key: cord-0875560-iwcpr7bg authors: ZIERT, Yvonne; ABOU-DAKN, Michael; BACKES, Clara; BANZ-JANSEN, Constanze; BOCK, Nina; BOHLMANN, Michael; ENGELBRECHT, Charlotte; Mia GRUBER, Teresa; IANNACCONE, Antonella; JEGEN, Magdalena; KEIL, Corinna; KYVERNITAKIS, Ioannis; LANG, Katharina; LIHS, Angela; MANZ, Jula; MORFELD, Christine; RICHTER, Manuela; SELIGER, Gregor; SOUROUNI, Marina; VON KAISENBERG, Constantin Sylvius; WEGENER, Silke; PECKS, Ulrich; VERSEN-HÖYNCK, Frauke VON. title: Maternal and neonatal outcomes of pregnancies with COVID-19 after medically assisted reproduction – results from the prospective Covid-19-Related Obstetric and Neonatal Outcome Study (CRONOS) date: 2022-04-19 journal: Am J Obstet Gynecol DOI: 10.1016/j.ajog.2022.04.021 sha: 36af6e9e902f0085301254831b5b2bbad417f1bf doc_id: 875560 cord_uid: iwcpr7bg Background Severe acute respiratory syndrome coronavirus type 2 infections in pregnancy have been associated with maternal morbidity, admission to intensive care, and adverse perinatal outcomes such as preterm birth, stillbirth and hypertensive disorders of pregnancy. It is unclear whether in women with COVID-19 medically assisted reproduction additionally affects maternal and neonatal outcomes. Objective To evaluate the effect of medically assisted reproduction on maternal and neonatal outcomes of women with COVID-19 in pregnancy. Study design A total of 1,485 women with COVID-19 registered in the Covid-19 Related Obstetric and Neonatal Outcome Study, a multicentric prospective observational cohort study, were included. Maternal and neonatal outcomes of 65 pregnancies achieved with medically assisted reproduction and 1,420 spontaneously conceived pregnancies were compared. We used univariate und multivariate (multinomial) logistic regressions to estimate (un)adjusted odds ratios and 95% confidence intervals for adverse outcomes. Results Compared to women after spontaneous conceptions with COVID-19, the incidence of COVID-19 associated adverse outcomes (e.g. pneumonia, admission to intensive care, death) was not different than in women after medically assisted reproduction pregnancies. Yet, the risk of obstetric and neonatal complications was higher in pregnancies achieved through medically assisted reproduction. However, medically assisted reproduction was not the primary risk factor for adverse maternal and neonatal outcomes, e.g. pregnancy-related hypertensive disorders, gestational diabetes mellitus, cervical insufficiency, peripartum hemorrhage, delivery by caesarean section, preterm birth or admission to neonatal intensive care. Maternal age, multiple pregnancies, nulliparity, BMI >30 (before pregnancy) and multiple gestation contributed differently to the increased risks of adverse pregnancy outcomes in women with COVID-19, independent of medically assisted reproduction. Conclusion Although women with COVID-19 who conceived through fertility treatment experienced a higher incidence of adverse obstetric and neonatal complications than women with spontaneous conceptions, medically assisted reproduction was not the primary risk factor. diabetes mellitus, cervical insufficiency, peripartum hemorrhage, delivery by 115 caesarean section, preterm birth or admission to neonatal intensive care. Maternal 116 age, multiple pregnancies, nulliparity, BMI >30 (before pregnancy) and multiple 117 gestation contributed differently to the increased risks of adverse pregnancy outcomes 118 in women with COVID-19, independent of medically assisted reproduction. pregnancy to be associated with severe maternal morbidity and mortality and neonatal 137 complications compared to non-infected individuals [1] [2] [3] [4] [5] . Data from the CRONOS 138 (Covid-19-Related Obstetric and Neonatal Outcome Study) registry in Germany, which 139 prospectively enrolls women with confirmed SARS-CoV-2 infection during their 140 pregnancy, suggest a higher risk for preterm birth and stillbirth, and confirm a high rate 141 of severe COVID-19 requiring intensive care 6, 7 . This is especially true for pregnant 142 women with comorbidities such as obesity, diabetes mellitus, hypertension, and older 143 women [8] [9] [10] [11] . These factors are also often present in women seeking fertility treatment. 144 However, there are limited data on whether the interaction of risk factors and infertility 145 treatment further worsens outcomes in pregnancies with At the beginning of the pandemic in March 2020, fertility clinics postponed treatments 147 for several weeks to months due to great uncertainty. Centers returned to their regular 148 programs after the introduction of safety measures and the availability of vaccinations. 149 Nevertheless, many patients are still unsure and have a high need for advice about 150 the risks of a SARS-CoV-2 infection especially since pregnancies after fertility 151 treatment are already associated with a significantly higher incidence of adverse 152 obstetric and neonatal outcomes such as preeclampsia, fetal growth restriction, and 153 preterm birth compared to spontaneous conceptions 12-15 . 154 For better counseling, it is important to know whether COVID-19 affects outcomes 155 specifically in women undergoing fertility treatment more often than in women who 156 conceive after spontaneous conception. Therefore, we evaluated the risk of adverse 157 J o u r n a l P r e -p r o o f For collecting data, a reporting form was developed using the cloud-based electronic 181 data capture platform of the service provider castoredc.com (Amsterdam, 182 Netherlands). After patients had given informed consent, information on demographic 183 characteristics, comorbidities, previous and current pregnancy characteristics, SARS-184 CoV-2 specific symptoms and treatments, pregnancy and birth specific events and 185 neonatal outcomes were entered by each treating hospital in the data capture platform For evaluating whether pregnancies after fertility treatment compromise a greater risk 211 for adverse maternal and neonatal outcomes compared to spontaneous pregnancies, 212 a stepwise statistical analysis strategy was performed. Firstly, baseline data were 213 analyzed to identify statistically significant differences in baseline risks between 214 pregnancy with MAR and spontaneous conceptions (Table 1) . Secondly, it was 215 evaluated whether COVID-19 associated clinical outcomes ( Table 2 ) as well as 216 maternal and neonatal complications differed statistically significant between MAR 217 pregnancies and spontaneous conceptions (Supplemental Table 1 ). Thirdly, for those 218 maternal and neonatal outcomes with statistically significant differences between the 219 two study groups, separate multivariate models were calculated (Supplemental Tables 220 2 and 3) . 221 For comparing categorical variables between pregnancies after MAR and spontaneous 222 conceptions absolute and relative frequencies are presented for each group 223 separately. Statistical significance was tested for categorical baseline variables by 224 using Chi-square tests or Fishers' exact tests and for categorical maternal and 225 neonatal outcomes univariate (multinominal) logistic regression models were applied, 226 respectively. Continuous variables are shown as means and standard deviations for 227 each group. Statistical significance was tested for continuous baseline variables by 228 using independent t-tests and for continuous maternal and neonatal outcomes 229 univariate analysis of covariance, respectively. 230 In addition to p-values, risk estimators (odds ratios [OR] ovulation induction (OI) with (n=3) or without (n=3) intrauterine insemination (IUI) and 251 in 16 women (24.6%) fertility treatment was not further specified. 252 Overall, women who conceived through MAR were significantly older, and were more 253 likely to be nulliparous or to carry multiple pregnancies compared with those having 254 conceived spontaneously. Gestational age at onset of COVID-19 was comparable 255 between both groups. 256 257 COVID-19 associated maternal outcomes, e.g. need for inpatient treatment, 258 pneumonia, maternal admission to intensive care unit (ICU) and maternal mortality, 259 were not different among MAR and spontaneous conceptions (Table 2) . Also, the odds 260 for COVID-19 associated caesarean section, pregnancy termination or delivery were 261 comparable between both conception groups. 262 Adverse neonatal outcomes following birth within 4 weeks after onset of COVID-19, 263 resulted primarily from a significant higher rate of neonatal intensive care unit (NICU) 264 admissions in the MAR group, which is also the main driver behind the borderline 265 significant difference in the combined perinatal outcome (p=0.05) ( Table 2 ). This 266 significant difference is mainly driven by the higher number of multiple pregnancies in 267 MAR conceptions as the adjusted OR for the mode of conception is not significant 268 anymore when it is controlled for multiple gestations (Supplement Table 3 nulliparity, and multiple gestation, which significantly differed at baseline between both 292 groups, were included as a covariate. Since women with a BMI >30 were proportionally 293 more common in the MAR group and obesity is a known risk factor for adverse 294 outcomes, BMI >30 was also taken into accountalthough it was not statistically 295 significant in the study sample. Pregnancy-related hypertensive disorders showed a 296 borderline significant difference; therefore a multivariate model was also calculated for 297 this important outcome. 298 In the context of COVID-19 the multivariate models demonstrate that MAR was not a 299 statistically significant predictor for gestational diabetes mellitus, pregnancy-related 300 hypertensive disorders, caesarean section, cervical insufficiency, peripartum 301 hemorrhage, NICU admission and the combined perinatal outcome NICU admission, 302 stillbirth and neonatal death following delivery within four weeks after onset of COVID-303 19 . However, the risks are still descriptively higher in the MAR group (OR >1 We report that in women with MAR pregnancies the risk for COVID-19 associated 323 adverse outcomes, e.g. the need for inpatient treatment, pneumonia, oxygen 324 ventilation, maternal death and delivery as well as stillbirth and neonatal death 325 following birth within 4 weeks of onset of COVID-19 was comparable to those 326 pregnancies after spontaneous conceptions. MAR was also not the primary risk factor 327 of adverse maternal or neonatal outcomes in pregnancies affected by Instead, other factors, such as maternal age, nulliparity, BMI >30 or multiple gestation 329 were the key drivers. However, MAR conceptions were associated with a descriptively 330 higher risks of gestational diabetes mellitus, peripartum hemorrhage, cervical 331 insufficiency, caesarean section, preterm birth and admission to NICU. 332 Several cohort studies report an association between COVID-19 in pregnancy and 334 substantial increased maternal and neonatal morbidity and mortality compared to 335 pregnant women without a diagnosis of COVID-19 10 . This concerns among others, 336 preeclampsia 3, 16, 17 , gestational hypertension 18 , maternal death 19 , stillbirth 19 , preterm 337 delivery 17, 20 and poor fetal growth 18, 21 . Risks are significantly higher in women with 338 comorbidities, e.g. diabetes mellitus, hypertension, obesity, and in older women [8] [9] [10] [11] . 339 First data was provided by the ESHRE COVID-19 Working Group. It collected 80 cases 341 from 32 countries, including 67 live births, 10 miscarriages, 2 stillbirths and 1 maternal 342 death 22 . One third of the reported cases had an asymptomatic infection while 31.4% 343 were treated in hospital. The authors concluded that infections in pregnancies after 344 MAR do not lead to a higher risk of adverse outcomes compared to those after 345 spontaneous conceptions. This is somehow in line with our results, which demonstrate 346 that the conception mode is not the primary risk factor for adverse obstetric and 347 neonatal complications in COVID-19 affected women. Particularly encouraging is also 348 the fact that comparable incidences were reported for complications directly associated 349 to COVID-19 (e.g. pneumonia, ICU admission, death). 350 Engels Calvo et al. reported a higher incidence for preeclampsia and caesarean 351 section in a cohort of symptomatic and asymptomatic SARS-CoV-2 infected women 352 after IVF compared to spontaneous pregnancies 23 . This is in contrast to our 353 observations for both outcomes. One main difference in the analysis is the adjustment 354 for important confounders, which included maternal age and clinical presentation in the 355 Spanish study 23 . In the cohort 36 out of 74 women conceived with donor oocytes which 356 was not a covariate in the multinomial logistic regression model but is one of several 357 well-known risk factors for preeclampsia [24] [25] [26] . In addition, the higher rate of caesarean 358 section in IVF patients than in spontaneous conceptions can particularly be explained, 359 by the increased rate of multiple births in the Spanish study. Our multinominal logistic 360 regression model included clinical characteristics (e.g. age, nulliparity, multiple 361 gestation) which significantly differed between MAR pregnancies and spontaneous 362 conceptions as well as known potential confounders (e.g. BMI >30) for the respective 363 outcome. The models developed suggest that the (still) elevated though not statistically 364 significant risk of MAR pregnancies would be further reduced if additional risk factors 365 were considered. In our cohort of spontaneous conceptions a significant number of 366 stillbirths (2.5%) occurred within 4 weeks of COVID-19 onset which is higher than the 367 expected stillbirth rate of around 0.4% in Germany and requires further attention. There 368 were none of these cases in the MAR group, which may be due to the low number of 369 registered pregnancies on the one hand and the possibly better monitoring and earlier 370 delivery of these per se high-risk pregnancies on the other. 371 Compared to spontaneous conceptions, adverse maternal and neonatal outcomes are 372 more common among conceptions after MAR independent of onset of COVID-19 in 373 pregnancy 27, 28 . The main driver for adverse outcomes is the higher risk of multiple 374 gestations in IVF 29 . As the field moves toward single embryo transfer and the rate of 375 multiple gestations is decreasing it also becomes clear that other factors, e.g. the 376 choice of a programmed protocol in frozen-thawed embryo transfer cycles 30-32 or 377 subfertility 33 itself make a significant contribution to a higher incidence of adverse 378 outcomes. Subfertile women more often carry risk factors for pregnancy complications, 379 e.g. higher age, obesity or metabolic alterations 12, 34, 35 . Aside from an expected higher 380 rate of multiple gestations we confirmed these observations in our infertile cohort, 381 which was older and more often obese. The rate of nulliparity, which is a risk factor for 382 hypertensive disorders of pregnancy 36 , was also higher. The results from our 383 multivariate models demonstrate that MAR itself is not the primary risk factor for 384 adverse outcomes of pregnancies affected by COVID-19, e.g. gestational diabetes 385 mellitus, peripartum hemorrhage, cervical insufficiency, caesarean section, preterm 386 birth and admission to NICU, but that these women enter pregnancy with a higher 387 baseline risk. In this context, maternal age, multiple gestation and BMI >30 were the 388 main predictors of obstetric and neonatal complications. 389 Our findings are of clinical importance during an ongoing pandemic with a so far 391 unknown end. They will help advise couples seeking fertility treatment and reassure 392 that not the fertility treatment itself will add to the potential risk of adverse maternal and 393 neonatal outcomes when affected by COVID-19. Nevertheless, our data clearly show 394 again that other, potentially avoidable, risk factors (e.g. multiple gestation) lead to a 395 poorer outcome. 396 In the present study, we took advantage of a well-supervised prospective registry study 398 using a standardized electronic clinical report form. Items specifically targeting MAR 399 were incorporated and linked to COVID-19 and obstetric and neonatal outcomes. A 400 particular strength of our study is the differentiation between methods of conception 401 such as IVF/ICSI and ovulation induction with or without IUI, which ensures the quality 402 of the data entries. Since asymptomatic cases most likely are considered 'incidental 403 SARS-CoV-2 infection' cases requiring hospitalization for other reasons we focused 404 our analysis on symptomatic women. In our experience this approach avoids including 405 women who present to the hospital primarily because of obstetric complications, e.g. 406 spontaneous preterm delivery, fetal growth restriction, or preeclampsia. 407 Our study has a variety of limitations, including relatively small sample size of MAR 408 pregnancies and therefore differing cohort sizes. These factors make it difficult to 409 reliably show statistical correlations. Nevertheless, our cohort reflects the reality in 410 Data are shown as mean  standard deviation or absolute/relative frequencies (percentage). 1 Fisher's exact test. 436 BARALDI E. Coronavirus infection in neonates: a systematic review. Archives of 437 Disease in Maternal Coronavirus Infections and Neonates Born to Mothers with SARS-440 COVID-19 during pregnancy: an 445 overview of maternal characteristics, clinical symptoms, maternal and 446 neonatal outcomes of 10,996 cases described in 15 countries Infant Outcomes Following 449 Maternal Infection With Severe Acute Respiratory Syndrome Coronavirus 2 450 (SARS-CoV-2): First Report From the Pregnancy Coronavirus Outcomes 451 Registry (PRIORITY) Study Empfehlung und Begründung 453 der STIKO zur Impfung gegen COVID-19 von Schwangeren und Stillenden CoV-2 Infection in Germany-the CRONOS Registry Update: Characteristics of 459 Symptomatic Women of Reproductive Age with Laboratory CoV-2 Infection by Pregnancy Status -United States Clinical manifestations, risk factors, 469 and maternal and perinatal outcomes of coronavirus disease 2019 in 470 pregnancy: living systematic review and meta-analysis Systematic Review and Meta-488 Analysis of COVID Maternal and Neonatal Clinical Features and Pregnancy 489 Outcomes to Association of Maternal Perinatal 497 SARS-CoV-2 Infection With Neonatal Outcomes During the COVID-19 The effect of maternal SARS-CoV-2 500 infection timing on birth outcomes: a retrospective multicentre cohort study Perinatal outcomes 506 of pregnancies resulting from assisted reproduction technology in SARS-CoV-507 2-infected women: a prospective observational study EL 513 DEMELLAWY D. Oocyte donation pregnancies and the risk of preeclampsia or 514 gestational hypertension: a systematic review and metaanalysis Obstetric outcome after in vitro fertilization with single or double embryo 521 transfer Increased Preeclampsia 527 Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the 528 Absence of a Corpus Luteum 536 ANDERSEN AN. Perinatal outcome of singleton siblings born after assisted 537 reproductive technology and spontaneous conception: Danish national sibling-538 cohort study Pregnancy and birth outcomes in couples with infertility with and 540 without assisted reproductive technology: with an emphasis on US population-541 based studies 543 Comparison of the pregnancy outcomes of subfertile women after infertility 544 treatment and in naturally conceived pregnancies Clinical risk factors for pre-547 eclampsia determined in early pregnancy: systematic review and meta-548 analysis of large cohort studies ICU, intensive care unit; MAR, medically assisted reproduction Combined endpoint is composed of the following: pneumonia, ICU admission, mortality Based on women, who delivered within 4 weeks after onset of COVID-19 symptoms and  24 weeks of gestation and is composed of the following endpoints: NICU admission, stillbirth and neonatal death. AUTHOR CONTRIBUTIONS Yvonne Ziert: Conceptualization, Methodology, Formal analysis, Visualization, Writing-Original draft preparation Data curation, Reviewing and Editing Clara Backes: Data curation, Reviewing and Editing Data curation, Reviewing and Editing Data curation, Reviewing and Editing Data curation, Reviewing and Editing Charlotte Engelbrecht: Data curation, Reviewing and Editing Data curation, Reviewing and Editing Antonella Iannaccone: Data curation, Reviewing and Editing Data curation, Reviewing and Editing Ioannis Kyvernitakis: Data curation, Reviewing and Editing Data curation, Reviewing and Editing Angela Lihs: Data curation, Reviewing and Editing Jula Manz: Data curation, Reviewing and Editing Christine Morfeld: Data curation, Reviewing and Editing Data curation, Reviewing and Editing Data curation, Reviewing and Editing Marina Sourouni: Data curation, Reviewing and Editing Constantin Sylvius von Kaisenberg: Data curation, Reviewing and Editing Silke Wegener: Data curation, Reviewing and Editing Ulrich Pecks: Conceptualization, Data curation, Methodology, Writing-Reviewing and Editing, Project administration, Funding acquisition Frauke von Versen-Höynck: Conceptualization, Supervision, Validation, Methodology, Writing-Original draft preparation, Reviewing and Editing without COVID-19 is not possible, so that the direct impact on outcomes vs. no SARS-CoV-2 infection) cannot be derived. 417 In summary, COVID-19 during pregnancy after MAR was not associated with a 419 substantial higher risk of COVID-19 associated adverse outcomes. However, maternal 420 and neonatal morbidity was increased compared to outcomes after spontaneous