The possibility of mother‐to‐fetus transmission of SARS‐CoV‐2, the cause of coronavirus
disease 2019 (COVID‐19), is currently a highly debated concept in perinatal medicine.
1
It has implications for the mother, fetus, and neonate, as well as for healthcare
providers present at the time of birth and caring for the child during the neonatal
period, including obstetricians, midwives, family doctors, anesthetists, pediatricians,
neonatologists, nurses, and respiratory therapists. At present the evidence for intrauterine
transmission from mother to fetus or intrapartum transmission from mother to the neonate
is sparse. There are limitations associated with sensitivity and specificity of diagnostic
tests used and classification of patients based on test results has also been questioned.
2
,
3
,
4
,
5
,
6
,
7
As a result, differing recommendations have emerged regarding which samples should
be collected and when, and how to distinguish infection from contamination,
8
,
9
,
10
,
11
making it difficult for clinicians “on the ground” to know which recommendations to
follow.
12
Additionally, a woman could be infected at any time during pregnancy and the impact
on the fetus when maternal infection occurs earlier in pregnancy may be different
than when it occurs in the two weeks prior to delivery. Infection during the first
or second trimester has the potential to cause miscarriage, preterm birth, birth defects
or possibly other features of congenital infection. In late gestation maternal infection,
we need to consider the possibility that the newborn could have active infection and
consequently at risk of adverse outcomes and also that the infant could pose a risk
to healthcare workers. Therefore, in this paper, we focus solely on newborn infants
whose mothers have documented or suspected COVID‐19 at the time of onset of labor
and delivery. Fortunately, the majority of neonates born to mothers with SARS‐CoV‐2
infection either do not become infected or exhibit mild symptoms at birth. However,
the fact that a significant proportion of maternal and neonatal infections can be
asymptomatic creates difficulty in ascertaining the disease burden on neonates and
the possibility of transmission to healthcare providers during resuscitation or admission
to a unit.
Unequivocal diagnosis of most fetal or neonatal infections is typically made by detection
of the organism in culture or by nucleic acid amplification tests that identify the
presence of the pathogen's RNA or DNA in amniotic fluid prior to onset of labor or
in properly collected fetal/neonatal blood or body fluid samples, or by histopathological
demonstration of the organism in fetal/neonatal tissues. Serology plays an important
role in diagnosis for certain congenital infections such as toxoplasmosis and syphilis.
The role of serology in the diagnosis of SARS‐CoV‐2 infection is still uncertain and
consequently it is difficult to envision how serology may contribute to newborn diagnosis
– especially when maternal infection occurs late in pregnancy and there may not have
been sufficient time for antibodies to be generated. Until there is a clear understanding
of appropriate diagnostic methods and interpretation of results for newborn infants,
a detailed classification system is likely to be helpful. Such a system could aid
healthcare practitioners in evaluating patients, determining appropriate infection
control measures, planning appropriate follow‐up for neonates and infants, allowing
large epidemiological studies and helping collaboration between international efforts
to learn about potential effects of maternal infections. In this paper, we present
such a classification.
In developing this system, we adopted an approach similar to Lebech et al
13
in creating five mutually exclusive categories of the likelihood of infection: (a)
confirmed, (b) probable, (c) possible, (d) unlikely, and (e) not infected. The first
and last categories (confirmed and not infected) are to be considered absolute and
confirmatory. The probable category denotes strong evidence of infection but a lack
of absolute proof. The possible category denotes evidence that is suggestive of infection
but is incomplete. The unlikely category applies when there is little support for
a diagnosis, but infection cannot be completely ruled out. Notably, a case may be
initially assigned to one category and later moved to another category as more information
is available. All five categories will not be applicable to all types of infections.
We have avoided terminology such as ‘vertical’ or ‘horizontal transmission’ and rather
developed a system that classifies transmission as congenital infection in intrauterine
death/ stillbirth, congenital infection in live born, neonatal infection acquired
intrapartum, or neonatal infection acquired postnatally,
14
which aligns with the actual pathological process as opposed to unknown directions
of transmission.
15
Our classification system is presented in Table 1. Currently, the classification system
takes into account the results of maternal testing, clinical status of the neonate
at birth, and results of neonatal testing. The criteria suggested are based on current
evidence. For the perinatal infection categories, it assumes that maternal status
is either definitive or probable and is in the vicinity of childbirth. These categories
may need to be modified as a clearer picture of the effects of SARS‐CoV‐2 infection
on developing fetus emerges.
Table 1
Classification System for Maternal‐Fetal‐Neonatal SARS‐CoV‐2 Infections
Patient
Category
Case Definition
Maternal infection during pregnancy
Symptomatic mother
Confirmed
Detection of the virus by PCR in a respiratory sample (nasopharyngeal/ nasal/broncho‐alveolar
lavage)
Possible
No testing done
Unlikely
a
No detection of the virus by PCR in a respiratory sample and no other cause identified
Not infected
a
No detection of the virus by PCR in a respiratory sample and other cause identified
Asymptomatic mother who has positive contact history
Confirmed
Detection of the virus by PCR in a respiratory sample
Unlikely
a
No detection of the virus by PCR in a single respiratory sample
Not infected
No detection of the virus by PCR in two respiratory samples taken at different time
points
Congenital infection with intrauterine fetal death/stillbirth
Fetal tissues or autopsy material
Confirmed
Detection of the virus by PCR from fetal or placental tissue or electron microscopic
detection of viral particle in tissue or viral growth in culture from fetal or placental
tissue
Possible
Detection of the virus by PCR in surface swab from fetus or placental swab on fetal
side
Unlikely
Detection of the virus by PCR in surface swab from maternal side of placenta only
and no testing done or no detection of the virus by PCR from fetal or placental tissue
Not infected
No detection of the virus by PCR or by electron microscopy in fetal tissue(s) on autopsy
Congenital infection in live born neonate
Clinical features of infection in newborn and mother with SARS‐CoV‐2 infection
Confirmed
Detection of the virus by PCR in umbilical cord blood
b
or neonatal blood collected within first 12 hours of birth or amniotic fluid collected
prior to rupture of membrane
c
Probable
Detection of the virus by PCR in nasopharyngeal swab at birth (collected after cleaning
baby) AND placental swab from fetal side of placenta in a neonate born via cesarean
section before rupture of membrane or placental tissue
Possible
a
No detection of the virus by PCR in nasopharyngeal swab at birth (collected after
cleaning baby) BUT presence of anti‐SARS‐CoV‐2 IgM antibodies in umbilical cord blood
or neonatal blood collected within first 12 hours of birth or placental tissue
Unlikely
No detection of the virus by PCR in nasopharyngeal swab at birth (collected after
cleaning baby) or umbilical cord blood, or neonatal blood collected within first 12
hours of birth or amniotic fluid AND antibody testing not done
Not infected
No detection of the virus by PCR in nasopharyngeal swab at birth (collected after
cleaning baby) or umbilical cord blood, or neonatal blood collected within first 12
hours of birth or amniotic fluid AND no anti‐SARS‐CoV‐2 IgM in umbilical cord blood
or neonatal blood collected within first 12 hours of birth
No clinical features of infection in newborn and mother with SARS‐CoV‐2 infection
Confirmed
Detection of the virus by PCR in cord blood
b
or neonatal blood collected within first 12 hours of birth
Probable
Detection of the virus by PCR in amniotic fluid collected prior to rupture of membrane
but no detection in umbilical cord blood or neonatal blood collected within first
12 hours of birth
Possible
Presence of anti‐SARS‐CoV‐2 IgM in umbilical cord blood or detection of the virus
by PCR in placental tissue but no detection of the virus by PCR in umbilical cord
blood or neonatal blood collected within first 12 hours of birth or amniotic fluid
Unlikely
No detection of the virus by PCR in cord blood or neonatal blood collected within
first 12 hours of birth or amniotic fluid collected prior to rupture of membrane
c
AND serology not done
Not infected
No detection of the virus by PCR in cord blood or neonatal blood collected within
first 12 hours of birth or amniotic fluid collected prior to rupture of membrane
c
AND no anti‐SARS‐CoV‐2 IgM in cord blood
Neonatal infection acquired intrapartum
Clinical features of infection in newborn and mother with SARS‐CoV‐2 infection
Confirmed
Detection of the virus by PCR in nasopharyngeal swab at birth (collected after cleaning
the baby) AND at 24‐48 hours of age AND alternate explanation for clinical features
excluded
Probable
Detection of the virus by PCR in nasopharyngeal swab at birth (collected after cleaning
baby) but not at 24‐48 hours of age AND alternate explanation for clinical features
excluded
Possible
No detection of the virus by PCR in nasopharyngeal swab at birth AND detection of
the virus by PCR in any of maternal vaginal/placental/cord/skin swab at birth AND
alternate explanation for clinical features excluded
Unlikely
No detection of the virus by PCR in nasopharyngeal swab at birth (collected after
cleaning baby) OR in any of maternal vaginal/placental/cord/neonatal nasopharyngeal/skin
swab at birth AND alternate explanation for clinical features not identified
Not infected
No detection of the virus by PCR in nasopharyngeal swab at birth (collected after
cleaning baby) OR in any of maternal vaginal/placental/cord/neonatal nasopharyngeal/skin
swab at birth AND alternate explanation for clinical features identified
No clinical features of infection in newborn and mother with SARS‐CoV‐2 infection
Confirmed
Detection of the virus by PCR in nasopharyngeal swab at birth (collected after cleaning
the baby) AND at 24‐48 hours of age
Possible
Detection of the virus by PCR in nasopharyngeal swab at birth (collected after cleaning
the baby) AND not at 24‐48 hours
Not infected
No detection of the virus by PCR in nasopharyngeal swab at birth AND no detection
of the virus by PCR in any of vaginal swab in mother/placental swab/skin/cord swab
at birth
Neonatal infection acquired postpartum
Clinical features of infection in newborn at ≥48 hours age (parent or caregiver may
or may not have SARS‐CoV‐2 infection or were not tested)
Confirmed
Detection of the virus by PCR in nasopharyngeal/rectal swab at ≥48 hours of birth
in a neonate whose respiratory sample tested negative by PCR at birth
Probable
Detection of the virus by PCR in nasopharyngeal/rectal swab at ≥48 hours of birth
in a neonate who was not tested at birth
Not infected
a
No detection of the virus by PCR in nasopharyngeal/rectal swab at ≥48 hours of birth
and other cause identified
This system is for maternal SARS‐CoV‐2 infection diagnosed prenatally or within 2‐3
weeks of birth.
Category definitions: Confirmed, Strong evidence of infection with confirmatory microbiology;
Probable, Strong evidence of infection but confirmatory microbiology lacking; Possible,
Evidence suggestive of infection but incomplete; Unlikely, Little support for diagnosis
but infection cannot be ruled out; Not infected, No evidence of infection.
Abbreviations: IgM, immunoglobulin M; PCR, polymerase chain reaction.
a
In highly suspicious cases, repeat sample may be needed due to test limitations.
b
Collected using sterile precaution and thorough cleaning of cord.
c
Includes sample taken at cesarean section performed before rupture of membranes.
John Wiley & Sons, Ltd
This article is being made freely available through PubMed Central as part of the
COVID-19 public health emergency response. It can be used for unrestricted research
re-use and analysis in any form or by any means with acknowledgement of the original
source, for the duration of the public health emergency.
We believe that this rapid, easy, and accessible system will also facilitate the development
of good clinical practice parameters and guidelines for managing neonates and ensuring
safety of families and healthcare providers. This classification system is dependent
on the availability of reliable diagnostic tests and emerging methods may lead to
its modification. We have not included testing of breast milk, maternal skin swabs,
or rectal swabs in the proposed classification as their roles in diagnosing maternal‐fetal‐neonatal
SARS‐CoV‐2 infections are unclear at this time. We expect refinements to this classification
system as additional data become available and further experience is gained.
CONFLICT OF INTEREST
All authors report no actual or potential conflicts of interest.