although women with COVID-19 who conceived
maternal and neonatal outcomes in 65 pregnancies achieved with through fertility treatment experienced a higher incidence of adverse
medically assisted reproduction and in 1420 spontaneously conceived obstetrical and neonatal complications than women with spontaneous
pregnancies were compared. We used univariate und multivariate conceptions, medically assisted reproduction was not the primary risk
(multinomial) logistic regressions to estimate the (un)adjusted odds ratios factor.
and 95% confidence intervals for adverse outcomes.
RESULTS: The incidence of COVID-19-associated adverse outcomes Key words: assisted reproduction, cohort study, COVID-19, fertility
(eg, pneumonia, admission to intensive care, and death) was not different treatment, maternal outcomes, neonatal outcomes, pregnancy, preterm
in women after conceptions with COVID-19 than in women after medically birth, SARS-CoV-2 infection

Introduction pregnancy outcomes. Indeed, observa- such as obesity, diabetes mellitus, hy-
During the COVID-19 pandemic, con- tional cohort studies report SARS-CoV- pertension, and older women.8e11 These
cerns arose as to whether infection by the 2 infections in pregnancy to be associ- factors are also often present in women
SARS-CoV-2 virus adversely affects ated with severe maternal morbidity and seeking fertility treatment. However,
mortality and neonatal complications there are limited data on whether the
compared with noninfected interaction of risk factors and infertility
Cite this article as: Ziert Y, Abou-Dakn M, Backes C, individuals.1e5 Data from the Covid-19- treatment further worsens outcomes in
et al. Maternal and neonatal outcomes of pregnancies Related Obstetric and Neonatal pregnancies with COVID-19.
with COVID-19 after medically assisted reproduction: Outcome Study (CRONOS) registry in At the beginning of the pandemic in
results from the prospective COVID-19-Related Obstet- Germany, which prospectively enrolls March 2020, fertility clinics postponed
rical and Neonatal Outcome Study. Am J Obstet Gynecol
2022;227:495.e1-11.
women with confirmed SARS-CoV-2 treatments for several weeks to months
infection during their pregnancy, sug- because of great uncertainty. Centers
0002-9378/$36.00 gest a higher risk of preterm birth and returned to their regular programs after
ª 2022 Published by Elsevier Inc.
https://doi.org/10.1016/j.ajog.2022.04.021 stillbirth and confirm a high rate of se- the introduction of safety measures and
vere COVID-19, requiring intensive care the availability of vaccinations. Never-
in these women.6,7 This is especially true theless, many patients are still unsure
for pregnant women with comorbidities and have a high need for advice about the

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2021 by 115 hospitals comprising a

AJOG at a Glance total cohort of 2819 cases. During the
Why was the study conducted? review of the registry and the plausi-
To evaluate the risk of adverse pregnancy outcomes by mode of conception in bility check, duplicate entries were
women with COVID-19. suspected in 10 cases; 8 of the cases
were confirmed and excluded after
Key findings contact with the entering hospital. In
Medically assisted reproduction is not the primary risk factor for adverse 98 cases, the week of gestation at the
maternal and neonatal outcomes in pregnancies with COVID-19. time of infection remained unknown,
and they were excluded, as this was
What does this add to what is known? considered mandatory information. In
Pregnancies with COVID-19 and pregnancies achieved through medically 63 other cases, it remained unclear
assisted reproduction are at a higher risk of adverse pregnancy outcomes. This whether women had been infected
study shows that in women with COVID-19, factors other than medically assisted during or before their pregnancy; these
reproduction such as maternal age, multiple pregnancies, body mass index >30, were also excluded. From the remaining
or multiple gestation are the key drivers for adverse maternal and neonatal 2,650 women with confirmed SARS-
outcomes. CoV-2 infection during their preg-
nancy, 1812 (68.3%) were symptom-
atic, 709 (26.8%) were asymptomatic,
risks of SARS-CoV-2 infection, espe- SARS-CoV-2 infection were eligible for and data on symptoms were not pro-
cially as pregnancies after fertility treat- inclusion. vided in 129 (4.9%) cases (Figure). The
ment are already associated with a All German maternity hospitals were final study cohort for the analyses
significantly higher incidence of adverse invited to participate in the CRONOS consisted of patients with COVID-19
obstetrical and neonatal outcomes such registry. By August 24, 2021, obstetri- (symptomatic SARS-CoV-2 infection)
as preeclampsia, fetal growth restriction, cians and neonatologists from 157 with valid information on whether or
and preterm birth compared with German hospitals and from the Kepler not medically assisted reproduction
spontaneous conceptions.12e15 University Hospital in Linz, Austria, (MAR) had been conducted before the
For better counseling, it is important confirmed to participate. Of these, 115 present pregnancy (n¼1485). Of these,
to know whether COVID-19 specifically hospitals actively provided data to 1331 (89.6%) had a confirmed SARS-
affects outcomes in women undergoing CRONOS. These maternity units atten- CoV-2 infection via a viral RNA detec-
fertility treatment more often than in ded 224,647 deliveries in 2020, account- ted by polymerase chain reaction
women who conceive after spontaneous ing for 29.1% of the births in Germany. testing, 30 (2.0%) via a detection of
conception. Therefore, we evaluated the Participating hospitals were asked to maternal SARS-CoV-2 antibodies, 45
risk of adverse maternal and neonatal register all women with SARS-CoV-2 (3.0%) via an antigen testing, and for
outcomes in SARS-Cov-2 infections by infection independent of the time point 75 cases, (5.1%) no information about
the mode of conception, emphasizing on of infection during pregnancy. the exact diagnostic test of SARS-CoV-2
symptomatic women with COVID-19. infection was available.
Data capture and study variables
Material and Methods For collecting data, a reporting form was Statistical analyses
Study design and setting developed using the cloud-based elec- For evaluating whether pregnancies after
CRONOS is a multicentric, prospective, tronic data capture platform of the ser- fertility treatment involve a greater risk
observational study established by the vice provider castoredc.com of adverse maternal and neonatal out-
German Society of Perinatal Medicine (Amsterdam, Netherlands). After the comes than spontaneous pregnancies, a
(DGPM) in April 2020 to rapidly pro- patients had given informed consent, stepwise statistical analysis strategy was
vide data to counsel women with SARS- information on the demographic char- performed. Firstly, the baseline data were
CoV-2 infection during their pregnancy. acteristics, comorbidities, previous and analyzed to identify statistically signifi-
Information on the study is available at current pregnancy characteristics, SARS- cant differences in the baseline risks be-
www.dgpm-online.org and from the CoV-2-specific symptoms and treat- tween pregnancy with MAR and
German Clinical Trials Register ments, pregnancy- and birth-specific spontaneous conceptions (Table 1).
(DRKS00021208); part of the study re- events, and neonatal outcomes were Secondly, it was evaluated whether
sults have been published recently.7 entered by each treating hospital in the COVID-19 associated clinical outcomes
Ethical approval was obtained for the data capture platform.7 (Table 2) and maternal and neonatal
study (University Hospital Schleswig- complications differed in a statistically
Holstein in Kiel, file number D 451/20, Cohort significant way between MAR pregnan-
and separate for each study side respec- The data presented here were collected cies and spontaneous conceptions
tively). Women with clinically confirmed between April 3, 2020 and August 24, (Supplemental Table 1). Thirdly, for

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FIGURE
Flowchart of the study cohort

Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

those maternal and neonatal outcomes In addition to P values, risk estimators determined, and no adjustment for
with statistically significant differences (odds ratios [OR] or mean difference multiplicity was applied. However, P
between the 2 study groups, separate [MD]) and corresponding 95% confi- values <.05 were considered to be sta-
multivariate models were calculated dence intervals (95% Cl) were calculated tistically significant.
(Supplemental Tables 2 and 3). for a comparison of maternal and
For comparing the categorical vari- neonatal complications. For the calcu- Results
ables between pregnancies after MAR lation of adjusted estimators in multi- The baseline maternal demographic and
and spontaneous conceptions, the ab- variate (multinominal) logistic clinical characteristics of 1420 (95.6%)
solute and relative frequencies are pre- regression models, the baseline variables women with spontaneous conceptions
sented for each group separately. The that significantly differed between both and those of 65 (4.38%) women with
statistical significance was tested for the the groups (confounders) or those that pregnancies achieved after MAR are
categorical baseline variables by using are known risk factors for adverse out- presented in Table 1. Of all MAR preg-
the chi-square tests or Fisher exact tests, comes were included in the models. nancies, most (n¼43; 66.2%) were ach-
and univariate (multinominal) logistic Statistical analyses were performed ieved through assisted reproductive
regression models were applied for the using Statistical Package for Social Sci- technology (ART) (ie, in vitro fertiliza-
categorical maternal and neonatal out- ences (SPSS; version 28; IBM Corp, tion [IVF] or intracytoplasmic sperm
comes. The continuous variables are Armonk, NY) for Windows (Microsoft, injection [ICSI]). Six women (n¼9.2%)
shown as means and standard deviations Redmond, WA). SPSS, by default, con- conceived after ovulation induction (OI)
for each group. The statistical signifi- ducts analyses by dropping cases for with (n¼3) or without (n¼3) intra-
cance was tested for the continuous which there are missing values, so the uterine insemination (IUI), and fertility
baseline variables by using independent t sample sizes may differ in the statistical treatment was not further specified in 16
tests and univariate analysis of covari- analyses. Inferential statistics were used women (24.6%).
ance for continuous maternal and in a descriptive manner. Thus, neither Overall, women who conceived
neonatal outcomes. global nor local significance levels were through MAR were significantly older

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TABLE 1
Baseline and pregnancy characteristics of the study participants
Maternal characteristics
MAR pregnancies n¼65 Spontaneous pregnancies n¼1420 P value
Maternal age (y) 34.095.12 30.905.14 <0.001
15e24 2 (3.1) 168 (11.8) 0.001
25e34 35 (53.8) 899 (63.3)
35e49 28 (43.1) 353 (24.9)
Nulliparity 42/65 (64.6) 529/1399 (37.8) <0.001
Smoking (before pregnancy) 4/63 (6.3) 107/1398 (7.7) 0.70
Maternal comorbidities
BMI >30 (before pregnancy) 18/63 (28.6) 275/1324 (20.8) 0.14
Cardiovascular comorbidities 3 (4.6) 53 (3.7) 0.73a
Diabetes mellitus (preexisting) 1 (1.5) 18 (1.3) 0.58a
Pulmonary comorbidities 3 (4.6) 49 (3.5) 0.49a
Hematologic comorbidities 2 (3.1) 16 (1.1) 0.18a
Current pregnancy characteristics
Multiple gestation 8/64 (12.5) 29/1416 (2.0) <0.001
Gestational age (wk) at onset of COVID-19 symptoms 27.259.56 27.609.92 0.78
First trimester 8 (12.3) 188 (13.2) 0.97
Second trimester 21 (32.3) 460 (32.4)
Third trimester 36 (55.4) 772 (54.4)
The data are presented as meanstandard deviation or absolute or relative frequencies (percentage).
BMI, body mass index; MAR, medically assisted reproduction.
a
Fisher exact test.
Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

and were more likely to be nulliparous or in the MAR group, which is also the ratio [OR], 1.97; 95% confidence inter-
carry multiple pregnancies than those main driver behind the borderline sig- val [CI], 1.00e3.86), cervical insuffi-
having conceived spontaneously. The nificant difference in the combined ciency (OR, 4.65; 95% CI, 1.72e12.56)
gestational age at onset of COVID-19 perinatal outcome (P¼.05) (Table 2). and were more likely to undergo cesar-
was comparable between both the This significant difference is mainly ean delivery (OR, 2.19; 95% CI,
groups. driven by the higher number of multiple 1.26e3.82). However, the cesarean de-
The COVID-19-associated maternal pregnancies in MAR conceptions, as the livery rate in multiple pregnancies was
outcomes, for example, need for inpa- adjusted OR for the mode of conception comparable between the conception
tient treatment, pneumonia, maternal is not significant anymore when it is groups (OR, 0.88; 95% CI, 0.16e4.71).
admission to intensive care unit (ICU), controlled for multiple gestations Peripartum hemorrhage occurred more
and maternal mortality, were not (Supplemental Table 3). Although 11 often in MAR pregnancies (OR, 3.33;
different among MAR and spontaneous stillbirths (2.5%) and 1 neonatal death 95% CI, 1.35e8.21). Furthermore, the
conceptions (Table 2). Moreover, the (0.2%) occurred in pregnancies after rate of pregnancy-related hypertensive
odds of COVID-19- associated cesarean spontaneous conception, no such cases disorders was higher though not statis-
delivery, pregnancy termination, or de- were registered in MAR conceptions. tically significantly different (OR, 2.39;
livery were comparable between both the Other maternal and perinatal out- 95% CI, 0.99e5.75; P¼.053). Children
conception groups. comes of births following spontaneous from MAR conceptions were delivered
Adverse neonatal outcomes following conceptions or after MAR independent preterm (OR, 2.98; 95% CI, 1.66e5.33)
birth within 4 weeks after the onset of of the onset of COVID-19 are shown in and admitted to the NICU (OR, 2.28;
COVID-19 resulted primarily from a Supplemental Table 1. Women after 95% CI, 1.25e4.16) more often than
significantly higher rate of neonatal MAR were more likely to be diagnosed those by birth from spontaneous con-
intensive care unit (NICU) admissions with gestational diabetes mellitus (odds ceptions. Although a rare event, neonatal

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TABLE 2
COVID-19-associated maternal and neonatal outcomes after medically assisted reproduction and spontaneous
conceptions
Spontaneous
MAR pregnancies pregnancies
Outcomes n¼65 n¼1420 OR 95% CI P value
Maternal outcomes
COVID-19-associated need for inpatient treatmenta 10/61 (16.4) 243/1349 (18.0) 0.89 0.45e1.78 .75
Pneumonia 6/60 (10.0) 135/1345 (10.0) 0.99 0.43e2.36 .99
ICU admission 2/61 (3.3) 75/1349 (5.6) 0.58 0.14e2.40 .45
Mortality 0/61 (0.0) 4/1349 (0.3) n.a. n.a. .99
COVID-19-associated indication for cesarean delivery 2/31 (6.5) 44/421 (10.5) 0.59 0.14e2.56 .48
COVID-19-associated reason for pregnancy termination 2/56 (3.6) 48/1185 (4.1) 0.88 0.21e3.71 .86
Delivery necessary for further maternal COVID-19 treatment 0/56 (0.0) 32/1185 (2.7) n.a. n.a. .99
Neonatal outcomes
Delivery within 4 wk after onset of COVID-19 symptoms 21/57 (36.8) 445/1177 (37.9) 0.96 0.55e1.66 .88
b
Combined perinatal outcome 9/21 (42.9) 105/445 (23.6) 2.43 1.00e5.93 .05
Stillbirth 0/21 (0.0) 11/444 (2.5) n.a. n.a. .99
NICU admission 9/21 (42.9) 94/440 (21.4) 2.76 1.13e6.75 .03
Neonatal death 0/21 (0.0) 1/428 (0.2) n.a. n.a. .99
Data are presented as absolute or relative frequencies (percentage).
CI, confidence interval; ICU, intensive care unit; MAR, medically assisted reproduction; n.a., not applicable; NICU, neonatal intensive care unit; OR, odds ratio.
a
The combined endpoint is composed of the following: pneumonia, ICU admission, and mortality; b Based on women who delivered within 4 weeks after the onset of COVID-19 symptoms and 24
weeks of gestation and is composed of the following endpoints: NICU admission, stillbirth, and neonatal death.
Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

death occurred proportionally more difference. Therefore, a multivariate outcomes. Gestational diabetes mellitus
often in MAR pregnancies (1/57¼1.8% model was also calculated for this is associated with BMI >30 (OR, 3.25;
vs 3/1,145¼0.3%). Neonatal death was important outcome. 95% CI, 2.25e4.70); pregnancy-related
not clinically linked to COVID-19 in any In the context of COVID-19, the hypertensive disorders are associated
of the cases. multivariate models demonstrate that with BMI >30 (OR, 2.37; 95% CI,
The results from multivariate (nomi- MAR was not a statistically significant 1.36e4.13) and nulliparity (OR, 2.74;
nal) logistic regression models for predictor of gestational diabetes melli- 95% CI, 1.57e4.77); cesarean delivery is
selected maternal and neonatal out- tus, pregnancy-related hypertensive dis- associated with maternal age (OR, 1.04;
comes are shown in Supplemental orders, cesarean delivery, cervical 95% CI, 1.01e1.06), BMI >30 (OR,
Tables 2 and 3. For estimating the insufficiency, peripartum hemorrhage, 1.80; 95% CI, 1.34e2.43), and nulli-
adjusted OR for MAR vs that for spon- NICU admission, and the combined parity (OR, 1.46; 95% CI, 1.12e1.91);
taneous conceptions, the variables of perinatal outcomes of NICU admission, cervical insufficiency is connected with
maternal age, nulliparity, and multiple stillbirth, and neonatal death following multiple gestation (OR, 14.46; 95% CI,
gestation, which significantly differed at delivery within 4 weeks after the onset of 5.35e39.09); peripartum hemorrhage is
baseline between both the groups, were COVID-19. However, the risks are still associated with maternal age (OR, 1.07;
included as a covariate. Because women descriptively higher in the MAR group 95% CI, 1.00e1.13) and multiple
with a BMI >30 kg/m2 were propor- (OR >1). MAR significantly increased gestation (OR, 3.47; 95% CI,
tionally more common in the MAR the risk of preterm birth (OR, 2.32; 95% 1.11e10.86); NICU admission is con-
group, and obesity is a known risk factor CI, 1.19e4.53), yet, multiple gestation nected to maternal age (OR, 1.07; 95%
for adverse outcomes, BMI >30 was also was the primary risk factor for preterm CI, 1.03e1.10) and multiple gestation
taken into account. However, it was not birth (OR, 15.92; 95% CI, 6.82e37.16). (OR, 11.38; 95% CI, 5.10e25.37); and
statistically significant in the study sam- All other multivariate analyses finally, the combined perinatal outcome
ple. Pregnancy-related hypertensive dis- demonstrate that risk factors other than is associated with multiple gestations
orders showed a borderline significant MAR are the main drivers for adverse (OR, 6.14; 95% CI, 1.90e19.91).

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Comment with our results, which demonstrate that delivery of these high-risk pregnancies
Principal findings the conception mode is not the primary per se on the other.
We report that in women with MAR risk factor for adverse obstetrical and Compared with spontaneous con-
pregnancies, the risk of COVID-19- neonatal complications in COVID-19- ceptions, adverse maternal and neonatal
associated adverse outcomes, for affected women. Particularly encour- outcomes are more common among
example, the need for inpatient treat- aging is also the fact that comparable conceptions after MAR independent of
ment, pneumonia, oxygen ventilation, incidences of complications were re- the onset of COVID-19 in preg-
maternal death, and delivery and also ported for those directly associated with nancy.27,28 The main driver for the
stillbirth and neonatal death following COVID-19 (eg, pneumonia, ICU adverse outcomes is the higher risk of
birth within 4 weeks of the onset of admission, and death). multiple gestations in IVF.29 As the field
COVID-19 was comparable with preg- Engels Calvo et al reported a higher moves toward single embryo transfer,
nancies after spontaneous conceptions. incidence of preeclampsia and cesarean and as the rate of multiple gestations
MAR was also not the primary risk factor delivery in a cohort of symptomatic decreases, it also becomes clear that
of adverse maternal or neonatal out- and asymptomatic SARS-CoV-2- other factors, eg, the choice of a pro-
comes in pregnancies affected by infected women after IVF than with grammed protocol in frozen-thawed
COVID-19. Instead, other factors, such spontaneous pregnancies.23 This is in embryo transfer cycles30e32 or sub-
as maternal age, nulliparity, BMI >30, or contrast to our observations for both fertility33 itself make a significant
multiple gestation were the key drivers. the outcomes. One main difference in contribution to a higher incidence of
However, MAR conceptions were asso- the analysis is the adjustment for adverse outcomes. Subfertile women
ciated with descriptively higher risks of important confounders, which included carry risk factors for pregnancy com-
gestational diabetes mellitus, peripartum maternal age and clinical presentation plications more often, eg, higher age,
hemorrhage, cervical insufficiency, ce- in the Spanish study.23 In the cohort, 36 obesity, or metabolic alterations.12,34,35
sarean delivery, preterm birth, and out of 74 women conceived with donor Beside an expected higher rate of mul-
admission to NICU. oocytes, which was not a covariate in tiple gestations, we confirmed these
the multinomial logistic regression observations in our infertile cohort,
Results in the context of what is model but is one of several well-known which was older and more often obese.
known risk factors for preeclampsia.24e26 In The rate of nulliparity, which is a risk
Several cohort studies report an associ- addition, the higher rate of cesarean factor for hypertensive disorders of
ation between COVID-19 in pregnancy delivery in IVF patients than in spon- pregnancy,36 was also higher. The re-
and substantially increased maternal and taneous conceptions can particularly be sults from our multivariate models
neonatal morbidity and mortality than explained by the increased rate of demonstrate that MAR itself is not the
pregnant women without a diagnosis of multiple births in the Spanish study. primary risk factor for adverse out-
COVID-19.10 This involves preeclamp- Our multinominal logistic regression comes of pregnancies affected by
sia,3,16,17 gestational hypertension,18 model included the clinical character- COVID-19, for example, gestational
maternal death,19 stillbirth,19 preterm istics (eg, age, nulliparity, and multiple diabetes mellitus, peripartum hemor-
delivery,17,20 and poor fetal growth, gestation), which significantly differed rhage, cervical insufficiency, cesarean
among others.18,21 The risks are signifi- between MAR pregnancies and spon- delivery, preterm birth, and admission
cantly higher in women with comor- taneous conceptions and also known to NICU, but that these women enter
bidities, eg, diabetes mellitus, potential confounders (eg, BMI >30) pregnancy with a higher baseline risk.
hypertension, and obesity; the risks are for the respective outcome. The models In this context, maternal age, multiple
also higher in older age.8e11 developed suggest that the (still) gestation, and BMI >30 were the main
Insight on the outcomes of pregnan- elevated though not statistically signifi- predictors of obstetrical and neonatal
cies achieved through MAR and cant risk of MAR pregnancies would be complications.
COVID-19 is sparse. The first data were further reduced if additional risk factors
provided by the ESHRE COVID-19 were considered. In our cohort of Clinical implications
Working Group. It collected 80 cases spontaneous conceptions, a significant Our findings are of clinical importance
from 32 countries, including 67 live number of stillbirths (2.5%) occurred during an ongoing pandemic with a so
births, 10 miscarriages, 2 stillbirths, and within 4 weeks of COVID-19 onset, far unknown end. They will help advise
1 maternal death.22 One-third of the which is higher than the expected couples seeking fertility treatment and
reported cases had an asymptomatic stillbirth rate of approximately 0.4% in will provide reassurance that the fertility
infection, whereas 31.4% were treated in Germany and requires further atten- treatment itself will not add to the po-
the hospital. The authors concluded that tion. None of these cases were present tential risk of adverse maternal and
infections in pregnancies after MAR do in the MAR group, which may be neonatal outcomes when a patient is
not lead to a higher risk of adverse out- because of the low number of registered affected by COVID-19. Nevertheless,
comes than those after spontaneous pregnancies on the one hand and the our data clearly show again that other,
conceptions. This is somehow in line possibly better monitoring and earlier potentially avoidable, risk factors (eg,

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multiple gestation) lead to a poorer spontaneous conceptions. The data MMWR Morb Mortal Wkly Rep 2020;69:
outcome. provide important information for 1641–7.
9. Wei SQ, Bilodeau-Bertrand M, Liu S, Auger N.
counseling couples who seek fertility The impact of COVID-19 on pregnancy out-
Strengths and limitations treatment and to provide reassurance comes: a systematic review and meta-analysis.
In this study, we took advantage of a about the risks that are not primarily CMAJ 2021;193:E540–8.
well-supervised prospective registry driven by MAR but other individual risk 10. Villar J, Ariff S, Gunier RB, et al. Maternal and
study using a standardized electronic factors compared with spontaneous neonatal morbidity and mortality among preg-
nant women with and without COVID-19 infec-
clinical report form. Items specifically conceptions with COVID-19 during tion: The INTERCOVID multinational cohort
targeting MAR were incorporated and pregnancy. With the growing number of study. JAMA Pediatr 2021;175:817–26.
linked to COVID-19 and obstetrical and SARS-CoV-2 infections worldwide, 11. Allotey J, Stallings E, Bonet M, et al. Clinical
neonatal outcomes. A particular strength further research is needed to confirm our manifestations, risk factors, and maternal and
of our study is the differentiation be- observations and to elucidate the impact perinatal outcomes of coronavirus disease 2019
in pregnancy: living systematic review and meta-
tween the methods of conception such as of different SARS-CoV-2 variants and of analysis. BMJ 2020;370:m3320.
IVF or ICSI and OI with or without IUI, infections after previous immunization 12. Pinborg A, Wennerholm UB,
which ensures the quality of the data on obstetrical and neonatal outcomes. n Romundstad LB, et al. Why do singletons
entries. Because asymptomatic cases are conceived after assisted reproduction technol-
most likely considered as “incidental Acknowledgments ogy have adverse perinatal outcome? System-
atic review and meta-analysis. Hum Reprod
SARS-CoV-2 infection” cases requiring The authors wish to thank all the participating
Update 2013;19:87–104.
hospitalization for other reasons, we hospitals for providing clinical information to the
13. Jackson RA, Gibson KA, Wu YW,
CRONOS database. This research would not
focused our analysis on symptomatic Croughan MS. Perinatal outcomes in singletons
have been possible without their efforts.
women. In our experience this approach following in vitro fertilization: a meta-analysis.
avoids including women who present to Obstet Gynecol 2004;103:551–63.
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infected pregancies after medically assisted and meta-analysis. Hum Reprod Update Loerrach, Loerrach, Germany (Dr Bohlmann); Department
reproduction. Hum Reprod 2021;36:2883–90. 2021;28:1–14. of Obstetrics, Charité e Universitätsmedizin Berlin, Ber-
23. Engels Calvo V, Cruz Melguizo S, Abascal- 32. Waschkies F, Kroning L, Schill T, et al. lin, Germany (Drs Engelbrecht and Gruber); Department
Saiz A, et al. Perinatal outcomes of pregnancies Pregnancy outcomes after frozen-thawed em- of Obstetrics and Gynecology, University of Duisburg-
resulting from assisted reproduction technology bryo transfer in the absence of a corpus luteum. Essen, Essen, Germany (Dr Iannaccone); Department of
in SARS-CoV-2-infected women: a prospective Front Med (Lausanne) 2021;8:727753. Gynecology and Obstetrics, University Hospital, LMU
observational study. Fertil Steril 2021;116: 33. Henningsen AK, Pinborg A, Lidegaard Ø, Munich, Munich, Germany (Dr Jegen); Department of
731–40. Vestergaard C, Forman JL, Andersen AN. Peri- Gynecology and Obstetrics, University Hospital Marburg,
24. Blázquez A, García D, Rodríguez A, natal outcome of singleton siblings born after Philipps University Marburg, Marburg, Germany (Dr Keil);
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Reprod Genet 2016;33:855–63. 34. Luke B. Pregnancy and birth outcomes in Albertinen Krankenhaus, Hamburg, Germany (Dr Lang);
25. Masoudian P, Nasr A, de Nanassy J, Fung- couples with infertility with and without assisted Department of Obstetrics and Gynecology, Klinikverbund
Kee-Fung K, Bainbridge SA, El Demellawy D. reproductive technology: with an emphasis on Suedwest, Boeblingen, Germany (Dr Lihs); Department of
Oocyte donation pregnancies and the risk of US population-based studies. Am J Obstet Obstetrics and Gynecology, City Hospital, Darmstadt,
preeclampsia or gestational hypertension: a Gynecol 2017;217:270–81. Deutschland (Dr Manz); Department of Obstetrics, Dia-
systematic review and metaanalysis. Am J 35. Raatikainen K, Kuivasaari-Pirinen P, kovere Henriettenstift, Hannover, Germany (Dr Morfeld);
Obstet Gynecol 2016;214:328–39. Hippeläinen M, Heinonen S. Comparison of Department of Neonatology, Kinderkrankenhaus auf der
26. Pecks U, Maass N, Neulen J. Oocyte the pregnancy outcomes of subfertile women Bult, Kinder- und Jugendkrankenhaus, Hannover, Ger-
donation: a risk factor for pregnancy-induced after infertility treatment and in naturally many (Dr Richter); Center for Reproductive Medicine &
hypertension: a meta-analysis and case series. conceived pregnancies. Hum Reprod Andrology and Department of Obstetrics & Prenatal
Dtsch Arztebl Int 2011;108:23–31. 2012;27:1162–9. Medicine, University Hospital, Halle (Saale), Germany (Dr
27. Sazonova A, Källen K, Thurin-Kjellberg A, 36. Bartsch E, Medcalf KE, Park AL, Ray JG. Seliger); Department of Obstetrics and Gynecology, Uni-
Wennerholm UB, Bergh C. Obstetric outcome High Risk of Pre-eclampsia Identification Group. versity Clinic, Muenster, Germany (Dr Sourouni);
after in vitro fertilization with single or double Clinical risk factors for pre-eclampsia deter- Department of Obstetrics, Gynecology and Reproductive
embryo transfer. Hum Reprod 2011;26:442–50. mined in early pregnancy: systematic review and Medicine, Hannover Medical School, Hannover, Germany
28. Kenigsberg S, Bentov Y. Does contempo- meta-analysis of large cohort studies. BMJ (Dr von Kaisenberg); Department of Obstetrics and Gy-
rary ART lead to pre-eclampsia? A cohort study 2016;353:i1753. necology, Ernst von Bergmann Hospital, Potsdam, Ger-
and meta-analysis. J Assist Reprod Genet many (Dr Wegener); Department of Obstetrics and
2021;38:651–9. Gynecology, University Hospital of Schleswig-Holstein,
29. Kulkarni AD, Jamieson DJ, Jones HW Jr, Author and article information Kiel, Germany (Dr Pecks); and Department of Obstetrics,
et al. Fertility treatments and multiple births in the From the Institute of Biostatistics, Hannover Medical Gynecology and Reproductive Medicine, Hannover
United States. N Engl J Med 2013;369: School, Hannover, Germany (Dr Ziert); Department of Medical School, Hannover, Germany (Dr von Versen-
2218–25. Obstetrics and Gynecology, St. Joseph Hospital, Berlin, Höynck).
30. von Versen-Höynck F, Schaub AM, Chi YY, Germany (Dr Abou-Dakn); Department of Obstetrics and Received Feb. 10, 2022; revised April 4, 2022;
et al. Increased preeclampsia risk and reduced Gynecology, München Klinik Harlaching, Munich, Ger- accepted April 7, 2022.
aortic compliance with in vitro fertilization cycles many (Dr Backes); Department of Gynecology and Ob- The authors declare no conflict of interest.
in the absence of a corpus luteum. Hypertension stetrics, Protestant Hospital of Bethel Foundation, CRONOS has been funded by Krumme-Stiftung, the
2019;73:640–9. University Medical School OWL, Bielefeld, Germany (Dr German Society of Perinatal Medicine (DGPM), and the
31. Rosalik K, Carson S, Pilgrim J, et al. Effects Banz-Jansen); Department of Obstetrics and Gynecology, Federal State of Schleswig-Holstein
of different frozen embryo transfer regimens on Klinikum Hanau, Hanau, Germany (Dr Bock); Department Corresponding author: Frauke von Versen-Höynck,
abnormalities of fetal weight: a systematic review of Obstetrics and Gynecology, St. Elisabeth Hospital MD, MSc. vonversen-hoeynck.frauke@mh-hannover.de

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SUPPLEMENTAL TABLE 1
Maternal and neonatal outcomes of women with COVID-19 after medically assisted reproduction and spontaneous
conceptions
MAR pregnancies Spontaneous pregnancies
Outcomes n¼65 n¼1420 OR 95% CI P value
Maternal outcomes
Gestational diabetes mellitus 11/65 (16.9) 133/1420 (9.4) 1.97 1.00e3.86 .048
a
Pregnancy-related hypertensive disorders 6/65 (9.2) 58/1419 (4.1) 2.39 0.99e5.75 .053
b
Stillbirth 1/57 (1.8) 15/1170 (1.3) 1.36 0.18e10.6 .76
Early and late miscarriage 0/57 (0.0) 13/1190 (0.9) n.a. n.a. .99
Mode of delivery
Spontaneous vaginal delivery 23/57 (40.4) 694/1189 (58.4)
Vaginal-operative delivery 3/57 (5.2) 69/1189 (5.8) 1.31 0.38e4.48 .67
Cesarean delivery 31/57 (54.4) 426/1189 (35.8) 2.19 1.26e3.82 .005
Premature labor 2/65 (3.1) 67/1419 (4.7) 0.64 0.15e2.67 .54
Premature rupture of membranes 9/65 (13.8) 125/1419 (8.8) 1.67 0.80e3.44 .17
Cervical insufficiency 5/65 (7.7) 25/1419 (1.8) 4.65 1.72e12.56 .002
Gestational cholestasis 2/65 (3.1) 19/1419 (1.3) 2.34 0.53e10.26 .26
Peripartum hemorrhage 6/56 (10.7) 41/1179 (3.5) 3.33 1.35e8.21 .009
Neonatal outcomes
Fetal growth restriction 0/65 (0.0) 37/1419 (2.6) n.a. n.a. .99
Gestational age (wk) at birth 38.213.4 39.013.42 0.79 c
1.71 to 0.11 .09
Preterm birth (<37 gestational wk) b
18/57 (22.8) 158/1177 (13.4) 2.98 1.66e5.33 <.001
Birthweight percentiles
<10th percentile 3/51 (5.9) 79/1120 (7.1) 1.24 0.38e4.09 .72
10the90th percentiles 44/51 (86.3) 932/1120 (83.2)
>90th percentile 4/51 (7.8) 109/1120 (9.7) 1.29 0.45e3.65 .64
5 min Apgar 9.161.46 9.2341.73 0.08 c
0.53 to 0.38 .75
5 min Apgar <7 1/57 (1.8) 52/1172 (4.4) 0.39 0.05e2.83 .35
Congenital malformations 3/57 (5.3) 26/1176 (2.2) 2.46 0.72e8.37 .15
NICU admission 16/57 (28.1) 172/1178 (14.8) 2.28 1.25e4.16 .007
NICU admission (excluding multiple gestations) 10/50 (20.0) 159/1154 (13.8) 1.21 0.57e2.55 .22
Respiratory support 9/57 (15.8) 102/1178 (8.7) 1.98 0.94e4.15 .07
Neonatal death 1/57 (1.8) 3/1145 (0.3) 6.79 0.69e66.39 .09
Data are shown as absolute or relative frequencies (percentage).
CI, confidence interval; HELLP, hemolysis, elevated liver enzymes and low platelets; ICU, intensive care unit; MAR, medically assisted reproduction; n.a., not applicable; NICU, neonatal intensive care
unit; OR, odds ratio.
a
HELLP þ other hypertensive disorders of pregnancy (eg, pregnancy-induced hypertension, preeclampsia); b Based on delivery  24 weeks of gestation; c Mean difference.
Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

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SUPPLEMENTAL TABLE 2
Multivariate model results for selected maternal outcomes of women with COVID-19 after medically assisted
reproduction and spontaneous conceptions
Outcomes Level OR 95% CI P value
Gestational diabetes mellitus
Mode of conception MAR 1.71 0.82e3.57 .16
Maternal age (y) 1.0 0.98e1.06 .32
Nulliparity Present 0.89 0.60e1.32 .55
BMI >30 (before pregnancy) Present 3.25 2.25e4.70 <.001
Multiple gestation Present 1.27 0.46e3.51 .65
a
Pregnancy-related hypertensive disorders
Mode of conception MAR 1.29 0.49e3.42 .60
Maternal age (y) 1.04 0.99e1.09 .16
Nulliparity Present 2.74 1.57e4.77 <.001
BMI >30 (before pregnancy) Present 2.37 1.36e4.13 .002
Multiple gestation Present 2.74 0.88e8.47 .08
Mode of delivery (Spontaneous vaginal delivery [reference])
Vaginal-operative delivery
Mode of conception MAR 0.93 0.26e3.32 .91
Maternal age (y) 1.01 0.96e1.07 .62
Nulliparity Present 6.51 3.51e12.10 <.001
BMI >30 (before pregnancy) Present 1.29 0.66e2.55 .45
Multiple gestation Present n.a. n.a. n.a.
Cesarean delivery
Mode of conception MAR 1.66 0.93e2.97 .09
Maternal age (y) 1.04 1.01e1.06 .004
Nulliparity Present 1.46 1.12e1.91 .005
BMI >30 (before pregnancy) Present 1.80 1.34e2.43 <.001
Multiple gestation Present 1.78 0.85e3.73 .13
Cervical insufficiency
Mode of conception MAR 2.86 0.89e9.14 .08
Maternal age (y) 1.04 0.96e1.13 .33
Nulliparity Present 1.39 0.59e3.24 .45
BMI >30 (before pregnancy) Present 0.57 0.18e1.76 .32
Multiple gestation Present 14.46 5.35e39.09 <.001
Peripartum hemorrhage
Mode of conception MAR 2.02 0.76e5.38 .16
Maternal age (y) 1.07 1.00e1.13 .047
Nulliparity Present 1.63 0.86e3.07 .13
BMI >30 (before pregnancy) Present 0.92 0.43e1.97 .83
Multiple gestation Present 3.47 1.11e10.86 .03
aOR adjusted for the effects of maternal age (years), nulliparity, BMI >30 (before pregnancy) and multiple gestation.
aOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; HELLP, hemolysis, elevated liver enzymes and low platelets; MAR, medically assisted reproduction; OR, odds ratio.
a
HELLP þ other hypertensive disorders of pregnancy (eg, pregnancy-induced hypertension, preeclampsia).
Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

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SUPPLEMENTAL TABLE 3
Multivariate model results for selected neonatal outcomes of women with COVID-19 after medically assisted
reproduction and spontaneous conceptions
Outcomes Level OR 95% CI P value
Preterm birth (<37 gestational wk)a
Mode of conception MAR 2.32 1.19e4.53 .01
Maternal age (y) 1.03 1.00e1.07 .10
Nulliparity Present 0.71 0.48e1.03 .07
BMI >30 (before pregnancy) Present 0.93 0.60e1.42 .73
Multiple gestation Present 15.92 6.82e37.16 <.001
NICU admission
Mode of conception MAR 1.39 0.71e2.75 .34
Maternal age (y) 1.07 1.03e1.10 <.001
Nulliparity Present 1.09 0.76e1.56 .66
BMI >30 (before pregnancy) Present 1.34 0.91e1.98 .14
Multiple gestation Present 11.38 5.10e25.37 <.001
Combined perinatal outcomesa,b
Mode of conception MAR 1.23 0.45e3.38 .69
Maternal age (y) 1.08 1.03e1.13 <.001
Nulliparity Present 1.53 0.93e2.50 .09
BMI >30 (before pregnancy) Present 1.86 1.10e3.20 .02
Multiple gestation Present 6.14 1.90e19.91 .001
aOR adjusted for the effects of maternal age (years), nulliparity, BMI >30 (before pregnancy) and multiple gestation.
aOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; MAR, medically assisted reproduction; NICU, neonatal intensive care unit; OR, odds ratio.
a
Based on delivery  24 weeks of gestation; b Combined endpoint composed of NICU admission, stillbirth, and neonatal death.
Ziert et al. Adverse pregnancy outcomes by mode of conception in women with COVID-19. Am J Obstet Gynecol 2022.

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