Alzamora et al recently described an interesting report of a neonate born to a mother
with severe novel coronavirus 2019 disease (COVID-19) by cesarean section. The infant
tested positive for real-time polymerase chain reaction (RT-PCR) for severe acute
respiratory syndrome-coronavirus-2 (SARS-CoV-2) 16 hours after delivery.[1] During the period of limited 5-day follow-up, this baby did not show an increased
antibody titer (immunoglobulin [Ig]-M or IgG). Similar positive cases of suspected
neonatal SARS-CoV-2 infection during the first 2 postnatal days have been reported.[2] While these patients appear to have acquired infection either by intrauterine or
intrapartum transmission, establishment of clear definitions for such transmission
is warranted ([Fig. 1]).
Fig. 1 Peripartum “vertical” transmission of SARS-CoV-2 infection: maternal COVID-19, timeline
of infectivity, symptom duration and antibody titers with modes of transmission and
neonatal status are shown. The inset graph shows the period of positive testing with
nasopharyngeal RT-PCR for SARS-CoV-2 in the blue shaded area. The duration of symptoms
is shown by the black bar on the horizontal axis. The titers of IgM (green line) and
IgG (red line) in typical patients as described in Li et al[16] are shown. Potential methods of intrauterine, intrapartum and immediate postnatal
transmission are depicted in the left panel. Neonatal testing status with nasopharyngeal
RT-PCR and serology titers are shown in the pink box for intrauterine transmission,
the orange box for intrapartum or immediate postnatal transmission, the yellow box
for superficial contamination/transient viremia and the green box for no evidence
of neonatal infection. COVID-19, novel coronavirus disease 2019; Ig, immunoglobulin;
RT-PCR, real-time polymerase chain reaction; SARS CoV-2, severe acute respiratory
syndrome-coronavirus-2.
Intrauterine transmission of SARS-CoV-2 has not been convincingly reported to date.[3] There is limited information available on intrauterine infection earlier in pregnancy
with resolution of maternal infection prior to the time of delivery; SARS-CoV-2 is
not known to cause chronic infection, therefore neonatal infection is not likely to
be active at delivery in this situation, and confirming transmission early in pregnancy
will be challenging in the absence of either a phenotype such as congenital Zika or
rubella syndrome or a pattern of increased numbers of miscarriages. Recently, miscarriage
secondary to SARS-CoV-2 infection at 34 weeks[4] and at 19 weeks of gestation with positive SARS-CoV-2 through RT-PCR from maternal
nasopharynx, placental submembrane, and cotyledon have been reported.[5]
When maternal infection occurs within 14 days before delivery, there is a theoretical
risk of intrauterine transmission, since infection may result in viremia potentially
leading to infection of the fetus through a disruption in the placental interface
or viral particles in the amniotic fluid ([Fig. 1]). Although many studies have not detected SARS-CoV-2 in amniotic fluid by RT-PCR,[3]
[6]
[7]
[8]
[9] a recently published report from Iran described the detection of SARS-CoV-2 in an
amniotic fluid sample obtained during cesarean section from a mother with severe COVID-19
who subsequently died.[10] The RT-PCR on the nasal and throat swabs in neonate after delivery were negative,
but the second test 24 hours later was positive.
Intrapartum or early postnatal infection could occur through exposure of the delivering
neonate to infected maternal blood or secretions. Both may be considered as examples
of “vertical” transmission. It is important to differentiate mechanisms of potential
maternal-fetal transmission, if possible, as timing and route of infection may affect
clinical outcomes. In addition, investigational therapies may be found to decrease
or eliminate intrauterine transmission.[11]
We start with several underlying assumptions ([Fig. 1]) as follows: (1) the incubation period is 1 to 14 days[12]
[13]; (2) intrauterine infection may potentially occur transplacentally via blood, or
via transmission through swallowed or aspirated amniotic fluid; (3) maternal viremia
is unlikely during the incubation period >48 hours before symptom onset and the likelihood
of positive SARS-CoV-2 through RT-PCR in blood samples is low (< 1%) in COVID-19 patients[9]; (4) intrapartum transmission may potentially occur due to exposure to maternal
blood, vaginal secretions, or feces; (5) early postnatal infection may occur via the
respiratory route or due to direct contact with the infected mother or other caretakers,
or potential transmission through breast milk (however, to date we are not aware of
any reports of viral presence in breast milk); and (6) SARS-CoV-2 virus may be transiently
detected for up to 24 hours after birth due to superficial contamination or transient
viremia (similar to HIV). It is possible that a similar situation may occur following
nasal or oral suctioning and/or intubation during neonatal resuscitation in the delivery
room leading to introduction or aspiration of maternal secretions into infant's airway.
In these cases, the infant's nasopharyngeal swab may be positive for RT-PCR on the
first day, but subsequent swabs might be negative and the infant's blood samples would
not show a positive IgM titer (with or without maternal IgG antibodies).
With these assumptions in mind, we propose the following definitions of vertical SARS-CoV-2
transmission ([Table 1]).
Table 1
Definitions of vertical SARS-CoV-2 transmission
|
Intrauterine transmission of SARS-CoV-2 during the peripartum period has likely occurred (even if the neonate
is asymptomatic) if there is evidence of both early exposure and persistence, that
is, at least one item in each of the following three categories:
|
-
The mother is positive for SARS-CoV-2 between 14 days prior to birth and 2 days after
birth.
-
Early exposure: the virus is detected in any of the following:
-
A swab of the neonatal respiratory tract (nasopharynx, oropharynx, or saliva) in the
first 24 hours of life.
-
Amniotic fluid.
-
Umbilical cord blood.
-
A neonatal blood sample in the first 24 hours of life.
-
Persistence: either of the following:
-
A swab of the neonatal respiratory tract (nasopharynx, oropharynx, or saliva) is positive
after 24 hours of postnatal life.
-
The neonate has a positive SARS-CoV-2 IgM assay in the first 7 days of postnatal life.
|
|
Intrapartum or early postnatal transmission of SARS-CoV-2 has likely occurred (even if the neonate is asymptomatic) if there
is lack of evidence of in utero exposure and evidence of intrapartum or early postnatal
transmission, that is, at least one item in each of the following three categories:
|
-
The mother or another person in close contact with the baby is positive for SARS-CoV-2
between 14 days prior to birth and 2 days after birth.
-
Early exposure: a swab of the neonatal respiratory tract (nasopharynx, oropharynx,
or saliva) in the first 24 hours of life is negative.
-
Persistence: either of the following:
-
A swab of the neonatal respiratory tract (nasopharynx, oropharynx, or saliva) is positive
between 24 hours and 2 weeks of postnatal life.
-
The neonate has a positive SARS-CoV-2 IgM assay in the first 2 to 3 weeks of postnatal
life.
|
|
Superficial exposure to SARS-CoV-2 or transient viremia has likely occurred if the neonate is asymptomatic and at least one item in each
of the following three categories is met:
|
-
The mother is positive for SARS-CoV-2 between 14 days prior to birth and 2 days after
birth.
-
Early exposure: the virus is detected in any of the following:
-
A swab of the neonatal respiratory tract (nasopharynx, oropharynx, or saliva) in the
first 24 hours of life.
-
Amniotic fluid.
-
Umbilical cord blood.
-
A neonatal blood sample in the first 24 hours of life.
-
No evidence of persistence or immune response.
-
A swab of the neonatal respiratory tract (nasopharynx, oropharynx, or saliva) is negative
between 24 and 48 hours of life.
-
The neonate has a negative SARS-CoV-2 IgM assay in the first 2 to 3 weeks of postnatal
life.
|
|
Recommendation
|
|
As a minimum, a swab of the respiratory tract in the first and second 24-hour periods
and a SARS-CoV-2 IgM assay at days 5 to 14 after birth; if initial SARS-CoV-2 IgM
is negative, this may be repeated at 2 to 3 weeks of age.
|
There are several limitations to the above definition. It is possible for a baby to
meet one or more of the early exposure criteria due to contamination with maternal
infectious material or transient viremia, and one or more of the persistence criteria
due to intrapartum or early postpartum infection with a very short incubation period.
In addition, IgM antibodies may be generated as soon as 3 days after symptom onset[14]
[15] but may take as long as 2 to 4 weeks. [15] Therefore, intrauterine transmission occurring late in pregnancy might yield a false-negative
result in the first 7 days of life, while intrapartum infection could potentially
yield a positive result by day 7.[17] Finally, our current understanding of IgM dynamics is based on adult data and will
be subject to revisiting once neonatal IgM data are available. This definition will
likely have decreased sensitivity for prematurely born neonates with more limited
capability for IgM production.[18] Extending the postnatal period for IgM positivity will increase sensitivity at the
cost of decreasing specificity for intrauterine infection as detection of postnatal
infection is possible after day 7 of life. Finally, the reliability of IgM assays
under development is not well known, sensitivities are not clear, nor is the rate
of cross-reactivities or false-positive rates. We do not see a role for IgG testing
in this situation. Distinguishing between intrapartum and early postnatal transmission
of SARS-CoV-2 presents a challenge given the variability in the incubation period
and the possibility that asymptomatic family members or health care providers may
be shedding the virus at the time of delivery.
This initial definition will likely need refinement but has value for standardizing
communications and for clarifying the term “vertical” transmission in distinguishing
when possible between intrauterine and intrapartum/postnatal transmission of SARS-CoV-2.
Standardized definitions also have implications for future research describing clinical
courses and for interrupting transmission.
