Maternal and perinatal outcomes in women with advanced maternal age affected by SARS-CoV-2 infection (Phase-2): The WAPM (World Association of Perinatal Medicine) Working Group on COVID-19

Objective

To elucidate the role of advanced maternal age (AMA) in determining the outcome of pregnancies complicated by SARS-CoV-2 infection.

Methods

Multinational cohort study included women with laboratory-confirmed SARS-CoV-2 infection from 76 centers in 27 different countries in Europe, United States, South America, Asia and Australia from 04 April 2020 till 28 October 2020. The primary outcome was a composite measure of maternal mortality and morbidity including admission to intensive care unit (ICU), use of mechanical ventilation (defined as intubation, need for continuous positive airway pressure, extra-corporeal membrane oxygenation), severe respiratory symptoms (including dyspnea and shortness of breath) or death.

Results

Eight hundred and eighty seven pregnant women were included in the study who were positive SARS-CoV-2 results by RT-PCR (reverse transcriptase-polymerase chain reaction) on their nasal and pharyngeal swab specimens (235 with and 652 with no AMA). The risk of composite adverse maternal outcome was higher in AMA group compared to that of under 35 years of age group, with an OR of 1.99 (95% CI 1.4–2.9; p=0.002). Likewise, women >35 years were also at higher risk of hospital admission (OR: 1.88, 95% CI 1.4–2.5; p<0.001), presence of severe respiratory symptoms (OR: 1.53, 95% CI 1.0–2.3; p=0.04) and/or admission to ICU (OR: 2.00, 95% CI 1.1–3.7; p=0.003); however, no difference was observed in terms of perinatal outcome risk.

Conclusion

Advanced maternal age is an independent risk factor for adverse maternal outcome in pregnancies complicated by SARS-CoV-2 infection. Accurate risk stratification of women presenting with suspected SARS-CoV-2 infection in pregnancy is warranted in order to identify a subset of women who may benefit from a personalized management, including elective hospitalization and/or prolonged surveillance in order to improve maternal outcome.

Keywords

SARS-CoV-2, COVID-19, Coronavirus, infection, pregnancy.

Introduction

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection spread towards the end of 2019 and is still a major public health problem. New cases of infection, hospitalization, admission to Intensive Care Unit (ICU) and death toll are increasing on a daily basis worldwide.[1,2] From the beginning of pandemic, pregnancy has been claimed to be potentially be associated with a higher burden of maternal mortality and morbidity compared to the general population, due to the peculiar cardiovascular and respiratory maternal adaptations occurring during pregnancy.[3,4]
Several cohort studies and systematic reviews evaluating the course of SARS-CoV-2 in pregnancy for maternal and perinatal outcomes have been published so far.[5–8] Despite the reassuring low rates of maternal-perinatal mortality and vertical transmission, in pregnancy, the risk of maternal admission to ICU appears to be higher, than that of age-matched non-pregnant women.[8–10]
The severity of SARS-CoV-2 infection in pregnancy has been reported to be associated with several risk factors. Among these, maternal age has been found to be an independent additional risk for adverse maternal outcome.[9] Still, the data for the relation between maternal age and outcome of pregnancies complicated by this infection is inconsistent. The aim of this study was to report the outcome of SARS-CoV-2 infection in pregnancies with AMA in a multinational cohort of pregnant women who were tested positive for SARS-CoV-2 infection.

Methods

This was a multinational, prospective cohort study involving pregnant women with a laboratory-confirmed SARS-CoV-2 infection, diagnosed from April the 4th, 2020 till October 28th, 2020. This study was designed as an open and web-based database study in 76 centers from 27 different countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Colombia, Czech Republic, Chile, Finland, Germany, Greece, Equatorial Guinea, India, Israel, Italy, Mexico, North Macedonia, Peru, Portugal, Republic of Kosovo, Romania, Russia, Serbia, Slovenia, Spain, Turkey, and The United States) by the World Association of Perinatal Medicine (WAPM) COVID-19 Study Group. The study was endorsed by WAPM. Ethical approval for the study was obtained from the Ethical Committee of Federico II University of Naples (nr.145/2020). The first phase of the study has already been published and comprised the data from April 4th, 2020 till June 1st, 2020.[4] Then, additional data (more details for fetal and neonatal outcome) was added and reevaluated by contributors for WAPM COVID-19 Study Phase-2 new database. Only confirmed cases with PCR were included in the evaluation. The cases with clinical diagnosis without positive PCR test were excluded. 
SARS-CoV-2 was diagnosed on the basis of The World Health Organization (WHO) interim guidance.[11] A confirmed case of SARS-CoV-2 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens.[11,12]
In the included centers, women were tested with RT-PCR of nasal and pharyngeal swab mostly because of having symptoms or history of exposure.
Neonates of mothers with positive SARS-CoV-2 results were usually tested within 24 hours after delivery by oro-nasopharyngeal swab RT-PCR. Data on recent exposure history, clinical symptoms or signs, laboratory findings, maternal and perinatal outcomes were collected. All medical records were anonymized and sent to the coordinator center at University of Naples Federico II (Naples, Italy) through the WAPM data platform. Data were entered into a computerized database and cross-checked. In case of missing data, requests for clarification were sent to the coordinator of each participating center.
The primary outcome was to compare the rates of maternal mortality and morbidity (admission to intensive care unit [ICU], use of mechanical ventilation [defined as intubation, need for continuous positive airway pressure, extra-corporeal membrane oxygenation], severe respiratory symptoms [including dyspnea and shortness of breath]). Secondary outcomes were a composite score of adverse perinatal outcome, including miscarriage, intrauterine death (IUD), neonatal death (NND), perinatal death (PND), admission to neonatal intensive care unit. Miscarriage was defined as pregnancy loss before 22 weeks of gestation, IUD as fetal loss at or after 22 weeks of gestation, while NND as death of a live-born infant within the first 28 days of life. PND was defined as IUD or NND.
Further details on criteria for maternal admission to ICU and neonatal admission to NICU are more extensively described elsewhere.[4]
All outcomes of AMA group were compared to that of non-AMA group. For the purpose of the analysis, AMA was defined as age >35 years. Subgroup analysis considering women >40 years was also performed. 
Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) v. 19.0 (IBM Inc., Armonk, NY, USA) and using Stata, version 13.1 (Stata Corp., College Station, TX, USA, 2014). Continuous variables were reported as means ± standard deviation (SD), while categorical variables as percentage. Univariate comparisons of dichotomous data were performed with the use of the Fisher’s exact test with continuity correction. Comparisons between groups were performed with the use of the Student’s t-test to analyze by assuming equal within-group variances for parametric data, and with the use of Mann-Whitney U tests for nonparametric data. Multivariate analysis was performed to evaluate potential predictors of the primary outcome. Logistic regression was reported as odds ratio (OR) and adjusted OR (aOR) with 95% confidence interval (CI). A p-value <0.05 was considered statistically significant.

Results

During the study period, 887 singleton viable pregnancies from 76 centers in 27 different countries, who were tested positive for SARS-CoV-2 by nasopharyngeal swab RT-PCR were included. Among these, 652 were <35 years old of age, 235>35 and 67>40 years. General characteristic of the study population is reported in Table 1.
There was no difference in mean gestational age at the diagnosis of the infection between AMA group and non-AMA group (25.4±8.1 vs 26.4±8.9, respectively; p=0.134). The incidence of nulliparity (44.7% vs 30.5%, p=0.001) and high-risk pregnancies (i.e. pre-existing or gestational medical conditions complicating the pregnancy) (40.4% vs 17.3%, p<0.0001) was higher in AMA group when compared to no-AMA group. When exploring the different clinical, radiologic and laboratory findings, women in AMA group were more likely to present with a symptomatic infection (64.3% vs 56.1%, p=0.039), while there was no difference in the occurrence of respiratory or non-respiratory symptoms, fever, lymphopenia, thrombocytopenia or increased serum LDH levels between the two study groups (Table 1).
The risk of composite adverse maternal outcome was higher in women with AMA compared to those <35 years (OR: 1.99, 95% CI 1.4–2.9; p<0.001) (Table 2). Likewise, women were also at higher risk of hospital admission (OR: 1.88, 95% CI 1.4–2.5; p<0.001), presence of severe respiratory symptoms (OR: 1.53, 95% CI 1.0–2.3; p=0.045), and admission to ICU (OR: 2.00, 95% CI 1.1–3.7; p=0.035) while there was no difference in the risk of adverse perinatal outcome between the two groups.
When restricting the analysis to women over 40 years of age, the risk of composite adverse maternal outcome was higher in women >40 compared to those <40 years of age (OR: 2.53, 95% CI 1.4–4.5; p=0.006). Likewise, women >40 had also a higher risk of in hospital admission (OR: 1.89, 95% CI 1.1–3.1; p=0.016), development of severe respiratory symptoms (OR: 2.28, 95% CI 1.2–4.2, p=0.012), admission to ICU (OR: 3.26, 95% CI 1.4–7.5; p=0.010) and/or need for invasive ventilation (OR: 4.18, 95% CI 1.6–11.2; p=0.009). At logistic regression analysis, AMA >35 (OR: 3.12, 95% CI 2.2–5.7; p=0.002), presence of a high-risk pregnancies (OR: 4.12, 95% CI 3.1–6.311; p=0.001) and nulliparity (OR: 3.11, 95% CI 2.9–6.2; p=0.001) were independently associated with adverse maternal outcome.

Discussion

This secondary analysis of the WAPM’s multinational cohort study on pregnant women with SARS-CoV-2 from 76 different centers, showed that risks of composite adverse maternal outcome, severe respiratory symptoms and admission to ICU are higher in pregnant women with AMA than youngers.
To our knowledge, this is the first study extensively assessing the role of AMA on the outcome of pregnancies complicated by SARS-CoV-2 infection. The WAPM study was one of the largest cohort of pregnant women with SARS-CoV-2 infection, with data collected from the beginning of the pandemic. Major strengths of the study are the enrollment of only confirmed SARS-CoV-2 cases, large sample size, the inclusion of both tertiary centers and community hospitals from many different countries and multitude of outcomes explored.
The major limitation was that the study population came mostly from women referred for suspected SARS-CoV-2 infection, due to symptoms or exposure, and consequently tested, thus leading to an intuitively lower percentage of asymptomatic women in the study cohort. Furthermore, different income level of countries and healthcare systems, and the heterogeneity in the management of both the mother and the fetus might have independently affected perinatal outcomes.
Women who delay childbearing are at increased risk of adverse pregnancy outcome, including miscarriage, fetal anomalies, pre-eclampsia, gestational diabetes and cesarean delivery compared to getting pregnant at younger age.[13,14] The reason for such association is likely to rely on the higher rate of chronic morbidities potentially affecting a pregnancy in advanced age.
In the present study, we reported that AMA represents an independent risk factor for adverse outcomes in pregnancies complicated by SARS-CoV-2 infection, irrespective of the presence of pregestational or gestational co-morbidities. The course of SARS-CoV-2 infection in pregnancy has been widely reported with a higher risk of maternal respiratory morbidity compared to non-pregnant counterparts, due to physiologic changes of pregnancy that might predispose them to a more severe clinical course.[3–9]
One of the largest systematic reviews recently published on this topic showed that pregnant women affected by COVID-19 were significantly more likely to need admission to ICU and invasive ventilation, compared to non-pregnant women of same reproductive age, and that increased maternal age, higher BMI, chronic hypertension and pre-existing diabetes were all significantly associated with a more severe course of SARS-CoV-2 infection in pregnancy.[9]
A likely explanation for the independent association between AMA and adverse pregnancy outcome may rely in the higher incidence of maternal chronic conditions in previous pregnancy of these women. However, the association between AMA and adverse maternal outcome persisted at logistic regression analysis, indicating an independent contribution of AMA in determining the outcome of pregnancies complicated by SARS-CoV-2 infection. Pregnancy induces marked changes in the respiratory and cardiovascular systems that are essential for meeting the increased metabolic demands of the mother and fetus. It is plausible that relative changes in the respiratory physiology with advancing age may predispose these women to a higher risk of developing pulmonary complications when affected by SARS-CoV-2 infection.
The findings from this study support an accurate risk stratification of pregnancies complicated by SARS-CoV-2 infection in order to maximize the maternal respiratory outcome. Pregnancies with co-morbidities and advanced age are at higher risk of developing complications.[15] A prolonged observation of women presenting with mild symptoms or elective hospital admission may represent a reasonable option in order to improve maternal outcome, although this assumption would require confirmation in randomized controlled trials.

Conclusion

Advanced maternal age represents an independent risk factor for adverse maternal outcome in pregnancies complicated by SARS-CoV-2 infection. Accurate risk stratification of women presenting with suspected SARS-CoV-2 infection in pregnancy is warranted in order to identify a subset of women who may benefit of a personalized management, including prolonged surveillance or elective hospitalization, in order to improve maternal outcomes.

The WAPM (The World Association of Perinatal Medicine) Working Group on COVID-19

It has been listed here accordingly to their contribution:
Francesco D’Antonio1, Cihat Şen2,3, Daniele Di Mascio4, Alberto Galindo5, Cecilia Villalain5, Ignacio Herraiz5, Resul Arısoy3, Ali Ovayolu6, Hasan Eroğlu6, Manuel Guerra Canales7, Subhashini Ladella8, Liviu Cojocaru9, Özhan Turan9, Şifa Turan9, Eran Hadar10, Noa A. Brzezinski-Sinai10, Sarah Dollinger10, Ozlem Uyanıklar11, Sakine Rahimli Ocakoğlu11, Zeliha Atak11, Tanja Premru-Srsen12, Lilijana Kornhauser-Cerar12, Mirjam Dru‰koviã12, Liana Ples13, Reyhan Gündüz14, Elif Ağaçayak14, Javier Alfonso Schvartzman15, Mercedes Negri Malbran15, Marco Liberati1, Francesca Di Sebastiano1, Ludovica Oronzi1, Chiara Cerra1, Danilo Buca1, Angelo Cagnacci16, Arianna Ramone16, Fabio Barra16, Andrea Carosso17, Chiara Benedetto17, Stefano Cosma17, Axelle Pintiaux18, Caroline Daelemans18, Elena Costa18, Ayşegül Özel19, Murat Muhçu19, Jesús S Jimenez Lopez20, Clara Alvarado21, Anna Luengo Piqueras22, Dolores Esteban Oliva22, Giovanni Battista Luca Schera23, Nicola Volpe23, Tiziana Frusca23, Igor Samardjiski24, Slagjana Simeonova24, Irena Aleksioska Papestiev24, Javier Hojman25, Ilgın Türkçüoğlu26, Antonella Cromi27, Antonio Simone Laganà27, Fabio Ghezzi27, Angelo Sirico28, Alessandra Familiari28, Giovanni Scambia28, Zulfiya Khodjaeva Gennady T. Sukhikh29, Ksenia A. Gorina29, Renato Augusto Moreira de Sa30, Mariana Vaz30, Otto Henrique May Feuerschuette31, Anna Nunzia Della Gatta32, Aly Youssef32, Gaetana Di Donna32, Alicia Martinez-Varea33, Gabriela Loscalzo33, José Morales Roselló33, Vedran Stefanovic34, Irmeli Nupponen34, Kaisa Nelskylä34, Rodrigo Ayala35, Rebeca Garrote Molpeceres36, Asunción Pino Vázquez36, Fabrizio Sandri37, Ilaria Cataneo37, Marinella Lenzi37, Esra Tuştaş Haberal38, Erasmo Huertas39, Amadeo Sanchez39, Pedro Arango39, Amanda Bermejo40, María Monica Gonzalez Alcantara41, Gökhan Göynümer42, Erhan Okuyan43, Ciuhodaru Madalina44, Ana Concheiro Guisan45, Alejandra Martínez Schulte46, Valentina Esposito47, Valentina De Robertis48, Snezana Zdjelar49, Milan Lackovic49, Sladjana Mihajlovic49, Nelly Jekova50, Gabriele Saccone51, Mehmet Musa Aslan52, Maria Carmela Di Dedda53, Maisuri Chalid54, Jose Enrique Moros Canache55, George Daskalakis56, Panos Antsaklis56, Enrique Criado Vega57, Elisa Cueto58, Chiara Taccaliti59, Alicia Yeliz Aykanat60, Şerife Özlem Genç61, Bernd Froessler62, Petya Angelova Radulova63, Danila Morano64, Beatrice Bianchi64, Maria Giulia Lombana Marino64, Gabriella Meccariello65, Bindu Rohatgi66, Antonio Schiattarella67, Maddalena Morlando67, Nicola Colacurci67, Andrea Villasco68, Nicoletta Biglia68, Ana Luiza Santos Marques69, Alessandra Gatti70, Daniela Luvero70, Roberto Angioli70, Alejandro Pittaro71, Albert Lila72, Blanka Zlatohlávková73
1Centre for High-Risk Pregnancy and Fetal Care, Department of Obstetrics and Gynecology, University of Chieti, Chieti, Italy
2Perinatal Medicine Foundation, Istanbul, Turkey
3Department of Perinatal Medicine, Memorial Hospital, Istanbul, Turkey
4Department of Maternal and Child Health and Urological Sciences, Sapienza University of Rome, Rome, Italy
5Fetal Medicine Unit, Maternal and Child Health and Development Network, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain
6Cengiz Gökçek Women’s and Children’s Hospital, Gaziantep, Turkey
7Hospital Clinico San Jose, Santiago de Chile, Chile
8Community Medical Centers, UCSF Fresno, Fresno, CA, USA
9Department of Obstetrics, Gynecology and Reproductive Science, University of Maryland Medical Center, Baltimore, MD, USA
10Helen Schneider Hospital for Women, Rabin Medical Center, Petach-Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
11Bursa City Hospital, Bursa, Turkey
12Department of Perinatology, University Medical Center, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
13Department of Obstetrics and Gynecology, Saint John Hospital, UMF Carol Davila Bucharest, Bucharest, Romania
14Department of Obstetrics and Gynecology, Dicle University, Diyarbakır, Turkey
15Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”, Buenos Aires, Argentina
16Academic Unit of Obstetrics and Gynaecology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
17Department of Obstetrics and Gynecology, Sant’Anna Hospital, University of Turin, Turin, Italy
18Department of Obstetrics and Gynecology, Hospital Erasme, Cliniques Universitaires de Bruxells, Brussels, Belgium
19Ümraniye Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
20Hospital Regional Universitario de Málaga, Malaga, Spain
21Clínica del Country, Bogotá, Colombia
22Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
23Department of Obstetrics and Gynecology, University of Parma, Parma, Italy
24University Clinic of Obstetrics and Gynecology, Skopje, North Macedonia
25División Obstetricia, Hospital de Clínicas “José de San Martín”, Buenos Aires, Argentina
26Department of Obstetrics and Gynecology, School of Medicine, SANKO University, Gaziantep, Turkey
27Department of Obstetrics and Gynecology, “Filippo Del Ponte” Hospital, University of Insubria, Varese, Italy
28Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario A Gemelli IRCCS - Università Cattolica del Sacro Cuore, Rome, Italy
29National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
30Assistência Obstétrica do Grupo Perinatal, Rio de Janeiro, Brazil
31Departamento de Ginecologia e Obstetrícia, Hospital Universitário Polydoro Ernani, Santiago, Brazil
32Department of Obstetrics and Gynecology, University of Bologna, Sant’Orsola Malpighi University Hospital, Bologna, Italy
33Servicio de Obstetricia y Ginecología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
34Department of Obstetrics and Gynecology, Neonatology and Intensive Care, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
35ABC Medical Center, Mexico City, Mexico
36University Clinic Hospital of Valladolid, Valladolid, Spain
37Unit of Obstetrics and Gynecology, Ospedale Maggiore, Bologna, Italy
38Hisar Intercontinental Hospital, İstanbul, Turkey
39Instituto Nacional Materno Perinatal, Lima, Peru
40Hospital Universitario de Móstoles, Mostoles, Spain
41Hospital Juan A. Fernandez, Buenos Aires, Argentina
42Department of Perinatology, Faculty of Medicine, Düzce University, Düzce, Turkey
43Batman Maternity and Child Health Hospital, Batman, Turkey
44Universitatea de Medicin? şi Farmacie Grigore T. Popa Iaşi, Iaşi, Romania
45Alvaro Cunqueiro University Hospital of Vigo, Vigo, Spain
46Hospital Angeles Lomas, Mexico City, Mexico
47University of Milan, Milan, Italy
48Fetal Medicine Unit, Di Venere Hospital, Bari, Italy
49KBC Dr Dragisa Misovic - Dedinje, Belgrade, Serbia
50Department of Neonatology, Obstetrics and Gynecology, University Hospital, Sofia, Bulgaria
51Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
52Sakarya University Training and Research Hospital, Sakarya, Turkey
53Department Gynecology and Obstetrics, Fornaroli Hospital, Magenta, Italy
54Department of Obstetrics and Gynecology, Hasanuddin University, Makassar, Indonesia
55Departamento de Ginecologia y Obstetricia, Centro Medico La Paz de Bata, Bata, Ecuatorial Guinea
56Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
57Division of Neonatology, Hospital Clínico “San Carlos”, Madrid, Spain
58Hospital Virgen de la Luz, Cuenca, Spain
59Ospedale Generale Regionale “F. Miulli”, Acquaviva delle Fonti, Italy
60Department of Obstetrics and Gynecology, Istanbul University-Cerrahpaşa Medical School, Istanbul, Turkey
61Karaman Public Hospital, Karaman, Turkey
62Department of Anaesthesia, Lyell McEwin Hospital, Adelaide, Australia
63University Hospital of Obstetrics and Gynecology, Sofia, Bulgaria
64Department of Medical Sciences, Section of Obstetrics and Gynecology, Azienda Ospedaliera-Universitaria Sant' Anna, University of Ferrara, Ferrara, Italy
65Ostetricia e Ginecologia Universitaria - Ospedale S. Anna e S. Sebastiano, Caserta, Italy
66Sulochana Clinic, Kolkata, India
67Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy
68Academic Division of Obstetrics and Gynecology, Mauriziano Umberto I Hospital, University of Turin, Turin, Italy
69Instituto de MedFetal e Diagnóstico por Imagem do Amazonas, Manaus, Brazil
70Campus Bio Medico, University of Rome, Rome, Italy
71Hospital Raul F. Larcade, Buenos Aires, Argentina
72Regional Hospital Gjakova, Kosovo, Republic of Kosovo
73Department of Obstetrics and Gynecology, Division of Neonatology, General Hospital in Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic

Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards: The authors stated that the standards regarding research and publication ethics, the Personal Data Protection Law and the copyright regulations applicable to intellectual and artistic works are complied with and there is no conflict of interest.

References

1. Perlman S. Another decade, another Coronavirus. N Engl J Med 2020;382:760–2. [PubMed] [CrossRef] 


2. World Health Organization (WHO). WHO Coronavirus (COVID-19) dashboard. [Internet]. Geneva: WHO. [cited 2020 October 26]. Available from: https://covid19.who.int


3. Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, et al. Outcome of Coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM 2020;2:100107. [PubMed] [CrossRef] 


4. WAPM (World Association of Perinatal Medicine) Working Group on COVID-19. Maternal and perinatal outcomes of pregnant women with SARS-COV-2 infection. Ultrasound Obstet Gynecol 2021;57:232–42. [PubMed] [CrossRef] 


5. Di Mascio D, Sen C, Saccone G, Galindo A, Grünebaum A, Yoshimatsu J, et al. Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19. J Perinat Med 2020;48:950–8. [PubMed] [CrossRef] 


6. Huntley BJF, Huntley ES, Di Mascio D, Chen T, Berghella V, Chauhan SP. Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by severe acute respiratory syndrome Coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol 2020;136:303–12. [PubMed] [CrossRef] 


7. Dubey P, Reddy SY, Manuel S, Dwivedi AK. Maternal and neonatal characteristics and outcomes among COVID-19 infected women: an updated systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2020;252:490–501. [PubMed] [CrossRef] 


8. Juan J, Gil MM, Rong Z, Zhang Y, Yang H, Poon LC. Effect of coronavirus disease 2019 (COVID-19) on maternal, perinatal and neonatal outcome: systematic review. Ultrasound Obstet Gynecol. 2020;56:15–27. [PubMed] [CrossRef] 


9. Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ 2020;370:m3320. [PubMed] [CrossRef] 


10. Petrilli CM, Jones SA, Yang J, Rajagopalan H, O’Donnell L, Chernyak Y, et al.; for PregCOV-19 Living Systematic Review Consortium. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ 2020; 369:m1966. [PubMed] [CrossRef] 


11. World Health Organization (WHO). Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) is suspected: interim guidance, 13 March 2020. Geneva: WHO; 2020.


12. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al.; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of Coronavirus disease 2019 in China. N Engl J Med 2020;382:1708–20. [PubMed] [CrossRef] 


13. Fitzpatrick KE, Tuffnell D, Kurinczuk JJ, Knight M. Pregnancy at very advanced maternal age: a UK population-based cohort study. BJOG 2017;124:1097–106. [PubMed] [CrossRef] 


14. Waldenström U, Cnattingius S, Vixner L, Norman M. Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study. BJOG 2017;124:1235–44. [PubMed] [CrossRef] 


15. D’Antonio F, Sen C, D, Mascio D, Galindo A, Villalain C, Herraiz I, et al.; WAPM Working Group on COVID-19. Maternal and perinatal outcomes in high vs low risk-pregnancies affected by SARS-COV-2 infection (Phase-2): The WAPM (World Association of Perinatal Medicine) working group on COVID-19. Am J Obstet Gynecol MFM 2021;100329. doi:10.1016/j.ajogmf.2021.100329  [PubMed] [CrossRef] 

	File/Dsecription
	Table 1. Comparison of different characteristics in pregnant women with those with no advanced age.
	Table 2. Comparison of the different maternal and fetal outcomes in pregnant women with those without advanced age.