Maternal infections: revisiting the need for screening in
pregnancy
Valentine Faure-Bardon1,2,*, Yves Ville1,2
- EA 73-28, Paris Descartes University, Sorbonne Paris Cité, Paris,
75005, France.
- AP-HP, Hospital Necker-E.M., Maternity, Paris, 75015, France
*Correspondence:valentine.faure@aphp.fr
Running head : Early Pregnancy Infection Screening
Abstract
The decision to implement screening for infections during pregnancy
depends upon epidemiological, economic, therapeutic and test performance
criteria. It therefore varies with public health priorities from country
to country.
When screening is implemented, first trimester has become the best time
slot to build individual care pathways also in this field. This is most
relevant for evaluating the risk of embryonic consequences, plan
diagnostic testing, initiate primary or secondary prevention and
increase the accuracy of ultrasound follow-up.
This is a critical appraisal of epidemiological data and current
international screening recommendations for infections in pregnancy.
Introduction
The decision to implement screening for infections during pregnancy
depends upon epidemiological, economic, therapeutic and test performance
criteria. It therefore varies with public health priorities from country
to country.
When screening is implemented, first trimester has become the best time
slot to build individual care pathways also in this field. This is most
relevant for evaluating the risk of embryonic consequences, plan
diagnostic testing, initiate primary or secondary prevention and
increase the accuracy of ultrasound follow-up.
This is a critical appraisal of epidemiological data and current
international screening recommendations for infections in pregnancy.
Pregnancy: an opportune time for women to be screened and
receive appropriate care for the mother and the unborn child
Hepatitis C
Hepatitis C affects 1% of the adult population (HCV
RNA–positive)1 and 0.38% of live born infants are
born from HCV–infected women in the USA1,3. The risk
of vertical transmission is around 5.8% and up to 10.8% when women are
co-infected with HIV. In contrast, this risk was negligible in women
with HCV antibodies but negative for HCV-RNA 2.
Neither mode of delivery nor breastfeeding seem to affect vertical
transmission3. However, invasive testing, internal
fetal monitoring, and prolonged rupture of membranes have been
empirically discouraged in the USA4.
International recommendations have long been to offer screening to high
risk women only (Table 1). However, since April 2020, the CDC and the
American Association for the Study of Liver Diseases
(AASLD)5 have ruled in favor of universal screening in
pregnancy when the prevalence of HCV infection is > 0.1%.
This should be done at booking using HCV antibody assay and confirmatory
RNA testing for positive serologies.
This is in line with recent epidemiologic and cost-effectiveness
evaluations as well as the development of new direct-acting antiviral
(DAA) therapy5. Infected women should be referred for
specialized medical evaluation. DAA is not yet approved for use in
pregnancy but when introduced post-partum, it treats infected women and
reduces the risk of HCV transmission to future offspring5,6.
Hepatitis B
Up to 6% of pregnant women are infected with hepatitis B in
high-prevalence areas such as Western Pacific and African
Regions7. In the absence of prophylaxis, hepatitis B
is passed to the child at birth from 90% and 10-20% of mothers who are
both (HBsAg) and (HBeAg)‐positive and (HBsAg) positivity alone
respectively8,9. The risk for the infected neonate to
develop chronic infection is 80-90 %. Infected offspring becomes a
reservoir for horizontal transmission during the first 5 years of
life.7 Universal screening in pregnancy is recommended
worldwide13 and should be repeated in the
3rd trimester in high risk-women (Table 1).
Prophylaxis is obtained through hepatitis B vaccination and hepatitis B
immunoglobulin (Ig) administration at birth in neonates born from
HBsAg-positive mother.
Antiviral treatment with telbivudine, lamivudine, and tenofovir is safe
in pregnancy11,12 and is indicated in cases with high
viral load (HBV DNA >200,000 IU/mL or 106copies/mL). It improves HBV suppression and reduces perinatal
transmission (RR=0.3)11,12. This strategy proved
cost-effective in the USA13. Vaccination remains a
goal and can be safely offered to seronegative women in early pregnancy7,10,14.
Human Immunodeficiency Virus (HIV)
Around 1.3 million HIV positive women become pregnant every year15 and in the US, 1 in 9 women with HIV are unaware
they have it 16. The highest prevalence of HIV among
adults aged 15 to 49 reaches 3.9% in Africas17.
Perinatal transmission occurs during pregnancy, at delivery, but also in
the postpartum period through breastfeeding. Without medical
intervention 15–30% of infants born to HIV-positive women will become
infected during gestation and delivery, with a further 5–15% becoming
infected through breastfeeding15. Universal screening
in pregnancy is recommended although not mandatory in any country for
ethical reasons (Table 1). In order to encourage its implementation,
some countries opted for systematic screening unless the woman
explicitly refuses (opt-out approach)18.
The performance of the HIV-1/2 antigen/antibody test is excellent with
99.8% to 100% sensitivity and 99.5% to 100% specificity and the
results are available within hours with rapid
HIV-tests19. Screening should be carried out as early
as possible in pregnancy, at best pre-conceptionally.
In the event of positive serology, immediate initiation of
antiretroviral treatment has proven effective to reduce MTCT down to
1.5%20,21 and virtually zero when treatment is
initiated before conception22. When maternal viral
load is significant, planned caesarean section covered by intravenous
Zidovudine is recommended across the board. However the viral load
threshold above which a planned caesarean section may be beneficial is
difficult to establish, which explains the discrepancy between
recommendations ranging between 50, < 1000, and <
400 copies/mL in the British, American and French recommendations
respectively23 2425.
Finally, serial screening in 1st and
3rd trimesters also benefits high-risk seronegative
women to discuss pre-exposure prophylaxis (PrEP)26 to
reduce the risk of MTCT27.
Chlamydia trachomatis
(ChT)
ChT is the most common sexually transmitted pathogen affecting up to
4.3% of sexually active women in the US and infections are largely
asymptomatic28 . In pregnancy, 1.7% of mostly
asymptomatic women were diagnosed with ChT29.
A review of 614,892 cases suggested that ChT infection in pregnancy
increases the odds of several adverse outcomes: preterm premature
rupture of membranes (OR = 1.81) endometritis (OR=1.69) low birthweight
(OR= 1.34), small for gestational age (SGA) (OR=1.14) and intrauterine
fetal demise (OR=1.44)30 . However, authors
highlighted that the literature in this review was complicated by
heterogeneity and that the association may not hold in higher quality
and prospective studies or those that use more contemporary nucleic acid
testing. In the largest recent prospective screening study it was found
similar outcomes in women who tested positive and were treated and those
who tested negative 31. Finally, the relationship
between ChT infection and miscarriage is unclear29,32.
Pregnant women infected with chlamydia can also pass the infection to
their infants during delivery. With regard to neonatal consequences,
some studies have estimated that 50–70% of infants born to mothers
with ChT will become infected with ChT, and 30–50% of these infants
will then develop chlamydial conjunctivitis, and 10–20% will develop
pneumonia33,34.
The evidence for screening and treatment in pregnancy is thin and there
is no international consensus on ChT screening in pregnancy and clinical
trials are still needed. It is recommended to screen at the first
prenatal visit In the US and Canada35 but this is
seldom in Europe (Table 1) 33. However, when a vaginal
swab shows positive for ChT in a symptomatic woman, there is a consensus
to treat.
Screening for infections that carry a risk of congenital
anomaly
Syphilis
In 2012, approximately 930,000 maternal syphilis caused 350,000 adverse
pregnancy outcomes including 143,000 fetal deaths/stillbirths, 62,000
neonatal deaths, 44,000 preterm/low weight births, and 102,000 infected
infants worldwide36. Those outcomes were respectively
21%, 9.3% and 5.8% more frequent than among women without
syphilis37. This led WHO to establish guidelines to
prevent vertical transmission, aiming for complete eradication of CS by
2030 15. The CDC raised awareness about the resurgence
of cases of congenital syphilis (CS) in the US having more than doubled
in 4 years, reaching a 20-year high38.
There are two types of serological tests: non-treponemal, (Venereal
Diseases Research Laboratory (VDRL); and treponemal (Treponema pallidum
haemagglutination assay (TPHA), and fluorescent treponemal antibody
absorbed (FTA-ABS) tests). A rapid syphilis treponemal test (RST) is
also available with antibody results in 15 minutes. This RST can be
performed in any setting without laboratory equipment unlike the other
tests. Screening at booking is recommended worldwide for effective
maternal treatment and WHO has issued empirical decision-making
flowcharts for screening and treatment 39. Serologic
testing is also recommended while exploring cases of intrauterine fetal
death38,39.
Benzathine penicillin G 2.4 million units is given once intramuscularly
in primary, secondary and latent syphilis of not more than two years.
This should be repeated weekly for 3 weeks in infections ongoing more
two years without evidence of treponemal infection 40.
Making syphilis screening universal, or even mandatory, may seem
excessive, particularly in low prevalence populations, but WHO argues
that this should be maintained and reinforced because it increases
equity, is cost-effective, acceptable to patients, correctly performed
by laboratories and, above all, it prevents severe obstetric
complications in the event of proven infection (Table 1).
Toxoplasmosis
Maternal primary infection (MPI) with Toxoplasma gondii is mostly
asymptomatic 41, but it carries a risk of neurological
and ocular sequelae in the offspring. Although congenital toxoplasmosis
(CT) poses a substantial burden of poor health with around 190,100 cases
worldwide per year 42, seroprevalence has dropped in
many countries over the last 20 years. In French pregnant women , it
decreased, from 54 % in 1995 to 37% in 201043 and a
similar decrease was observed in the US, down to
9.1%44. In France, the rate of seroconversion during
pregnancy was between 0.2% and 0.25% in 201545 and
since 2007 an overall prevalence was estimated around 3 to 4 cases per
10,000 live births (prevalence of severe forms: 0,1 in 10,000). However,
10% of CT infections are symptomatic, 25% of those are severe and over
10% lead to medical terminations of pregnancy following prenatal
diagnosis45.
Few countries offer routine screening for CT during pregnancy, and
France and Austria have been most proactive since the 1970s46,47(Table 1). Both programs have witnessed a decline
in the incidence of CT and in fetal and pediatric damage48,49.
The rationale for not offering screening includes low incidence of the
disease, cost of screening and lack of evidence regarding effectiveness
of antenatal treatment. However, recent publications from France and
Austria suggest that prenatal screening for prevention was cost-saving
and led to maintain current policies47,48.
Classically , it is assumed that cat and food hygiene and cooking,
particularly consumption of rare or raw meat are the main risk factors
for infection with toxoplasma 50,41.
However, the only two randomized clinical trials (RCT) testing education
approaches, showed no difference in seroconversion in relation with any
of those risk factors51,52.
MPI is the appearance of
specific G
globulins (IgG) in a previously seronegative patient or by marked
elevation of specific IgG in the presence of
specific Ig
M (IgM). The difficulty rests in the interpretation of positive IgM.
Indeed, IgM may persist for years following acute infection; therefore
isolated positive IgM are not absolute evidence of recent toxoplasmosis53. Algorithms of interpretation, using different
assays to measure Ig titers, IgG avidity and sequential serological
testing should be used to date MPI within expert
laboratories47.
MTCT is by transplacental passage of the parasite and the rate increases
with gestational age at seroconversion (OR= 1.17 for each additional
week )54. In one meta-analysis the rate of MTCT by
gestational age at seroconversion was 15% , 44%, 71% at 13, 26, 36
weeks respectively 55. The risk of maternal
seroconversion in the first weeks of pregnancy is < 5 %56,57.
Gestational age at maternal seroconversion is the major prognostic
factor in CT. The number of fetuses showing CT-related abnormalities on
ultrasound is higher in infections early in pregnancy, and in up to 78%
in the first trimester58. The proportion of
symptomatic infants before the age of 3 falls from 61% to 25% and 9%
following MPI at 13, 26 and 36 weeks respectively 59.
Infected fetuses can be asymptomatic or bear multisystemic damage
including brain injury 60 and even die in-utero61. Normal antenatal ultrasound follow-up is
associated ,with a negligible risk of abnormal neurological outcome,
even following first-trimester infection 57,62.
However normal ultrasound monitoring cannot exclude the risk of
chorioretinitis62. CT treated prenatally carries an
overall risk of chorioretinitis of 26 %, although mainly peripheral.57. Long-term follow-up is recommended since only 39%
of chorioretinitis are diagnosed at birth 57.
The rationale for antenatal treatment in CT is controversial. Treatment
regimens vary but are based upon spiramycin and
pyrimethamine–sulfamides (PS) (Figure 1)47,46.
None of the recent prospective 63, or randomized
studies 54 reported a significant effect of antenatal
treatment on MTCT or on the fetal prognosis although none could exclude
clinical benefits. The SYROCOT study reviewed 26 cohorts with 1,438
cases following prenatal screening and reported that treatment started
within 3 weeks of seroconversion reduced MTCT compared with late
(>8 weeks) treatment (p=0.05) 55. The
EMSCOT study found that prenatal treatment of infected fetuses, adjusted
for gestational age at MPI , reduces the risk of serious neurological
sequelae by 75% 64. In addition, in 300 infants with
CT, an interval > 8 weeks between MPI and intrauterine
treatment initiation was associated with an increased risk of
chorioretinitis 65. Finally, in the only RCT comparing
the two antenatal drug regimens, the incidence of prenatal cerebral
signs of CT following prophylactic administration was lower with PS than
with spiramycin 54.
Although CT can cause severe complications in the fetus, its decline in
prevalence and incidence and controversial data on the efficacy of
antenatal therapy explain that only a few countries in the world offer
screening in pregnancy. However, primary prevention and screening for
toxoplasmosis at first prenatal care visit is easy to implement with
cost-benefit studies pointing in this direction.
Cytomegalovirus
Cytomegalovirus is the most common congenital infection (cCMV),
affecting 0.5–2% of live births. It is the main non-genetic cause of
congenital sensorineural hearing loss and of neurological
damage6667. In high-income countries, about half of
infected newborns are infected as a result of MPI and the other half as
a result of non-MPI (reactivation or re-infection) 68.
Seroprevalence is high (50% in the USA and Europe, up to 100% in
southern countries) and women at higher risk for MPI during pregnancy in
high-income countries are typically young, multiparous, with high income68. In addition, it has recently been shown that women
delivering again within 3 years of a previous baby who is in childcare
have a 7% risk of MPI in the first trimester of the new pregnancy69.
The risk of MTCT depends upon the trimester of MPI. Summarizing the
results of the most relevant studies, it appears that the risk of
transmission after MPI in the 1st,
2nd and 3rd trimester, is 38%
(158/418), 40% (107/264), and 66% (78/118) respectively70–73.
Following MPI, only first-trimester infections can lead to sequelae74,75. In the natural history, approximately 30-35%
of newborns infected after first-trimester infection develop
neurological sequelae, and 25% suffer hearing loss, mostly
unilateral76.
Despite the high burden of cCMV infection, , screening for MPI during
pregnancy is not recommended by any public health authority but Germany77,78. This is due to older concerns about sensitivity
and specificity of serological tests, difficulty in establishing the
prognosis of an infected fetus, and the lack of validated prenatal
treatment options79. However, some issues need an
update:
First, MPI is reliably identified by serologic testing based on IgG and
IgM followed by IgG avidity testing in IgM positive cases. Low CMV IgG
avidity indicates MPI within the preceding 3–4 months. Sensitivity and
specificity of this algorithm depends mainly on the performance of the
IgM kits used, the accuracy of the “low” range of IgG values, and the
timing of serology screening80,81
Secondly, the prognosis of fetal infection relies upon standardized
prenatal assessment82. Although gestational age at
infection is a major prognostic factor75,76,83, other
parameters including sequential ultrasound (US) examinations in second
and third trimesters, platelet count in fetal blood, and prenatal
Magnetic Resonance Imaging (MRI) have all been shown to independently
predict the outcome of infected fetuses in different studies70,84–89 . The combination of ultrasound and MRI has
a negative predictive value of 95 to 99 % 82,83,90.
Finally, the first indication of antivirals in fetal cCMV infection was
to reduce the risk of sequelae in a fetus with proven fetal infection.
In a phase II open-label trial, oral valaciclovir (8 g/d) given in
pregnancies with mildly symptomatic fetuses was associated with a higher
chance of delivering an asymptomatic neonate (82%), compared with an
untreated historical cohort (43%)91. CMV-hyperimmune
globulins did not prove to be effective in this indication92. The focus has recently addressed the efficacy of
secondary prevention by giving treatment as soon as MPI is biologically
proven in the first trimester in order to reduce the risk of MTCT and
therefore the risk of sequelae. In a randomized double-blind,
placebo-controlled study , Valaciclovir at a dose of 8 g/day reduced the
rate of fetal infection by 71%93. CMV-hyperimmune
globulins have been studied in this indication and there was a
statistically significant difference when compared to untreated
historical cohorts 94 (MTCT= 2.5% vs 35.2% in the
treatment and historical groups respectively). However, this could not
be shown through RCT including cases up to 28 weeks’ which may have
decreased the impact of hyperimmune globulins 92.
Maternal screening in early pregnancy would also benefit seronegative
women, since individual primary prevention measures in these women have
proven to be effective in significantly preventing MPI.
The recent and solid data highlighting 1) the typical profile of the
pregnant women at risk of MPI, 2) the first trimester of pregnancy as
the only one at risk of sequelae 3) the reduction of MTCT with antenatal
valaciclovir, bring new perspectives for implementation of screening in
early pregnancy.
Rubella
Rubella is a leading vaccine-preventable cause of birth defects since
the early 1970s. Before the introduction of the vaccine, up to 4 babies
per 1,000 live births were born with congenital rubella syndrome (CRS),
an often devastating condition 95. This includes low
birth weight, deafness, mental retardation, cardiac and eye
malformations 96,97 . The risk of MTCT is 80-90%,
54% and 25% when maternal rash occurs before 12 ,at 13-14 and after 20
weeks of pregnancy respectively 95,98.98. The risk of sequelae is constant before 12 weeks
and nil after 16 weeks; in-between, a third of the fetuses develop
sequelae, particularly deafness96,98.
In 2015, the WHO Region of the Americas became the first in the world to
be declared free of endemic transmission of rubella103whereas CRS rates are highest in the WHO African and South-East Asian
regions where vaccination coverage is lowest. However, even in countries
where endemic virus has disappeared, cases emerge, mainly due to
non-immune migratory human
flows97,99,100. Screening with
rubella specific antibodies during pregnancy is not/no longer
recommended in some industrialized countries such as the United Kingdom
or the US. It remains mandatory in France (Table 1).
The search for proof of immunity at the very beginning of pregnancy
seems essential both to set up primary prevention measures and, above
all, to consider vaccination after delivery, even before discharge from
maternity ward.
Varicella
The incidence of varicella zoster virus (VZV) infection in pregnancy is
around 1.2/10,000 101 and the MTCT is 25%102. Sequelae have only been observed in 2 % of
infected fetuses and only before 20 weeks 103. The
damage is ubiquitous including IUGR, skin lesions, neurological, eye,
skeletal, gastrointestinal and genitourinary
anomalies104. Maternal VZV infection also carries a
risk of severe neonatal varicella in an estimated 17%-30% when it
occurs between d-5 and d+2 relative to the date of
delivery105. Non-immune pregnant women exposed to VZV
(household contact, face-to-face contact > 5 minutes or in
the same room > 1 hour) should receive post-exposure
prophylaxis with anti-VZV-immunoglobulins, ideally within 96 hours, and
no later than 10 days after infection105. The effect
of this therapy has mostly been studied in order to reduce the risk of
maternal morbidity that exists in case of MPI. The live attenuated VZV
vaccine is contraindicated in pregnant women. Care givers should enquire
about the immunological status of pregnant women for VZV (personal
history of chickenpox, vaccination, or serology if in doubt) to prevent
from exposing themselves to a situation as trivial as a child who has
chickenpox in the first part of their pregnancy.
Conclusion
Infections during pregnancy can impact the prognosis of the fetus, the
newborn and the infant. Young healthy pregnant women are often not aware
of those risks, and first prenatal care visit is a key time slot in the
obstetrical calendar to also raise those issues. Hepatitis B and C, HIV,
genital Chlamydia infection are not rare diseases and should no longer
be suspected only in precarious or marginal populations. Vertical
transmission of these infections, from women who do not know they are
carriers, maintains a significant incidence of chronic diseases.
Rubella, syphilis, VZV, Toxoplasma Gondii and CMV infections can lead to
severe birth defects, especially when the fetus is in contact with the
pathogen in early pregnancy. These infections are preventable by primary
prevention measures implemented early enough. The WHO criteria
validating the implementation of screening may not all strictly be met
for these infections. However, the duty to provide accurate information,
which frequently goes hand in hand with the maternal request to search
for immunity, is in agreement with the principles of benevolence and
non-malevolence guiding our practice.
Disclosure of Interests
Valentine Faure-Bardon has no disclosures.
Yves Ville reports non-financial support from Ferring SAS, non-financial
support from Siemens health Care, non-financial support from GE medical,
outside the submitted work .
Contribution to
Authorship
YV and VFB designed and wrote the paper.
Details of ethics approval
Not required
Funding
No funding source was necessary for this work
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