Maternal infections with an increased risk of transmission to the foetus; a literature review

Introduction

During pregnancy, the woman may contract multiple infections associated with foetal risk. Infections acquired in utero or during the birth process are major causes of foetal and neonatal mortality, contributing significantly to the early and subsequent morbidity of the child.

To reduce this risk, it is necessary a quarterly screening testing, or more often if the patient reported exposure to infection, for as many pathogens as possible. Depending on the time of infection and the type of microorganism involved, significant foetal malformations may result.

These abnormalities are mainly the result of the action of infectious, physical agents, metabolic conditions or chemicals, and can cause foetal death as well as physical, behavioral and intellectual deficits [1]. The most accepted infectious teratogens are usually defined as TORCH (toxoplasma, other infection, rubella, cytomegalovirus, herpes simplex).

Discussions

If a woman is infected prenatal, perinatal, peripartum or even postnatal, these pathogens cause birth defects. Brent RL. et al. conducted a study on the causes of birth defects and concluded that in most of the patients in the group the cause remained unknown; the rest was genetic involvement [2].

Chen G. et al. analysed the relationships between exposure to environmental contraceptive risk factors and the risk of common congenital structural defects and showed that exposure to toxic substances in the work environment was the highest risk factor. Genital tract infections that associate with high fever during the first trimester of pregnancy and the administration of potential teratogenic drugs, such as hypnotics and anticonvulsants, could significantly increase the risk of structural birth defects. The correlation between oral contraceptive intake within six months before pregnancy and the risk of birth defects had no statistical significance [3].

A major importance in detecting infections that can complicate pregnancy is to perform the screening tests.

TORCH profile - includes testing for: • Toxoplasma gondii • Others (chickenpox, syphilis, hepatitis and human immunodeficiency viruses) • Rubella • Cytomegalovirus (CMV) • Herpes simplex virus (HSV) Congenital toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. The primary infection during pregnancy can lead to congenital diseases. Most foetuses with congenital toxoplasmosis are asymptomatic or have no apparent birth defects. Although the subclinical disease is apparently asymptomatic, there may be fever, maculopapular rash, hepatosplenomegaly, microcephaly, convulsions, jaundice, thrombocytopenia, even generalized lymphadenopathy. The classic triad of congenital toxoplasmosis consists of chorioretinitis, hydrocephalus and intracranial calcifications. A fetus with hydrocephalus may cause a dystocia of vaginal birth, requiring caesarean section.

Children with subclinical congenital toxoplasmosis who do not receive treatment have an increased risk of long-term sequelae. The most common late manifestation is chorioretinitis, which can lead to vision loss, intellectual deficit (mental retardation), deafness, seizures and spasticity [4].

Package C. et al. evaluated the effect of screening on the diagnosis of congenital toxoplasmosis and the effectiveness of prophylaxis and treatment, thus supporting the recommendation of the Obstetricians and Gynaecologists Society of Canada not to perform routine screening in the Canadian population for Toxoplasma gondii due to low prevalence and will be reserved only for pregnant women thought to be exposed to the risk of primary infection with Toxoplasma gondii [5]. If acute Toxoplasma gondii infection is suspected, repeated testing should be performed within 2 to 3 weeks.

Amniocentesis is reserved for the identification of Toxoplasma gondii in amniotic fluid by polymerase chain reaction: if primary maternal infection is diagnosed, if serological testing cannot confirm or rule out acute infection or in the presence of abnormal ultrasound findings (intracranial calcification, hydrocephalus, microcephaly, hepatosplenomegaly or severe intrauterine growth restriction).

After an infection with Toxoplasma gondii, it is recommended to delay conception for 6 months.

Syphilis (spirochete Treponema Pallidum) present in pregnancy and not treated properly can cause congenital syphilis and induce premature birth [6]. Treponema pallidum easily infects the placenta, with transplacental transmission to the fetus that can occur from about 9-10 weeks of gestation, regardless of the stage of the maternal disease [2]. It is important that the manifestations of congenital infection are influenced by gestational age, maternal condition, maternal treatment and the immune response of the fetus. Foetal abnormalities are the result of a strong inflammatory response to T. pallidum.

After infection of the placenta, the transplacental passage of the spirochete to the foetal circulation leads to foetal liver infections and dysfunctions, followed by infection of the amniotic fluid, foetal haematological abnormalities (anaemia, thrombocytopenia), ascites, hydrops and foetal IgM production. Hepatomegaly is thought to be caused by inflammation, extramedullary haematopoiesis, and hepatic congestion [7].

Infection of the new-born at birth may result from contact with maternal secretions or spirochetes containing blood, which is why it would be preferable to consider the birth by caesarean section [8].

Congenital syphilis - occurs when the spirochete Treponema pallidum is transmitted from a pregnant woman to the fetus. It can result in foetal hydrops, premature birth with long-term associated morbidity, or mortality at birth. Because of this morbidity, great emphasis is placed on routine screening for syphilis in all pregnant women [9]. Many cases of congenital syphilis develop because the mother has not received prenatal care. Most new-borns with congenital syphilis are asymptomatic at birth. The common infection may occur in the fetus from birth or may occur later in childhood.

Cheng JQ. et al., in an over 3-years study, had 477,656 pregnant women tested for syphilis, of which 2208 (0.5%) were confirmed positive. From 2003 to 2005, they collected epidemiological and treatment data from 2019 cases of positive syphilis. Of these, 1855 (91.9%) of pregnant women received treatment. Of the 1,020 babies born, 92 (9.0%) had congenital syphilis. If we exclude mothers who had children with positive syphilis without undergoing prenatal screening, the success rate of the project for mother-child transmission intervention was 99.1%, thus demonstrating the importance of testing for pregnant women with syphilis [9].

Chickenpox virus (VZV) is one of eight herpes viruses. Contracted in childhood, it generally produces mild manifestations. In adults, it presents noisy symptoms with a risk of significant morbidity and mortality. Primary infection in pregnancy causes pneumonia with VZV with a very severe maternal prognosis, which can lead to congenital foetal abnormalities with devastating consequences [10]. Most cases of congenital chickenpox syndrome occur in new-borns whose mothers were infected between 8 and 20 weeks of gestation and have the following manifestations [11-14]: − cutaneous scars, which can be depressed and pigmented in the dermatomeric distribution − neurological abnormalities (mental retardation, microcephaly, hydrocephalus, convulsions, Horner syndrome) − cortical atrophy and convulsions − ocular abnormalities (optic nerve atrophy, cataract, chorioretinitis, microphthalmia, nystagmus) − limb abnormalities (hypoplasia, atrophy, paresis) − gastrointestinal abnormalities (gastroesophageal reflux, atresia or intestinal stenosis) − low weight at birth.

Prenatal diagnosis - consists of PCR (polymerase chain reaction) testing of foetal blood or amniotic fluid for VZV DNA together with ultrasonography to detect foetal abnormalities [11, 15-16].

Depending on the maternal and foetal diseases diagnosed prenatally, it will be decided how to give birth with the lowest risk of worsening the symptoms. Sanchez MA et al. conducted a prospective cohort study between 1993 and 2006 to describe the prevalence of congenital chickenpox syndrome (CVS) in the population of likely infected pregnant women. Positive IgM cases were subjected to monthly ultrasounds and foetal blood (FB) sampling (including anti-VZV IgM and virus culture). The amniotic fluid sample for PCR was added to the diagnosis of positive IgM cases after 1997. The rate of foetal infection in this cohort was 0.8%, but the best expected prevalence of CVS, according to authors findings, should be 0.39% among infected women [17].

Hepatitis B virus (HBV) infection during pregnancy is usually mild and is not associated with increased mortality or teratogenicity [18-19]. However, cases of increased incidence of low weight at birth a prematurity have been reported in mothers with acute HBV infection [20-21]. The infection rate of new-borns in HBV-positive mothers is 90% for new-borns who do not receive human immunoglobulin antihepatitis B and hepatitis B vaccination at birth [22]. Mother-to-child transmission can occur in the uterus, at birth, or after birth. However, most infections occur at birth, which is why a caesarean delivery is to be considered.

Worldwide, hepatitis B and C are the most common causes of chronic viral hepatitis in children and adults [23]. Thanks to hepatitis B vaccination programs, the hepatitis C virus (HCV) has become the leading cause of chronic viral hepatitis in children, with vertical transmission being the main source of infection [24-27]. Vertical transmission refers to viral transmission from mother to child, during pregnancy, birth or the first 28 days of life [28]. Obstetric management at birth should minimize the duration of foetal exposure to maternal fluids and blood [28].

Slowik MK. et al. conducted a study on the presence of hepatitis B and C viruses in infants and young children. The diagnosis of chronic HBV is confirmed by positive serological tests on two occasions, at a distance of at least 6 months. The diagnosis of HCV in the new-born should be postponed until after the child reaches the age of 1, as infants may have transient viremia [29].

The lack of an effective HCV vaccine (still under development) and the risk of mother-to-child transmission, increase the number of children with vertically acquired HCV. More effective and fewer toxic therapies are needed for young patients with HBV and HCV, as well as methods of stopping perinatal HBV and HCV transmission.

HIV (Human Immunodeficiency Virus) is the etiological factor of acquired immunodeficiency syndrome (AIDS). The HIV virus infects cells of the immune system, especially CD4 + T lymphocytes or T helper lymphocytes, being able to synthesize its own genetic information in a form that can be incorporated into the genome of the host cell. Here it persists in a latent state or causes the destruction of cells following the replication of viral particles that will infect other CD4 + lymphocytes, causing the gradual and progressive destruction of the host's immune system. Patients are contagious through blood, sexual secretions, transplacental and breast milk. The number of CD4 cells should be assessed at least every three months during pregnancy. For patients who have received combination antiretroviral therapy (ART) with consistent viral suppression and CD4 counts above the threshold for opportunistic infections, monitoring of CD4 cell counts may be performed every six months [30,31].

Determining the exact gestational age in the fetus is especially important for HIV-positive pregnant women, as it may be necessary to terminate the pregnancy prematurely to reduce the risk of transmitting HIV infection. It is recommended to give birth by caesarean section at 38 weeks of gestation in case of viremia > 1000 copies / ml [32].

The earliest possible association of ART, together with the choice of birth by scheduled caesarean section and the complete lack of breastfeeding determine the expected neonatal results, the risk of vertical transmission decreasing up to 1-2%.

HIV infection in children is most often caused by mother-to-child transmission. Sturt A.S. et al. analysed the 3 means of maternal-foetal transmission: during pregnancy, during birth and breastfeeding. They associated antiretroviral therapy in these patients and evaluated its effectiveness in reducing the rate of foetal illness. They demonstrated that the association of ART with caesarean section before the onset of labour and the total lack of breastfeeding reduced the risk of maternal-foetal transmission up to 1-2% [33].

Congenital rubella - its major impact occurs during pregnancy, when it can have devastating effects on the developing fetus. If the primary infection occurs as close as possible to birth, Rubella can cause a mild, self-limiting disease.

Congenital rubella syndrome (CRS) may include growth retardation, hepatosplenomegaly, thrombocytopenia, purpura, hyperbilirubinemia, deafness, cataracts, heart malformations, neurological and endocrinological sequelae.

Important cardiac abnormalities include pulmonary artery stenosis, aortic or pulmonary valve stenosis, ventricular septal defect (DSV), aortic coarctation, Fallot tetralogy. When diagnosed antepartum, it directs the obstetrician in choosing the way to terminate the pregnancy, in order to reduce the aggravation of the foetal pathology.

An update of cardiovascular malformations in congenital rubella syndrome was performed by Oster M.E. et al. They analysed 10 studies and identified 121 patients with a history of catheterization. 78% of them had stenosis of the pulmonary artery, and 62% had atrial canal persistence (PDA). In 49% of cases, both pulmonary artery stenosis and PDA were present, while isolated pulmonary artery stenosis and isolated PDA were found in 29% and 13% of cases, respectively. Of the 12 patients in the 10 studies with echocardiographic data, PDA was more common than pulmonary artery stenosis, but this finding is very limited by the small number of patients and echocardiography performed. Although published studies on cardiovascular malformations (CVM) in congenital rubella syndrome (CRS) have reported that PDA is the most commonly associated cardiovascular malformation with CRS, of the cases of CRS assessed by catheterization, pulmonary artery stenosis was actually more common than PDA. The combination of pulmonary artery stenosis and PDA was more common than branched pulmonary artery stenosis or PDA alone. Isolated pulmonary artery stenosis was twice as common as isolated PDA [34].

Congenital cytomegalovirus - Cytomegalovirus (CMV) infection is the leading cause of non-hereditary neurosensory deafness (SNHL), being detected in an asthma in new-borns with asymptomatic disease [35,36].

At birth, only about 10% have symptoms, with clinical manifestations like rush, neonatal jaundice, hepatosplenomegaly, thrombocytopenia, small birth weight for gestational age ("small for age"), microcephaly, intracranial calcifications, chorioretinitis, convulsions [37].

In a prospective multicentre study involving 539 very low birth weight infants (VLBW), the cumulative incidence of postnatal CMV infection at 12 weeks postnatal was 7%. Transmission occurred from CMV-positive breast milk in almost all cases (96%) and there were no transfusion-related infections. 5 out of 29 (17%) infants infected with CMV developed symptomatic CMV disease, and three infants (10%) died [38].

Herpes simplex virus - herpes simplex virus (HSV) infection during pregnancy poses an increased risk to the developing fetus and the new-born.

Most cases of neonatal HSV infection are acquired perinatal. HSV is transmitted to the baby during birth, mainly through the infected birth canal. The risk of transmission is higher when the primary HSV infection occurs during pregnancy [39]. Although many new-borns with HSV are born prematurely, most appear normal at birth. The infection is manifested by rash on the skin, eyes or mouth (SEM - "Skin, Eye, Mouth"), central nervous system (CNS) damage or disseminated disease involving several organs.

The initial manifestations of CNS disease are often nonspecific and include temperature variations (fever/ subfebrile), respiratory stress, lethargy and inadequate nutrition. They can progress fairly quickly to hypotension, jaundice, disseminated intravascular coagulation (CID), apnoea, and shock. Lesions (herpetiform vesicles) of the skin may or may not be present and can develop late. The absence of skin lesions complicates the recognition of the infection [39].

Brown Z.A. et al. studied the rate of neonatal HSV infection. They analysed 58,362 pregnant women who tested positive for HSV. Of these, 202 women were diagnosed with HSV during labour and only 10 (5%) transmitted the disease to the new-born. Caesarean delivery significantly reduced the rate of HSV transmission among women diagnosed with HSV (1 in 85 caesareans vs. 9 in 117 vaginal) [39].

Conclusions

No teratogenic agent should be described qualitatively as a teratogenic, as a teratogenic exposure includes not only the agent, but also the dose and trimester of pregnancy when the exposure should occur.

When assessing the risk of exposure, the dose is a crucial component in determining the risk.

Teratogens follow a dose-response toxicological curve. This means that each teratogen has a threshold dose below which there is no risk of teratogenesis, regardless of when the exposure occurred during pregnancy.

It is easier to exclude an agent as the cause of birth defects than to conclude definitively that it is responsible for them, due to the existence of genocopies of teratogenic syndromes. The administration of drugs before and especially during pregnancy must be carried out carefully, with the knowledge of their potential teratogenic effects.

Most foetal malformations have a genetic component. Infections associated with pregnancy cause an unfavorable prognosis on it, causing abortion, premature birth, foetal malformations or even foetal death.

Congenital structural defects are affected by a number of related environmental risk factors.

All pregnant women should be tested for syphilis as early as possible during pregnancy to prevent mother-to-child transmission.

Foetal chickenpox syndrome is a serious and rare condition in the new-born that can be prevented by vaccinating the mother before pregnancy.

The transmission of HIV infection from mother to fetus is dependent on the time of exposure of the fetus to maternal secretions.

Congenital rubella syndrome is associated with significant cardiovascular malformations.

Rates of neonatal HSV infection may be reduced by caesarean delivery and by limited vaginal examination during labor.

In the case of pregnant women with CMV infection, the main source of transmission is postnatal, through breast milk.

Abbreviations

AIDS - Acquired immunodeficiency syndrome ART - Combined antiretroviral therapy CID - Disseminated intravascular coagulation CMV – Cytomegalovirus CNS - Central nervous system CRS - Congenital rubella syndrome CVM - Cardiovascular malformations CVS - Congenital chickenpox syndrome DNA - Deoxyribonucleic acid DSV - Ventricular septal defect FB - Foetal blood HBV - Hepatitis B virus

HCV - Hepatitis C virus HIV - Human Immunodeficiency Virus HSV - Herpes simplex virus PCR - Polymerase chain reaction PDA - Patent ductus arteriosus SEM - “Skin, Eye, Mouth” SNHL - Non-hereditary neurosensory deafness TORCH-toxoplasma, other infection, rubella, cytomegalovirus, herpes simplex VLBW - Very low-birthweight VZV - Chickenpox virus