Assessing the Mother-to-infant Transmission Capabilities of COVID-19 Infection Among Pregnant Women in Ontario, Canada
Conditions: SARS-CoV-2, Covid19, Corona Virus Infection, Infectious Disease Transmission, Vertical, Pregnancy
Sponsor: Ottawa Hospital Research Institute

 
 
 
 
 
 
 
 
The COVID-19 Ontario Pregnancy Event (COPE) Network 
 
 
 
Study Title:   
 Assessing the mother-to-infant transmission capabilities of COVID-19 infection 
among pregnant women in Ontario, Canada 
 
 
Study Design:  
  
A multi-centre, prospective cohort study 
 
 
 
Date and Version No:  
  
15 November 2024, Version 11.0 
 
Sponsor/Coordinating Centre:  
Ottawa Hospital Research Institute (OHRI) 
 
 
Principal Investigator: 
  
Dr. Darine El-Chaâr 
 
  
Ottawa Hospital Research Institute, 613-737-8551 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
BORN 
Better Outcomes Registry and Network 
CHEO 
Children’s Hospital of Eastern Ontario 
CoV 
Coronaviruses 
COVID-19 
Coronavirus Disease 2019 
CTO 
Clinical Trials Ontario 
ddPCR 
Droplet digital PCR 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic acid 
H1N1 
Influenza A virus subtype H1N1 
HCP 
Healthcare professional 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
MERS 
Middle East Respiratory Syndrome 
MRN 
NSO 
Medical Record Number 
Newborn Screening Ontario 
OHRI 
Ottawa Hospital Research Institute 
PCR 
PHIPA 
Polymerase Chain Reaction 
Personal Health Information Privacy Act 
REB 
Research Ethics Board 
RNA 
Ribonucleic acid 
RT-qPCR or RT-PCR 
Real-time Fluorescent Quantitative PCR 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome coronavirus 2 
SCC 
Study Coordinating Centre 
SOP 
Study Standard Operating Procedures 
TCPS 2 
Tri-Council Policy Statement  2 
The COPE Network 
The COVID-19 Ontario Pregnancy Event (COPE) Network 
TOH 
The Ottawa Hospital 
VTM 
Viral Transport Media 
 
 
 
 

 
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1. BACKGROUND AND RATIONALE 
In response to the rapid global spread of cases and deaths, the World Health Organization (WHO) characterized 
the novel Coronavirus Disease 2019 (COVID19) outbreak as a global pandemic on March 11, 2020.1 Since the 
initial detection in Wuhan, China in December 2019, the number of COVID-19 cases has reached alarming rates 
and continues to rapidly increase. As of April 14th, 2020 there have been almost 1,844,863 confirmed cases and 
117,021 deaths globally.2 Currently there are no antivirals available and therapeutic treatments are limited; 
numerous clinical research investigations commencing imminently.  
1.1 Transmission, clinical presentation and diagnosis of COVID-19 
The name of virus responsible for the COVID-19 outbreak, Severe Acute Respiratory Syndrome (SARS) 
coronavirus 2 (SARS-CoV-2), was chosen based on its genetic similarities with the coronavirus that caused the 
SARS outbreak in 2003.3 The exact origin of the virus is currently unknown.4 Existing literature supports that the 
novel β-Coronavirus (termed SARS-CoV-2) belongs to the family Coronaviridae, from the order Nidovirales, which 
are all enveloped, non-segmented positive-sense RNA viruses which may cause illness in humans and animals.5,6 
The Coronaviridae family of viruses include causative viruses such as Severe Acute Respiratory Syndrome (SARS) 
and Middle Eastern Respiratory Syndrome (MERS).7 Much like influenza and other respiratory viruses, SARS-CoV-
2 is primarily transmitted person-to-person through close inhalation of respiratory droplets formed during a 
cough, sneeze or exhale.8 People without the disease can also acquire the infection by touching surfaces 
contaminated by SARS-CoV-2, defined as fomite transmission, then touching mucous membranes found in the 
face such as the eyes, nose, or mouth or by faecal transmission.9 Clinical manifestations among adults include 
fever, cough, myalgia, headache and shortness of breath.10 Severe cases can result in life threatening pneumonia 
and acute respiratory distress syndrome.11 The incubation period is estimated to be between 1 and 14 days, with 
97.5% of cases developing symptoms within 10.5 days (95% CI: 7.3‐15.3) of infection.12 Due to the small number 
of cases, it is not yet certain whether pregnancy and childbirth aggravate clinical presentation of COVID-19. 
1.2 Implications of COVID-19 infection for pregnant women 
Currently, there are limited data on the clinical characteristics of COVID-19 infection in pregnant women, 
including any adverse impacts on the developing fetus.8 Three early case-series reports from China reported a 
total of 31 pregnancies affected by COVID-19. One of the case series included nine pregnant women in Wuhan, 
all hospitalized with COVID-19 pneumonia during the third trimester of pregnancy. Clinical manifestations were 
similar to those reported among non-pregnant adults and included fever, cough, myalgia, malaise and sore 
throat. No women required mechanical ventilation, there were no maternal deaths and newborn Apgar scores 
at 1 and 5 minutes were high.13 Another case series included 13 COVID-19-infected pregnant women admitted 
to hospital in other areas of China. The study reported that three of the women were discharged from hospital 
with an ongoing pregnancy, while the other 10 women were delivered by cesarean, five urgently for fetal 
indications (three for fetal distress, one for premature rupture of membranes and one stillbirth).14 The third 
Chinese case series included 10 live born infants exposed to maternal COVID-19 infection while in utero and 
reported six preterm and two small-for-gestational-age infants. One infant born at 34 weeks’ gestation 
developed complications and died nine days after birth. Other clinical complications in the newborns were also 
reported, including prolonged hospitalization and respiratory distress.15  
 
More recently, Breslin et al. reported a case series which included 43 confirmed COVID-19 pregnant women that 
presented to an affiliated pair of New York City hospitals between March 13 and March 27, 2020.16  Disease 
severity among these pregnant women were similar to previous reports in non-pregnant individuals: 86% mild, 
9.3% severe and 4.7% critical. None of the neonates were tested positive for COVID-19 through PCR testing of 
nasopharyngeal swab samples. Although cases were initially identified through routine testing of symptomatic 
patients, New York City later initiated universal testing of all obstetrical admissions on March 22nd which 
additionally allowed for the capture of asymptomatic cases. Among the 43 cases reported, an unexpectedly large 
proportion of patients were initially asymptomatic (n=14) and presented a milder course of disease. Considering 
12 of these asymptomatic positive cases were identified through this new universal testing strategy, the authors 
advocate for universal testing of all pregnant women upon admission for delivery.16 Although reports of COVID-

 
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19 cases among newborns and young infants have been rare thus far, healthcare providers need to be extra 
vigilant when assessing newborn babies delivered by infected mothers, as early identification and isolation are 
imperative to virus control. 
 
1.3 Susceptibility to and severity of COVID-19 in pregnancy 
It is well-established that certain infections disproportionately impact pregnant women leading to increased 
rates of hospitalization and complications, likely due to physiological, physical, and immunological adaptations 
to pregnancy.17 Based on the lack of information currently available, we are unable to fully understand the risks 
and susceptibility of SARS-CoV-2 infection during pregnancy. Di Mascio et al. recently conducted a systematic 
review reporting pregnancy and perinatal outcomes of CoV spectrum infections during pregnancy.18 They found 
a total of 19 case series studies with 79 pregnancies affected by CoV infections: 41 pregnancies in the review 
(51.9%) were affected by COVID-19, 26 (32.9%) by SARS and 12 (15.2%) by MERS. Among the six studies reporting 
information on COVID-19 infection during pregnancy, preterm birth (<37 weeks’ gestation) was the most 
commonly reported adverse pregnancy outcome, occurring in 41.1% (95% CI: 25.6-57.6) of cases. These COVID-
19 infected pregnant women also had higher rates of miscarriage, pre-eclampsia, and perinatal death, compared 
to the general population. Whether these complications are a result of COVID-19 infection requires further 
investigation.  
 
1.4 The effects of previous outbreaks on pregnant women 
Coronaviruses (CoV) are a family of single-stranded RNA viruses, named for the appearance of crown-like 
proteins that project on the viral envelope.8  Apart from SARS-CoV-2, two other notable human strains of 
coronaviruses include SARS-CoV and Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV). The 
WHO reported 774 and 858 deaths associated with SAS-CoV19 and MERS-CoV20, respectively. Within a short time 
interval, the novel SARS-CoV-2 coronavirus has led to more deaths than these two previous strains combined.21   
Evidence of poor maternal and perinatal outcomes from several other outbreaks of viral respiratory illness over 
the past 20 years (i.e., 2009 A/H1N1 influenza pandemic,22–25 SARS26,27 and MERS8) indicate a need for enhanced 
surveillance of pregnant women during this current pandemic to determine whether COVID-19 poses any threat 
to maternal, fetal or infant heath. 
Although SARS and MERS are not identical to SARS-CoV-2, evidence on the effects of these viruses during 
pregnancy can help to guide obstetrical care and inform control measures.  
 
1.5 Testing for the presence of SARS-CoV-2 
According to the WHO, real-time fluorescent quantitative PCR (RT-qPCR or RT-PCR) is currently recognized as the 
gold standard for clinical detection of SARS-CoV-2.28 Still, RT-PCR is limited by the ability to detect the virus in the 
sample, and is especially problematic in cases with low viral load in the infected patient’s throat,29 resulting in a 
false negative rate currently reported to be between 30 to 33%.30,31 Numerous factors may influence RT-PCR 
testing results including sample collection and transportation, RNA extraction and degradation in storage, and 
effective functioning of the kit.32 Despite these limitations of RT-PCR, especially among low viral load specimens, 
all maternal and neonatal case reports published thus far have only tested for the presence of SARS-CoV-2 using 
RT-PCR.  
Droplet digital PCR (ddPCR), a biotechnological refinement of PCR, has shown improved sensitivity and accuracy 
for SARS-CoV-2 detection, especially for tests involving low viral load samples.28,33 Further, COVID-19 testing 
using ddPCR has demonstrated lower rates of false negatives and positives, compared to RT-PCR testing.34 Thus, 
ddPCR can be used in combination with RT-PCR to improve detection and robustness of estimates.  
 
1.6 Mother-to-infant transmission 
A crucial question that remains unanswered concerns whether SARS-CoV-2 can be transmitted by the infected 
pregnant mother to the infant during pregnancy, delivery or post-partum. Mother-to-infant transmission after 
maternal primary infection can occur during several time periods: intrauterine life via trans-placental viral 
transfer, delivery via ingestion or aspiration of vaginal secretions and postpartum through breastfeeding.35 Due 

 
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to the scarce evidence currently available, the mother-to-child transmission capabilities of SARS-CoV-2 are not 
yet fully understood.  
 
The small number of studies published thus far have not detected any evidence of vertical transmission from 
mother to fetus/infant13–15,36,37; however, several newborns have tested positive for SARS-CoV-2 with case 
studies purporting the potential for vertical transmission.38–41 Further assessment is warranted as nearly all of 
the published findings included women infected during the third trimester of pregnancy and delivered by 
cesarean section.42  
 
The placenta is a superior example of a pregnancy diary and typically undergoes morphological changes in 
response to environmental stimuli. A case report of one COVID-19 positive pregnancy found that all collected 
biological specimens, including a placenta sample, tested negative for SARS-CoV-2.43 Another review of three 
placentas found no morphological changes related to infection, though all of the women in this case series 
contracted the virus late in the third trimester and long after the placenta had undergone the bulk of its 
development.13 Furthermore, the role of the SARS-CoV-2 in various placental lesions (e.g., preeclampsia, 
abnormal placentation, intrauterine growth restriction [IUGR], and disruption of the chorionic membrane) has 
yet to be explored. 
 
In addition to the consideration of vertical transmission, mothers may pass SARS-CoV-2 onto their infants via 
breastmilk or combination feeding, similar to women infected with HIV-1. High levels of the HIV-1 virus in the 
mother increases the RNA viral load in maternal plasma and breastmilk which increases the rate of postnatal 
transmission by nearly 30%.44 The potential for neonatal transmission also includes the impact of aerosol 
production during the breastfeeding process which warrants additional evaluation.  As a result of the unclear 
and conflicting findings, we cannot rule out the potential for SARS-CoV-2 to permeate through infected 
breastmilk via consumption or inhalation to infect a nursing infant.  
 
In view of these uncertainties, we propose to undertake a study of COVID-19-infected pregnant women admitted 
to hospitals for birth across Ontario.  
 
2. AIM & STUDY OBJECTIVE 
The overall aim of this research is to generate clinical evidence regarding the impact of COVID-19 infection during 
pregnancy on maternal, fetal and infant health.  
 
Our objective will be to assess the mother-to-infant transmission potential of SARS-CoV-2 among pregnant 
women delivering at hospitals across Ontario with confirmed or suspected COVID-19. 
 
3. METHODOLOGY 
3.1 Study Design 
In order to assess the mother-to-infant and potential vertical transmission of SARS-CoV-2 infection in pregnant 
women, maternal and neonatal biological samples will be prospectively collected from women with confirmed 
or suspected COVID-19 at participating hospitals across Ontario.  Samples will be tested for the coronavirus 
serology and viral load. 
 
 
3.2 Study Setting 
The COVID-19 Ontario Pregnancy Event (COPE) Network is a provincial collaboration that was established in 
response to the pandemic, and currently consists of 12 participating hospitals across Ontario. This network, 
consisting of physicians and scientists from various institutions across the province, will help unite the resources 

 
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and expertise necessary to answer critical research questions related to SARS-CoV-2 infection during pregnancy.  
The current list of participating sites can be found in Section 6.1.  
 
3.3 Study Population 
The study population will consist of pregnant women with confirmed COVID-19 at any point during pregnancy 
or suspected COVID-19 at time of delivery (as identified at local hospital) , who will be delivering at a participating 
hospital within Ontario (current list of participating sites can be found in Section 6.1).  
 
3.4 Recruitment 
In this global emergency of COVID-19, information regarding the effects of infection during pregnancy are 
urgently required to help inform obstetrical recommendations, guidelines and practice. Given the low number 
of cases reported thus far, any pregnant woman admitted to a participating hospital with either suspected or 
confirmed COVID-19 infection, at any point during pregnancy, will be included in the study.  
 
To facilitate rapid generation of evidence, ensure complete capture of cases, and prevent unnecessary burden 
on healthcare professionals, we will use an alteration to the consent procedures. This study poses minimal risk 
to the participants, and given the current circumstances of a global pandemic, and the additional precautions to 
manage this population, an alternation to the consent requirements are justified to ensure that this research can 
be carried out.45 Using a verbal consent script, the healthcare provider will explain the research study and 
collection of samples to the participant. Verbal consent will be obtained at a pre-natal visit (in-person, virtual, or 
telephone), at the time of admission or prior to delivery. If the healthcare provider is unable to obtain verbal 
consent prior to delivery, sample collection will proceed and consent will be obtained prior to breastmilk and/or 
neonatal nasopharyngeal swab collection. At this time, consent for use of any previously collected samples will 
also be sought. 
 
3.5 Study Outcomes 
Outcomes for the study objective will be ascertained through the collection and testing of biological samples 
from the mother and/or infant. Specifically we will: 
1) 
Assess maternal nasopharyngeal or oropharyngeal swab, vaginal mucosa, ano-rectal swab, 
amniotic fluid, placenta (including subamniotic swab), breastmilk, cord blood and neonatal 
nasopharyngeal swab for RNA particles of coronavirus, by ddPCR. 
2) 
Assess maternal serum for anti-coronavirus antibodies, by immunoassay. 
3) 
Examine the impact of coronavirus on the neonate with respect to serology and viral load, in 
addition to placenta pathology findings and ddPCR. 
4) 
Assess vertical transmission and the effect of coronavirus through placental pathology 
examination using placental pathology synoptic report (Appendix 2). 
 
3.6 Data Collection 
3.6.1 Timing of Sample Collection 
Upon admission to labour and delivery, and prior to delivery wherever possible, the following maternal sample 
types will be collected: nasopharyngeal or oropharyngeal swab, peripheral blood, ano-rectal swab and vaginal 
mucosa collected through a vaginal swab. At delivery, wherenever possible, we will collect an amniotic fluid 
sample through direct syringe aspiration. Should the maternal biological samples not be able to be collected 
prior to or during delivery, samples may be collected post-delivery, prior to discharge.  
 
Immediately following delivery, we will collect cord blood and placenta samples (including submaniotic swab). 
Prior to discharge from the hospital, we will collect a neonatal nasopharyngeal swab sample (approximately 12-
24 hours post-birth) and a breastmilk sample (nearest to first lactation as possible). The timing of sample 

 
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collection is summarized in Table 2 presented below. Pathologists at each participating site will be requested to 
send the local placenta pathology report and slides (or scanned slides if slides are not feasible), collected as per 
standard of care.  
 
 
 
 
 
Table 2. Timing of biological sample collection 
Biological sample 
Timing of sample collection 
Prior to delivery 
At delivery 
Post delivery 
 
 
Maternal 
peripheral 
blood 
X 
 
 
Maternal nasopharyngeal 
or oropharyngeal swab 
X 
 
 
Maternal vaginal mucosa 
X 
(swab prior to rupture of 
membranes, if possible) 
 
 
Maternal ano-rectal swab 
X 
 
 
Amniotic fluid 
 
X 
 
 
Cord blood 
 
X (from blood 
gases) 
 
 
Placenta 
(includes 
subamniotic swab) 
 
 
X (ex vivo) 
 
Neonatal nasopharyngeal 
swab 
 
 
X (12-24 hours post-birth) 
 
 
 
 
 
 
 
 
 
 
Breastmilk sample 
 
 
 
X 
 
 
3.6.2 Sample Collection Process and Storage 
In order to reduce sample degradation and ascertain consistency between sites, samples will be collected and 
stored as per the Lab Manual following requirements for working with biohazardous materials and 
Transportation of Dangerous Goods (TDG) while abiding by local institutional obligations.  We will collect date of 
diagnosis for participants. Should the date of diagnosis not be available, we will use date of COVID-19 hospital 
admission as the estimated date of viral onset. Details of sample collection (e.g. date, time, methodology) will 
be documented on the Sample Collection Information Form. The Form will be used to review duration of infection 
where appropriate, and relationship to gestational age. Figure 1 presents the general study workflow related to 
all samples variants. Detailed sample collection procedures are outlined in the Lab Manual which is provided to 
each participating site.  
 
Samples collected at each participating site will be affixed with a patient label containing the patient name and 
medical record number [MRN]. At least one patient label will be shipped alongside samples to identify patient 
source of the samples. This will avoid the possibility of errors, and will also reduce the workload of the healthcare 
staff collecting the samples during a pandemic urgent situation. Further, the patient identifiers on these samples 
(patient name and MRN) will be used to link the clinical data to the BORN Ontario Birth Registry for supplemental 
pregnancy and demographic information upon participant consent. 

 
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Figure 1: Study Workflow 
 
3.6.3 Shipment of Samples 
All specimens will be transported as UN3373 Biological Substance Category B with appropriate packaging, 
labelling and documentation.  
 
Samples will be received by the Study Coordinating Centre (SCC), the Ottawa Hospital Research Institute (OHRI). 
The patient identifiers will be removed and a COPE Network unique study ID will be affixed and the study ID and 
participant information will be retained in a master log stored on the secure network at the OHRI. The SCC 
andauthorized personnel at participating sites will have access to their master file through the hospital shared 
drive, which is stored on the SCC hospital shared drive.  Once the samples are received and assigned a study ID, 
the samples will then be distributed to specific laboratories within Ottawa for analysis (see Table 3 for list of 
laboratories within Ottawa).  
 
Table 3. Laboratories receiving shipped samples 
Institution 
Name of laboratory 
Responsible personnel 
 
 
 
 
 
 
 
 
 
 
 
3.6.4 Data Linkage with the BORN Ontario Birth Registry 
The Better Outcomes Registry and Network (BORN) Ontario birth registry is a province-wide database, held and 
administered at the Children’s Hospital of Eastern Ontario (CHEO). The database captures all hospital births >500 
grams or >20 weeks’ gestation in the province. The routine data collection includes information on maternal 
demographics and health behaviours, pre-existing health problems, obstetric complications and birth outcomes. 
Data are collected from medical records, clinical forms, and patient interview when a woman is admitted to 
hospital to give birth.  
 
In response to the urgent public health crisis, BORN Ontario recently approved the collection of data for any 
cases of COVID-19 infected pregnant individuals admitted to Ontario hospitals between March 1, 2020 and 
March 1, 2021 (or until the pandemic is declared over and 40 weeks pass to allow collection from newly pregnant 
individuals who will continue their pregnancy) for the registry purpose of facilitating and improving care. This 

 
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includes information from Ontario hospitals on COVID-19 laboratory results, illness, and outcomes. In order to 
support the analysis and minimize hospital staff burden, we will utilize the data collected as part of this BORN 
Ontario COVID-19 initiative to provide clinical and demographic information on our participants. Please refer to 
Appendix 1 for a list of the data elements (COVID-19 Case Report Form) that will be collected through the study 
through the data linkage with BORN Ontario. 
 
BORN Ontario has policies for the secure transfer and retention of personal health information in accordance 
with Ontario’s health privacy legislation, the Personal Health Information Protection Act (PHIPA). The data and 
personal health information (PHI) collected by BORN is securely held, and all analyses will be performed within 
the BORN secure network environment. The data will be accessible only to the BORN Ontario Analyst who links 
and assembles the files, and to the study staff at the OHRI who will be responsible for conducting the analyses.  
 
COVID-19 data collection in BORN Ontario is currently optional for hospitals in the province. To ensure data 
completeness, some sites may complete the Case Report Form which will capture the same data that is collected 
in BORN Ontario and additional laboratory or clinical variables from routine clinical tests performed for COVID-
19 suspected or positive patients  Data in the CRF will be sent to the SCC securely and confidentially using a 
restricted-access database in SharePoint.  
 
Data from medical charts and sample analysis will be sent to BORN Ontario for linkage with the BORN Ontario 
data, including both the COVID-19 data and routinely collected perinatal and infant health data, upon participant 
consent.  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 

 
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3.9 COPE Network Site-Specific Placental Control Group 
Evidence has shown that placentas not complicated by SARS-CoV-2 may also display pathological changes, thus 
highlighting the importance of including a sufficient number and variety of controls that would allow valid 
comparisons to be made. Subgroup analyses based on mode of delivery (cesarean section vs. vaginal) as well as 
maternal comorbidities (including but not limited to: preeclampsia, chronic hypertension, gestational and 
chronic diabetes, IUGR) will necessitate having sufficient controls with these characteristics.   
 

 
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In addition to the control participants recruited at TOH, COPE Network Sites with capacity to collaborate will be 
asked to send slides and pathology reports of placentas that, to the best of their knowledge, were not 
complicated by SARS-CoV-2. The following clinical indications may warrant placental pathology examination and 
would provide valuable control comparisons:  
• 
Multiple births (both dichorionic and monochorionic) 
• 
Preterm birth (<34 weeks of gestation)  
• 
Placenta previa  
• 
Elective Cesarean section delivery  
• 
Clinical suspicion of abruption  
• 
Compromised clinical condition of neonate (intensive care admission, cord pH<7.0, Apgar score 
of less than 5 at 5 minutes, ventilatory assistance, hematocrit less than 25%, hydrops fetalis, 
congenital anomalies)  
• 
Fetal congenital anomalies  
• 
Maternal cancer history  
 
Placentas that were sent for pathology examination for reasons listed above, between April 2020 to July 
2021 may be included in the ‘pandemic’ control group, and placentas sent to pathology prior 
to March 2019 (i.e., a year prior to the beginning of the pandemic) will be included in the ‘pre-pandemic’ 
control group for the purpose of comparing COVID-19 placental pathology to background pathology during 
both time points. 
 
 
 
4. STATISTICAL METHODS 
4.1 Sample Size  
Due to the novel nature of this study, the anticipated sample size it not yet known and therefore a typical power 
calculation cannot be performed. As of March 2nd 2021, Ontario has a total of 303, 763 confirmed COVID-19 cases 
reported.50 Considering a total of approximately 13 major Ontario hospital sites will be involved in this study, our 
sample is anticipated to range anywhere from 150 to upwards of 200 participants. 
 
4.2 Analysis Plan 
4.2.1 Droplet Digital PCR  
We will follow manufacturer instructions of the Bio-Rad QX200 Droplet Digital PCR System. We will employ a 
multiplex strategy that will co-amplify the viral RNA coding for the N gene in the FAM channel using US CDC 
primers and probe (N1) and Hong Kong primers and probe (N).46,47 The Hex channel will contain primers and 
probe for the viral RNA coding for the E gene (E-Sarbeco) designed by the WHO48 and an internal RT and 
amplication control, RNAse P. This custom multiplex primer probe approach will promote high sensitivity in FAM 
with confirmatory specificity in Hex.49 In brief, the 20 uL reaction mixture comprises 5 uL of Supermix, 2 uL of 
reverse transcriptase, 1 uL of 300 mM DTT from One-Step RT-ddPCR Advanced Kit for Probes (Bio-Rad), 1 uL of 
mixture of primers and probe and 11 uL of RNA template. Each reaction mix was converted to droplets using the 
QX200 Droplet Generator (Bio-Rad,), transferred to a 96-well plate (Bio-Rad), heat sealed and amplified in a 
GeneAmp System 9700 thermal cycler (Applied Biosystems). The thermal cycling conditions were as follows: 45 
for 10 min (reverse transcription); 95 for 5 min; and 40 cycles of 95 for 15 sec, and 58 for 30 sec. The cycled plate 
was then transferred to the QX200 Droplet Reader (Bio-Rad) and analyzed using the QuantaSoft droplet reader 
software (Bio-Rad). Reactions containing more than 10,000 droplets were treated as effective and involved in 
data analysis.  
 
DdPCR data analysis will be performed using Quanta Soft analysis software v 1.7.4.0917 (Bio-Rad) which was 
included with the droplet reader and will be used to calculate the concentration of the target DNA sequences, 

 
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along with their Poisson-based 95 % confidence intervals.  The positive populations for each primer/probe are 
identified using positive and negative controls with single (i.e., not multiplexed) primer–probe sets. The 
concentration reported by QuantaSoft equals copies of template per microliter of the final 1× ddPCR reaction, 
which will also used in all the results. In addition, plots of linear regression will be conducted with GraphPad 
Prism 7.00, and probit analysis for lower limit of detection (LLoD) will be conducted with StatsDirect software 
v3.2.9. Lower limit of quantitation (LLoQ) and LLoD are defined as the lowest concentration at which 95 % and 
50 % of positive samples are detected, respectively.   
 
We will summarize the nucleic acid test results of all clinical samples collected (vaginal mucosa, amniotic fluid, 
cord blood, placenta, maternal nasopharyngeal/oropharyngeal and neonatal nasopharyngeal swab, breastmilk) 
to ascertain the possibility of intrauterine vertical transmission and post-partum feeding transmission. A positive 
test result reflects the presence of coronavirus in these clinical samples and will be indicative of possible mother-
to-infant transmission. Laboratory test results however will be considered within the context of clinical 
observations and epidemiological data when making the final diagnosis decisions. In addition, binary logistic 
regression will be conducted to further investigate the association between coronavirus in placenta and the 
presence of fetal/neonatal complications. 
 
4.2.2 Antibody Testing 
IgG, IgM and IgA antibodies to coronavirus will be evaluated in maternal and cord blood samples to assess 
whether patients (mothers and infants) have been recently exposed to the virus. IgG, IgM and IgA levels will be 
measured using a commercially available colorimetric enzyme-linked immunosorbent assay (ELISA), with all 
reagents prepared as per the manufacturer’s protocol. 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
  
 
 
 
 
  

 
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6. Addition of maternal and cord blood sample data from the INVIVO-P Biobank to the 
COPE Network dataset 
 
6.1 Rationale 
During the COVID-19 pandemic, many research initiatives sought to address important questions pertaining to 
the impact of SARS-CoV-2 infections in pregnancy.  A separate initiative conducted in Quebec, Canada included 
the collection of biological samples into the Integrated View of Immune Variation on Outcomes of Pregnancy 
(INVIVO-P) Biobank. INVIVO-P samples were collected from pregnant patients of the Centre Hospitalier 
Universitaire Sainte-Justine who had a confirmed SARS-CoV-2 infections in pregnancy. Maternal and cord blood 
samples from INVIVO-P were previously analyzed by Dr. Langlois at the University of Ottawa for assessment of 
SARS-CoV-2-specific antibodies (IgG, IgM, and IgA) against the spike (S), receptor binding domain (RBD) and 
nucleocapsid (N) proteins, as was done for COPE Network Samples.  
 
The study team is requesting the use existing data from the INVIVO-P dataset and COPE Network Study dataset 
to create a combined dataset from which to evaluate the perinatal transmission potential of SARS-CoV-2 and 
patterns of antibody transfer following prenatal infection. 
 
6.2 Data Sources 
• 
INVIVO-P Dataset: The INVIVO-P biobank included samples from 29 individuals with confirmed SARS-
CoV-2 infections who delivered at the Centre Hospitalier Universitaire Sainte-Justine.  The INVIVO-P 
dataset includes maternal, fetal and neonatal baseline characteristics and outcomes and COVID-19 

 
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disease characteristics. Also included are the findings from serological analysis of maternal and cord 
blood plasma samples.  
 
The INVIVO-P dataset will be combined with the COPE Network Study dataset to create a single dataset of 
maternal, fetal and newborn characteristics, outcomes and COVID-19 profiles including serology results. 
 
6.3 Contracts and ethics 
 INVIVO-P participants provided informed consent to the sharing of the data and samples for research. 
 
A material and data transfer agreement is already in place to between OHRI and Centre Hospitalier Universitaire 
Sainte-Justine to cover the transfer of de-identified data (MTA E8817).  
 
7. ETHICAL CONSIDERATIONS 
The study will be submitted for Research Ethics Board (REB) approval.  The study will be initiated by the OMNI 
Research Group upon written Research Ethics Board approval. The Site Investigator will obtain their site ethics 
approval and as applicable, ongoing renewals of the study protocol, protocol amendments, and all other relevant 
documents from their local REB. Copies of REB approvals must be forwarded to the Study Coordinating Center 
prior to the study initiation or continuation at the site. 
 
Revisions and/or amendments to the protocol must be documented and approved by the REB prior to 
implementation.  In addition, the study will be conducted in accordance with the protocol, ICH/GCP as applicable, 
and applicable local regulatory requirements and laws. 
 
7.1 Risks 
Participation in this study poses minimal risk to the participants or to their infants. There is no risk to the mother 
or infant to have placenta samples collected, as standard of care will be followed, placenta tissue will be sent for 
pathology for evaluation as per the existing procedure for maternal cases with infection.  If the study participant 
has decided to breastfeed, they will be asked to provide a breastmilk sample which can be collected by the 
mother in isolation, should they agree to.     
 
7.2 Benefits 
The results of this may be beneficial to the participants and their infants, as COVID-19 case ascertainment 
information may be made available by sample analysis.  While the results of sample analysis are research results, 
any results that may impact the care of a participants will be communicated to the staff and/or participant as 
they become available. 
 
The study may not be directly beneficial to the participants or their infants in the cases of confirmed maternal 
diagnosis or negative sample ascertainment in infants, however the results of this study will help to guide 
clinicians in determining best mode of delivery and feeding practices in future COVID-19 pregnancies.  
Clarification of vertical transmission and mother-to-infant feeding transmission will provide essential information 
to health care providers globally for care management in pregnancy. The results from this study will be shared 
with health care professionals including general practitioners, obstetricians and gynecologists, policy makers and 
health care planners. 
 
7.3 Data Management Plan 
A master file which will contain a comprehensive list of all participants, with their associated study ID, will be 
held by the SCC at the OHRI. This file will be updated as samples arrive from participating centres and will be 
used to assign study IDs and link collected samples to participants. This spreadsheet will be stored on internal 

 
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hospital shared drive with limited user access to the study team. Authorized personnel at participating sites will 
have access to their master file that is stored on the SCC hospital shared drive. 
All study data will be securely stored for a period of 10 years after study termination. After this period of time, 
all study documents will be securely destroyed and/or deleted from all hospital servers. 
A data sharing agreement will be in place prior to any study conduct. All data released from the OHRI or 
participating sites, including CHEO and the University of Ottawa, will be provided via electronic file transfer and 
will include only de-identified data, with the exception of data sent to BORN Ontario which is required to be 
identified for linkage purposes External data transfer will be conducted to comply with N2 SOPs on Secure File 
Transfers. Data received by the study investigators will be stored securely on encrypted, institutional servers. 
 
7.4 Confidentiality 
Privacy is a fundamental value, perceived by many as essential for the protection and promotion of human 
dignity (TCPS). Every effort should be made to protect the right of the participant for privacy according to 
jurisdictional regulations. All personal health information will be treated in a confidential manner and will be 
subject to all legal and regulatory legislation within the jurisdiction of the research participant regarding the 
collection, use and disclosure.  
 
Multiple measures will be put in place to protect participant confidentiality and privacy during the study. Prior 
to analysis, a unique patient study ID number will be generated that contains no identifiable information relating 
to the patient. A master list will be kept in a password-protected document stored on the OHRI secure network 
with restricted access available only to necessary study personnel.  Applicable government regulations, CHEO, 
The Ottawa Hospital and the University of Ottawa research policies and procedures will be followed.  
As with any multi-centre study conduct, sample and data transfer between participating institutions poses small 
confidentiality risks. Mitigiation strategies are in place including de-identification of data where possible, 
execution of a Sample/Data Sharing Agreement with each institution prior to study conduct, and ensuring that 
all study staff are compliant to local institutional and regulatory body privacy policies and data management 
processes.  
 
8. STUDY TEAM & TIMELINE 
8.1 Study Team 
The team at SCC will consist of researchers with clinical and epidemiological expertise in perinatal and infectious 
disease research. Dr. Darine El-Chaâr (Maternal-fetal Medicine Specialist at TOH with expertise in clinical and 
epidemiologic obstetric research) will lead both the COPE Network and this project.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 

 
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9. KNOWLEDGE TRANSLATION (KT) and SIGNIFICANCE 
9.1 Knowledge Translation 

 
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Results of interest will be disseminated to appropriate clinical care team. To reach health care professionals, who 
expect clear, action-oriented messaging delivered through their professional organizations, we intend to 
leverage our various knowledge user-based partnerships (e.g. BORN, SOGC) to permit local, provincial, and 
national disseminations of findings to be delivered through various modalities. In keeping with more traditional 
forms of knowledge translation, we plan to distribute the project results to HCP and researchers in the maternal 
and fetal health fields through local, national, and international presentations, CME activities, and publications.  
Where possible, we will have involved trainees present internally at their local institution supported by their local 
supervisor.   
 
9.2 Strengths and Significance 
As of April 15th, 2020, we have limited information on the clinical course and consequences of COVID-19 infection 
in pregnant women. Early case series reports from China show no evidence of severe adverse outcomes among 
infected pregnant women.13,14 13,14 There is currently insufficient evidence concerning possible vertical 
transmission from mother-to-infant. To date, there is no information from other countries in Europe where the 
burden of illness has been high. Additional data are rapidly needed to robustly evaluate the health of pregnant 
women and infants following COVID-19 infection during pregnancy. We expect the new evidence generated by 
our research to be of high interest and relevance for public health officials and health care professionals providing 
maternal and newborn care during this extraordinary global outbreak of a novel viral respiratory illness. 
 
Our decision to collect several varieties of clinical samples from the COVID-19 infected women will allow for a 
complete investigation of the maternal-infant transmission potential of the virus. In Ontario, many hospitals are 
fortunate to have an electronic hospital information system to identify cases in real-time without the 
requirement for any additional clinical or hospital resources. The ability to compile this clinical data on a 
provincial level is a strength, given that many case series reports during epidemic/pandemic time periods lack a 
large enough sample for clinical significance. Further, collaboration of sites will aid to facilitate rapid generation 
of evidence during the pandemic. We expect the new evidence generated by our research to be of high interest 
and relevance for public health officials and health care professionals providing maternal and newborn care 
during this extraordinary global outbreak of a novel viral respiratory illness. 
 
 

 
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 APPENDIX 1 BORN Ontario COVID-19 Case Report Form  
 
Please refer to the Case Report Form on the BORN Ontario website, as amended 
https://www.bornontario.ca/en/news/born-data-collection-on-covid-19.aspx

 
 
 
APPENDIX 2 Placenta Pathology Report