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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]


Overview

Congenital and perinatal infections represent major causes of permanent disability among children worldwide. Linked together by the acronym TORCH, denoting Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes virus, congenital infections can result from only a modest number of human pathogens that cross the placenta and infect the fetus. Although congenital rubella syndrome has been eliminated in the Americas by immunization, several pathogens discussed in this chapter cannot currently be prevented by vaccines or effectively treated with the available antimicrobial drugs. Due to the immaturity of the immune system, newborn infants are at risk for postnatally acquired infections with certain viruses and several bacteria. This chapter summarizes the epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of selected pathogens that can damage the developing nervous system. As emphasized by the persisting challenges of preventing congenital cytomegalovirus infection and the emergence of severe brain damage associated with congenital Zika syndrome, these pathogens remain important causes of cerebral palsy, epilepsy, and intellectual disability.

Historical Perspective

  • For approximately 100 years,The concept that certain human pathogens can damage the developing nervous system in utero or perinatally has been appreciated. Although women encounter numerous infectious agents during their pregnancies, relatively few pathogens cross the placenta and cause intrauterine fetal infections.
  • In the 1970s investigators at Emory University and the Centers for Disease Control and Prevention (CDC) coined the term TORCH, an acronym underscoring Toxoplasma gondii, rubella virus, cytomegalovirus, and herpesviruses as important, potential causes of congenital infection (Nahmias, 1974). The TORCH concept emphasized that these agents can produce similar clinical manifestations in infected infants. Although congenital rubella virus syndrome has since disappeared in countries with compulsory immunization against this virus (CDC, 2005; WHO, 2017), the TORCH agents, as well as more recently recognized pathogens, such as lymphocytic choriomeningitis virus and Zika virus, remain major causes of long-term neurodevelopmental disabilities among children throughout the world (Bale, 2009).
  • The discussion uses the terms congenital and intrauterine interchangeably to indicate that infections occurred before the birth of the infant. By contrast, infections that take place after the birth of the infant are designated perinatal. Because certain perinatal infections, such as those due to enteroviruses, parechoviruses, and herpes simplex viruses, can also damage the immature developing brain, the chapter appropriately contains current information regarding the recognition and management of these infections as well. The agents causing congenital or perinatal infections can produce permanent hearing loss, vision loss, cerebral palsy, cognitive impairment, developmental delay, behavioral disorders or epilepsy in surviving infants and children.[1]

Classification

Perinatal infection is vertically transmitted infection ,which starts at gestational ages between 22[2] and 28 weeks[3] (with regional variations in the definition) and ending seven completed days after birth[2]

Heading text

Pathophysiology

In the spectrum of optimal virulence, vertical transmission tends to evolve benign symbiosis, so is a critical concept for evolutionary medicine. Because a pathogen's ability to pass from mother to chd depends significantly on the hosts' ability to reproduce, pathogens' transmissibility tends to be inversely related to their virulence. In other words, as pathogens become more harmful to, and thus decrease the reproduction rate of, their host organism, they are less likely to be passed on to the hosts' offspring, since they will have fewer offspring.[4]. Although HIV is sometimes transmitted through perinatal transmission, its virulence can be accounted for because its primary mode of transmission is not vertical. Moreover, medicine has further decreased the frequency of vertical transmission of HIV. The incidence of perinatal HIV cases in the United States has declined as a result of the implementation of recommendations on HIV counselling and voluntary testing practices and the use of zidovudine therapy by providers to reduce perinatal HIV transmission.[5]. The price paid in the evolution of symbiosis is, however, great: for many generations, almost all cases of vertical transmission continue to be pathological—in particular if any other routes of transmission exist. Many generations of random mutation and selection are needed to evolve symbiosis. During this time, the vast majority of vertical transmission cases exhibit the initial virulence. In dual inheritance theory, vertical transmission refers to the passing of cultural traits from parents to children.[6].

 
 
 
maternal infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
placental infection and inflammation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
intrauterine growth retardation
 
 
 
fetal infection

Causes

Causal routes

The main routes of transmission of vertically transmitted infections are across the placenta (transplacental) and across the female reproductive tract during childbirth. Transmission is also possible by breaks in the maternal-fetal barrier such by amniocentesis[7] or major trauma.

Transplacental

The embryo and fetus have little or no immune function. They depend on the immune function of their mother. Several pathogens can cross the placenta and cause perinatal infection. Often, microorganisms that produce minor illness in the mother are very dangerous for the developing embryo or fetus. This can result in spontaneous abortion or major developmental disorders. For many infections, the baby is more at risk at particular stages of pregnancy. Problems related to perinatal infection are not always directly noticeable.

Apart from infecting the fetus, transplacental pathogens may cause placentitis (inflammation of the placenta) and/or chorioamnionitis (inflammation of the fetal membranes).

During childbirth

Babies can also become infected by their mothers during birth. Some infectious agents may be transmitted to the embryo or fetus in the uterus, while passing through the birth canal, or even shortly after birth. The distinction is important because when transmission is primarily during or after birth, medical intervention can help prevent infections in the infant.

During birth, babies are exposed to maternal blood, body fluids, and to the maternal genital tract without the placental barrier intervening. Because of this, blood-borne microorganisms (hepatitis B, HIV), organisms associated with sexually transmitted diseases (e.g., Neisseria gonorrhoeae and Chlamydia trachomatis), and normal fauna of the genitourinary tract (e.g., Candida albicans) are among those commonly seen in infection of newborns.

Types of infections

Bacteria, viruses, and other organisms are able to be passed from mother to child. Several vertically transmitted infections are included in the TORCH complex:

  1. T – toxoplasmosis from Toxoplasma gondii
  2. O – other infections (see below)
  3. R – rubella
  4. C – cytomegalovirus
  5. H – herpes simplex virus-2 or neonatal herpes simplex

Other infections include:

Hepatitis B may also be classified as a vertically transmitted infection. The hepatitis B virus is large and does not cross the placenta. Hence, it cannot infect the fetus unless breaks in the maternal-fetal barrier have occurred, but such breaks can occur in bleeding during childbirth or amniocentesis.[7]

The TORCH complex was originally considered to consist of the four conditions mentioned above,[14] with the "TO" referring to Toxoplasma. The four-term form is still used in many modern references,[15] and the capitalization "ToRCH" is sometimes used in these contexts.[16] The acronym has also been listed as TORCHES, for TOxoplasmosis, Rubella, Cytomegalovirus, HErpes simplex, and Syphilis.

A further expansion of this acronym, CHEAPTORCHES, was proposed by Ford-Jones and Kellner in 1995:[17]

Differentiating types of perinatal infection

Disease characteristics symptoms and signs Lab finding & Other evaluation
Toxoplasmosis Classic triad Chorioretinitis: Hydrocephalus, Intracranial calcifications (ring-enhancing lesions), Petechiae and purpura (blueberry muffin rash)
  • Mother: T. gondii-specific IgM antibodies
  • Fetus: PCR for T. gondii DNA in amniotic fluid
  • Newborn

CT/MRI: intracranial calcifications, hydrocephalus, ring-enhancing lesions T. gondii-specific IgM antibodies (CSF, serum) PCR for T. gondii DNA (CSF, serum) Ophthalmological evaluation: chorioretinitis

Syphilis Early congenital syphilis (onset < 2 years),Jaundice and hepatosplenomegaly,Lymphadenopathy,Nasal discharge (sniffles),Maculopapular rash (with desquamation of the palms and soles),Skeletal abnormalities (e.g., osteodystrophy),Late congenital syphilis (onset > 2 years),Facial abnormalities: Frontal bossing, rhagades, Hutchinson triad (saddle nose, Hutchinson teeth, mulberry molars), Interstitial keratitis, Sensorineural deafness, Saber shins *Newborn and mother

Initial test: RPR or VDRL (serum) Confirmatory test: dark-field microscopy or PCR of lesions or bodily fluids See “Diagnostics” in syphilis.

  • Fetus: repeated ultrasound examinations (placentomegaly, hepatomegaly, ascites, and/or hydrops fetalis)
Listeriosis Spontaneous abortion and premature birth

Meningitis, sepsis Vesicular and pustular skin lesions (granulomatosis infantiseptica)

Culture from blood or CSF samples (pleocytosis)
Varicella zoster virus (VZV) IUGR, premature birth,Chorioretinitis, cataract,Encephalitis,Pneumonia,CNS abnormalities,Hypoplastic limbs *Newborn and mother

Usually clinical diagnosis is confirmed by appearance of skin lesions (See chickenpox and shingles.) DFA or PCR of fluid collected from blisters or cerebrospinal fluid (CSF) Serology

  • Fetus: PCR for VZV DNA (in fetal blood, amniotic fluid) and ultrasound to detect fetal abnormalities
Parvovirus B19 Aplastic anemia,Fetal hydrops * Mother: serologic assays for IgG and IgM against parvovirus B19

Positive IgM and negative IgG: very recent infection → refer to specialist Positive IgM and IgG: acute infection → refer to specialist Positive IgG and negative IgM: maternal immunity → reassurance Negative IgG and negative IgM: no maternal immunity → counseling

  • Fetus

PCR for parvovirus B19 DNA (amniotic fluid or blood) Doppler ultrasound of fetal vessels in suspected hydrops fetalis

Rubella Petechiae and purpura (blueberry muffin rash)

Congenital rubella syndrome (rare in developed countries):IUGR,Sensorineural deafness,Cataracts,Heart defects (e.g., PDA, pulmonary artery stenosis),CNS abnormalities (e.g., intellectual disability, speech defect),Hepatitis

*Newborn and mother

PCR for rubella RNA (throat swab, CSF) Serology (abnormally high or persistent concentrations of IgM and/or IgG antibodies) Viral culture (nasopharynx, blood)

  • Fetus

IgM antibody serology (chorionic villi, amniotic fluid) PCR for rubella RNA (chorionic villi, amniotic fluid) Newborn and mother

Cytomegaly virus (CMV) Jaundice, hepatosplenomegaly,IUGR,Chorioretinitis,Sensorineural deafness,Periventricular calcifications, Petechiae and purpura (blueberry muffin rash),

Microcephaly,Seizures

*Fetus and newborn: CNS imaging may show hydrocephalus, periventricular calcifications, or intraventricular hemorrhage.
  • Newborn and mother: CMV IgM antibodies (blood), Viral culture or PCR for CMV DNA (urine, saliva)
  • Fetus :Viral culture or PCR for CMV DNA (amniotic fluid), CMV IgM antibodies (fetal blood)
Herpes simplex virus (HSV) Premature birth, IUGR, Skin, eyes, and mouth involvement: vesicular lesions, keratoconjunctivitis, Localized CNS involvement: meningitis ,Disseminated disease: multiple organ involvement, sepsis * Mother: typically clinical diagnosis
  • Fetus: The ultrasound may show CNS abnormalities.
  • Newborn (and mother)
  • Standard: viral culture of HSV from skin lesions, conjunctiva, oro/nasopharynx, or rectum

Alternative: PCR for HSV DNA (CSF, blood)

Epidemiology and Demographics

disease prevalence/ epidemiology
congenital toxoplasmosis reported to be anywhere from 1 in 1000 to 1 in 10,000 births.[19]The rate of congenital infection is about 15% in the first trimester, 25% in the second trimester, and 60% in the third trimester.[20]The severity of congenital infection, however, increases with gestational age. Spiramycin has been reported to decrease the rate of fetal infection by 60%.[21]
congenital rubella syndrome The prototype of the perinatal infections was first recognized by the Australian ophthalmologist Gregg in 1941 during a rubella epidemic.[22]Although large numbers of cases occur in epidemics, the sporadic incidence is low. Eighty to 90% of the adult population is immune, and with the use of rubella vaccine, the susceptible population can be further reduced. Nonetheless, sporadic cases do occur, posing a serious threat to the pregnant woman and her fetus. Although the incidence of rubella reached an all-time reported low in 1988, there has been a distinct increase in the incidence since then, reaching the highest level since 1982 during 1990. Distinct outbreaks seemed to occur in two settings: (1) in locations in which unvaccinated adults congregate, such as workplaces, colleges, and prisons, and (2) among children in religious communities with low levels of vaccination.There also has been an increase in the reported cases of congenital rubella syndrome, but the absolute numbers are quite small.[23]
cytomegalovirus CMV is acquired by 1–2% of all newborns, and approximately 10% of these newborns show some evidence of damage if they are carefully followed. This makes the incidence of significant neonatal infection 1 in 500 to 1000 births. Congenital transmission of CMV can occur with primary infection, reactivation or recurrent maternal infection during pregnancy, although the risk of congenital infection is much higher with primary infection (30–40% with primary infection versus less than 1% with recurrent infection). Maternal recurrent CMV occurs more frequently than primary infection (1–14% vs. 0.7–4%). [24] There is a steady acquisition of CMV from birth to the reproductive age, by which time 50% of women have serologic evidence of prior infection.CMV is transmitted by contact with infected blood, saliva, urine or by sexual contact. CMV is isolated from the endocervix of 3–5% of sexually active women. This provides for additional exposure during the birth process.[25]
Herpesvirus Most (85%) genital infections are caused by Herpesvirus hominis (HSV) type II, with the major perinatal concern being infection acquired by the infant during the birth process.48 Such infections are infrequent (1 in 5000–20,000), but the morbidity and mortality are high. In contrast, the frequency of maternal infection is relatively high. When prenatal patients are screened by both endocervical culture and observation for lesions, the rate is 0.5–1.0%. The comparison of these rates would indicate a relatively low attack rate, although some authors have suggested that the risk of neonatal infection is as high as 50% when vaginal delivery occurs through an infected birth canal.[26]
Parvovirus The annual incidence of acute parvovirus infection during pregnancy is 1 in 400 pregnancies. The seroconversion rate is approximately 16%. The risk of acute infection is highest for susceptible pregnant women with school age children and those who are teachers. The risk of vertical transmission to the fetus is 33%. [27]
human immunodeficiency virus The human immunodeficiency virus (HIV) epidemic is now over 30 years old. The number of cases of people living with HIV/AIDS globally rose from 29 million in 2001 to 33.2 million in 2007.[28]
Varicella zoster virus The varicella zoster virus (VZV) is a member of the herpesvirus group but is not as well known for its perinatal impact. This is in part due to the fact that infection is rare in pregnancy (90% of adults are immune).[29]
Hepatitis It is not known to cause any fetal or neonatal disease but is, nonetheless, a serious illness. Anyone, pregnant or not, who is exposed by contact or travel in endemic areas should receive immune serum globulin (0.02–0.05 mL/kg). If exposure is prolonged and close, the higher dose should be used and repeated every 4–6 months.[30]
Influenza Influenza is one of the more common viral infections to which pregnant women are exposed. When epidemics occur, the problem is magnified because of the patient's susceptibility to a new strain. In addition to the risks of seasonal influenza, pregnant women have experienced excess mortality during the influenza pandemics of 1918–19, 1957–58, and, most recently, the 2009 H1N1 pandemic.[31]
Mumps Mumps is a rare complication of pregnancy, with estimates of incidence varying from 0.8 to 10 cases per 10,000. The severity of the disease is not greater in pregnancy, and 30% of infections are asymptomatic.[32]
Genital condylomata Although the exact prevalence is not known, new techniques, especially DNA sequencing, provide evidence of the ubiquity of this infection. Although the major concern about HPV in women is its role in genital dysplasia and neoplasia, the other concern in pregnancy is fetal/neonatal infection.[33]
group B streptococcal infection Despite the high colonization rate of GBS, the attack rate is quite low. Early-onset infection occurs at a rate of 3–4 per 1000 live births and is manifest within the first 5–7 days of life, usually within 48 hours.[34]
Listeriosis here is very little known about its ecology, colonization rates, or attack rates. There are several reasons for this lack of information, including the difficulties in culturing the organism in the laboratory and its morphologic similarity to diphtheroids [35]
Tuberculosis During the 19th and early 20th centuries, it was the subject of many novels and dramatic operas. The advent of chemotherapeutic agents radically changed the attitudes toward and management of this dreaded disease.[36]The development of effective treatment has essentially reduced the possibility of this disease having any substantial effects on pregnancy.There may be an increase in disease activity in the postpartum period, but since the advent of effective therapy this has little clinical significance. [37]
Syphilis The incidence of syphilis in adults has risen dramatically in the past few years, particularly in endemic urban areas. Congenital syphilis is also seen with increasing frequency in these same areas.[38]
Gonorrhea Maternal infection most often is asymptomatic, and in some populations the rate of endocervical colonization exceeds 5%. Salpingitis rarely occurs in the first trimester, and with PROM, cervical colonization can lead to chorioamnionitis in late pregnancy. [39] Disseminated gonorrhea occurs in pregnancy;[40] gonococcal arthritis has a special propensity for pregnancy, with 40% of cases occurring in gravidas.[41]
Mycoplasmas These associations have not been conclusively established, and, consequently, treatment should be used only if there is reasonable evidence for causality in a given situation.[42]
Chlamydia The rate of asymptomatic cervical infection in obstetric populations is high (5–10%), as is urethral infection in the male (sexual transmission occurs). Newborns acquire the organism at birth in significant numbers, and conjunctivitis is common. [43]
Salmonella Typhoid fever is currently a rare disease in the United States. When the disease does occur in pregnancy, it may, like any serious febrile illness, result in spontaneous abortion or premature labor. In those cases in which the exposure of the fetus to maternal disease has been less than 2–3 weeks, the organism has not been recovered from aborted fetuses.[44]
Trichomonas vaginalis Trichomonas vaginalis is likely the most common parasite to infect women. Newborns can be infected at birth; however, the manifestations are generally benign.[45]
Malaria Malaria is not a common problem for obstetric practice in the United States, but in endemic areas it is a serious concern and a leading cause of anemia in pregnancy. Perhaps the most likely consideration is a pregnant woman who must travel to an endemic area [46]
Candidiasis Vaginitis caused by Candida albicans is very common during pregnancy. [47]
Coccidioidomycosis Coccidioides immitis most often produces a rather benign and self-limited respiratory infection. It is endemic in the Southwestern United States and in 10% of cases progresses to disseminated infection. If the latter occurs in pregnancy, the placenta may be involved; however, there are no documented cases of congenital infection.[48]

Age

  • Patients of all age groups may develop perinatal infection.

Gender

  • perinatal infection affects boy and girls children equally.

Race

  • There is no racial predilection for perinatal infection.

Risk Factors

  • Common risk factors in the development of Perinatal infection. [49]are
Fetal causes maternal causes
Birth weight chorioamnionitis
Ceseran delivary Hypertension (pregestational and gestational including preeclampsia)
Multiple delivary Diabetes (pregestational and gestational)
Fetal distress
Meconium aspiration
Patent ductus arteriosus

Infant outcomes

Infant outcome
Mechanical ventilation
Pneumothorax
Respiratory distress syndrome
Chronic lung disease
Necrotizing enterocolitis
Interventricular hemorrhage
Hypoxic - ischemic encephalopathy
Retinopathy of prematurity
Extracorporeal life support
In hospital death

In addition, we evaluated combined grade 3 and grade 4 intraventricular hemorrhage and combined stages 3 through 5 ROP to align with common categorization of these more clinically important outcomes.

Natural History, Complications and Prognosis

Early clinical features include

Feature CMV LCM VIRUS Rubella virus Toxoplasma gondii Treponema pallidum Zika virus
Systemic
Jaundice +++ - ++ +++ +++ -
Hepatosplenomegaly +++ - ++ +++ ++ -
Rash Petechial Bullous (rare) Petechial “blue-berry” Petechial Petechial -
Anemia ++ - + - + -
Neurologic/eye
Microcephaly ++ + ++ +/- - +++
Macrocephaly +/- ++ - +++ - +
Chorioretinitis + +++ + +++ + ++
Cataract - - ++ - - +
-: not seen; +/: rare; +: occasional; ++: common; +++: very common.[50]


Diagnosis

Diagnostic Criteria

  • The diagnosis of [perinatal diagnosis] [51]is made when
  • Chlamydia can be diagnosed by taking a cotton swab sample of the cervix and vagina during the third trimester of the pregnancy. Chlamydial cell cultures take three to seven days to grow. DNA probes are available for more rapid diagnosis.
  • Past or recent infection with cytomegalovirus (CMV) can be identified by documentation of seroconversion of a previously seronegative patient (the development of IgG antibodies to CMV in a patient who was previously negative for these antibodies) and CMV can be grown from body fluids.[52]
  • Genital herpes is suspected with the outbreak of a particular kind of genital sore. The sore can be cultured and tested to confirm that HSV-2 is present.
  • Hepatitis B can be identified through a blood test for the hepatitis B surface antigen (HBsAg) in pregnant women. The test is part of prenatal health programs.
  • Human immunodeficiency virus (HIV) can be detected using a blood test and is part of most prenatal screening programs.
  • Human papillomavirus (HPV) causes the growth of warts in the genital area. The wart tissue can be removed with a scalpel and tested to determine what type of HPV virus caused the infection.
  • Pregnant women are usually tested for antibodies to rubella, which would indicate that they have been previously exposed to the virus and, therefore, would not develop infection during pregnancy if exposed.
  • Group beta streptococcus (GBS) can be detected by a vaginal or rectal swab culture and sometimes from a urine culture. Blood tests can be used to confirm GBS infection in infants who exhibit symptoms.
  • Pregnant women are usually tested for syphilis as part of the prenatal screening, generally with a blood test.
  • ZIKA virus Methods for testing include both serologic and molecular tests. Laboratory tests in include ZIKV IgM, ZIKV NAT, and plaque reduction neutralization testing.[53]

History and Symptoms

If a developing fetus is infected by a TORCH agent, the outcome of the pregnancy may be miscarriage, stillbirth, delayed fetal growth and maturation (intrauterine growth retardation), or early delivery. In addition, newborns infected by any one of the TORCH agents may develop a spectrum of similar symptoms and findings. These may include

  • listlessness (lethargy),
  • fever,
  • difficulties feeding,
  • enlargement of the liver and spleen (hepatomegaly),
  • and decreased levels of the oxygen-carrying pigment (hemoglobin) in the blood (anemia).In addition, affected infants may develop
  • areas of bleeding, resulting in reddish or purplish spots or areas of discoloration visible through the skin (petechia or purpura);
  • yellowish discoloration of the skin, whites of the eyes, and mucous membranes (jaundice);
  • inflammation of the middle and innermost layers of the eyes (chorioretinitis); and/or other symptoms and findings.

Each infectious agent may also cause additional abnormalities that may vary in degree and severity, depending upon the stage of fetal development at time of infection and/or other factors. Following is a more specific description of the TORCH agents. Toxoplasmosis is an infectious disease caused by the microscopic parasitic organism called Toxoplasma gondii. Classic triad of toxoplasmosis Chorioretinitis (a form of posterior uveitis), Diffuse intracranial calcifications,Hydrocephalus Rubella is a viral infection characterized by fever, upper respiratory infection, swelling of the lymph nodes, skin rash, and joint pain. Severely affected newborns and infants may have visual and/or hearing impairment, heart defects, calcium deposits in the brain, and/or other abnormalities. Cytomegalovirus (CMV) Infection is a viral infection that may occur during pregnancy, after birth, or at any age. In severely affected newborns, associated symptoms and findings may include growth retardation, an abnormally small head (microcephaly), enlargement of the liver and spleen (hepatosplenomegaly), inflammation of the liver (hepatitis), low levels of the oxygen-carrying pigment in the blood due to premature destruction of red blood cells (hemolytic anemia), calcium deposits in the brain, and/or other abnormalities.Neonatal Herpes is a rare disorder affecting newborns infected with the Herpes simplex virus (HSV). This disorder may vary from mild to severe. In most cases, the disorder is transmitted to an infant from an infected mother with active genital lesions at the time of delivery. In the event that a mother has a severe primary genital outbreak, it is possible that a mother may transmit the infection to the fetus. After delivery, direct contact with either genital or oral herpes sores may result in neonatal herpes. Severely affected newborns may develop fluid-filled blisters on the skin (cutaneous vesicles), lesions in the mouth area, inflammation of the mucous membrane lining the eyelids and whites of the eyes (conjunctivitis), abnormally diminished muscle tone, inflammation of the liver (hepatitis), difficulties breathing, and/or other symptoms and findings. Parvovirus B19 Infection during pregnancy occurs in 1–5% of pregnancies. The virus can cause miscarriage, fetal anaemia, hydrops fetalis (abnormal accumulation of fluid in the fetal tissues), myocarditis, and/or intrauterine fetal death. Syphilis Early congenital syphilis: Hepatomegaly and jaundice, Rhinorrhea with white or bloody nasal discharge , Maculopapular rash on palms and soles , Skeletal abnormalities (e.g., metaphyseal dystrophy, periostitis) Generalized lymphadenopathy (nontender ListeriosisIntrauterine transmission ,Increased risk of premature birth and spontaneous abortion ,Early-onset syndrome: granulomatosis infantiseptica ,Severe systemic infection characterized by disseminated abscesses (may develop in any organ system) ,Most common findings: respiratory distress and skin lesions,Signs of meningitis may already develop.Transmission during birth or postnatally (via contact with the mother or contaminated environment) enterovirus Wide spectrum of clinical presentations, from non-specific febrile illness to fatal multisystem disease, Fever, irritability,poor feeding, lethargy,Maculopapular rash in 50% ,Respiratory symptoms in 50% ,Gastrointestinal symptoms in 20% , Hepatitis in 50% May have myocarditis, meningoencephalitis

Physical Examination

Finding(s) Possible congenital infections
Intrauterine growth retardation Rubella, cytomegalovirus (CMV), toxoplasmosis
Anemia with hydrops Parvovirus B19, syphilis, CMV, toxoplasmosis
Bone lesions Syphilis, rubella
Cerebral calcification
  • Toxoplasmosis (widely distributed)
  • CMV and herpes simplex virus (HSV) (usually periventricular)
  • Parvovirus B19, rubella, human immunodeficiency virus (HIV)
  • Lymphocytic choriomeningitis virus
Congenital heart disease Rubella
Hearing loss (commonly progressive) Rubella, CMV, toxoplasmosis, syphilis
Hepatosplenomegaly CMV, rubella, toxoplasmosis, HSV, syphilis, enterovirus, parvovirus B19
Hydrocephalus Toxoplasmosis, CMV, syphilis, possibly enterovirus
Hydrops, ascites, pleural effusions Parvovirus B19, CMV, toxoplasmosis, syphilis
Jaundice with or without thrombocytopenia CMV, toxoplasmosis, rubella, HSV, syphilis, enterovirus
Limb paralysis with atrophy and cicatrices Varicella
Maculopapular exanthem Syphilis, measles, rubella, enterovirus
Microcephaly CMV, toxoplasmosis, rubella, varicella, HSV
Myocarditis/encephalomyocarditis Echovirus, coxsackie B, other enterovirus
Ocular findings CMV, toxoplasmosis, rubella, HSV, syphilis, enterovirus, parvovirus B19
Progressive hepatic failure and clotting abnormalities Echovirus, coxsackie B, other enterovirus, HSV, toxoplasmosis
Pseudoparalysis, pain Syphilis
Vesicles HSV, syphilis, varicella, enterovirus

Laboratory Findings

  • rubella may be diagnosed by detection of specific IgM, but virus detection is the technique of choice.
  • VZV may be diagnosed by serological techniques in up to 71% of cases. Detection of virus in vesicle scrapings or swabs from the oropharynx is the technique of choice for neonatal HSV.
  • enterovirus infections are best diagnosed by detection of viral RNA.
  • HIV-1 may be diagnosed within 3 months of birth by testing serial blood samples with a combination of techniques. Maternal infection with HBV, HCV, HIV and HTLV1/11 may be diagnosed by serological techniques and genital PVs by detection of viral DNA. Chorionic villus samples, amniotic fluid and fetal blood may be obtained for prenatal diagnosis of infection.
  • detection of virus in amniotic fluid is the technique of choice for prenatal diagnosis of CMV, insufficient data is currently available to determine whether it may be used for intrauterine rubella.
  • The most reliable technique for diagnosis of fetal B19 infection is detection of viral DNA .

the use of TORCH screening should be discouraged.[54]

Electrocardiogram

There are no ECG findings associated with [perinatal inectioon].

X-ray

There are no x-ray findings associated with perinatal infection.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with perinatal infection.CT scan may be helpful in the diagnosis of Toxoplasmosis include dilated ventricles with multiple subependymal and parenchymal calcifications .

MRI may be helpful in the diagnosis of [Toxoplasmosis]. Findings on MRI suggestive of/diagnosis include ring enhanced lesion

Imaging features of selected congenital infections [55]

Imaging feature CMV LCM virus Rubella virus Toxoplasma gondii Zika Virus
Calcifications +++ +++ +++ +++ +++
Polymicrogyria +++ ++ - - +++
Hydrocephalus + (passive) ++ (obstructive and passive) - ++ (obstructive) ++ (obstructive and passive)
Lissencephaly ++ + - - ++
Cerebellar hypoplasia ++ + - - ++
White matter lesions +++ +/- ++ + ++
Fetal brain disruption - - - - +++

CMV=cytomegalovirus; LCM virus =lymphocytic choriomeningitis virus. (-) absent; (+) uncommon or rare; (++) common; (+++) very common.

There are no other diagnostic studies associated with perinatal infection

Treatment

Disease Medical Therapy Surgery prevention
Toxoplasmosis *Mother: immediate administration of spiramycin
  • Fetus: When confirmed or highly suspected, switch to pyrimethamine, sulfadiazine, and folinic acid.
  • Newborn: pyrimethamine, sulfadiazine, and folinic acid.[56]
*Avoid raw, undercooked, and cured meats.
  • Wash hands frequently, especially after touching soil (e.g., during gardening).
  • Avoid contact with cat litter. [56]
Rubella Intrauterine rubella infection

> 16 weeks: reassurance Congenital rubella syndrome: supportive care (based on individual disease manifestations) and surveillance (including monitoring for late-term complication

*Immunization of seronegative women before pregnancy
  • Nationally notifiable condition: Suspected congenital rubella syndrome must be reported to the local or state health department.[57]
Cytomegalovirus Fetus

Severe anemia: intrauterine blood transfusions Thrombocytopenia: platelet transfusions Newborn Supportive therapy of symptoms (e.g., fluid/electrolyte imbalances, anemia, thrombocytopenia, seizures, secondary infections) Ganciclovir, valganciclovir, or foscarnet Mother: valacyclovir is the only therapy approved during pregnancy; trials with CMV specific hyperimmune globulin ongoing.

Frequent hand washing

Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics) [58]

Herpesvirus Acyclovir & Supportive care only for herpes simplex [59] :Cesarean section in women with active genital lesions or prodromal symptoms (e.g., burning pain) *Antiviral therapy (acyclovir) beginning at 36 weeks of gestation for individuals with a known history of HSV lesions
  • Cesarean section in women with active genital lesions or prodromal symptoms (e.g., burning pain)[60]
Parvovirus Intrauterine fetal blood transfusion in cases of severe fetal anemia *Hand hygiene (frequent hand washing)
  • Pregnant women with risk factors for TORCH infection should avoid potentially contaminated workplaces (e.g., schools, pediatric clinics).[61]
Acquired immunodeficiency syndrome (AIDS) As a result of the AIDS Clinical Trials Group (ACTG) Protocol 076, the US Public Health Service[62] published recommendations for the use of ZDV or AZT to reduce the risk of HIV transmission from infected women to their infants. These recommendations are as follows:
  • Antepartum: ZDV, 100 mg orally five times per day, starting at 14–34 weeks.
  • Intrapartum: ZDV, 2 mg/kg intravenously (IV), loading dose, given over 1 hour, followed by 1 mg/kg/hr IV until delivery.
  • Newborn: ZDV syrup 2 mg/kg orally every 6 hours, beginning 8–12 hours after birth for the first 6 weeks of life
Vertical transmission reduced to approximately 2% if a scheduled cesarean section is performed.82, 83 It is not yet known if there is a significant benefit from cesarean delivery in patients who have viral loads of less than 1000 copies/ml who are on HAART. Maternal morbidity is greater with cesarean delivery, particularly in those women with low CD4 cell counts. Therefore, women who are HIV positive must be counseled about the maternal risks and potential benefits of both ZDV prophylaxis and cesarean delivery so that they can make informed choices. If cesarean delivery is chosen, it should be performed electively at 38 weeks of gestation. ZDV should begin 3 hours prior to delivery. It is important to use perioperative prophylactic antibiotics to reduce maternal infectious morbidity. The management of labor (if the patient chooses this option) should include avoidance of scalp electrodes and scalp sampling. Research is needed to determine the appropriate management of HIV-infected women who present with rupture of membranes and who have an undetected viral load.[63] ,[64] The newborn should be carefully cleaned of maternal blood and secretions, especially when drawing blood. There is no evidence that the postpartum course is altered. The virus has been isolated from breast milk, and although the risk of transfer is not known, breastfeeding is not recommended when there is a suitable alternative, as exists in the developed world.84, 85 A final step in the case of the HIV-infected patient is to see that the patient receives ongoing care. Even if she is asymptomatic after delivery, she will require support and surveillance for disease progression[65] ,[66]
Varicella zoster virus For pregnant women or newborns with (severe) infection: acyclovir

Administer postexposure prophylaxis in newborns if mother displays symptoms of varicella < 5 days before delivery: IgG antibodies (varicella-zoster immune globulin, VZIG)

*Immunization of seronegative women before pregnancy
  • VZIG in pregnant women without immunity within 10 days of exposure

[67]

Hepatitis Hepatitis A:pregnant or not, who is exposed by contact or travel in endemic areas should receive immune serum globulin (0.02–0.05 mL/kg). If exposure is prolonged and close, the higher dose should be used and repeated every 4–6 months.[68] * Hepatitis B: infants born to mothers with circulating HBV. These infants, if chronically infected, are at high long-term risk for hepatic cancer. Because of this and because it is possible to prevent perinatal transmission, particularly if infection occurs in late pregnancy, testing for HBV surface antigen is recommended as a part of routine prenatal testing. [69] Infants born to HBV-positive mothers should receive 0.5 mL of hepatitis B immune globulin within 12 hours of birth and simultaneously receive the first dose of HBV vaccine (half the adult dose). The remaining doses should follow the adult schedule. There is no reason to modify the obstetric management because cesarean delivery will not modify the risk. The HBV vaccine now in use is a recombinant product, poses no infectious risk, and can be used in pregnancy for women at risk. Complete immunization requires the initial dose with repeated doses at 1 and 6 months. Healthcare workers should know their HBV immune status and, if susceptible, should be vaccinated.* Hepatitis C: At present, no vaccine is available for HCV, and there are insufficient data to recommend pregnancy termination. The management of the pregnant woman infected with HCV must be individualized until further evidence is available to make reasonable recommendations.[70]
Influenza Prompt empiric treatment with appropriate neuraminidase inhibitors (oseltamivir and zanamivir) appeared to decrease the risk of severe disease. [71] Preterm delivery and cesarean delivery were commonly associated with maternal illness with preterm birth rates as high as 30% and cesarean section rates of nearly double the current national baseline.[72] Influenza vaccination is now an important component of antenatal care. The CDC recommends that women who will be pregnant during the flu season (October through mid May) be vaccinated. [73] Vaccination may be performed in all three trimesters. Specific vaccines prepared for epidemic strains are more effective than the poly antigenic preparations. Complications of vaccination are generally mild, except for Guillain-Barré syndrome. This is characterized by progressive ascending paralysis but fortunately is usually self-limited and reversible. Evidence from the swine flu epidemic of 1976 suggests that the incidence is approximately 1 in 100,000 vaccinations. The frequency of complications does not appear to be altered by pregnancy. The theoretical risks of vaccination are outweighed by its benefits.
Genital condylomata The treatment of choice for large-volume and symptomatic disease is the carbon dioxide (CO2) laser, [74] and it is suggested that treatment with it be carried out in the third trimester to reduce the chances of recurrence from latent HPV infection at the time of delivery. Interferons have been used successfully [75] but are not yet approved for clinical use.Trichloroacetic acid is the best choice for isolated or small-volume genital disease.[76] There is almost never a reason to perform a cesarean section for condylomata if the patient is seen sufficiently early in pregnancy to accomplish treatment.
Group B streptococci As stated earlier, penicillin is the drug of choice for GBS treatment and prophylaxis. Ampicillin is an acceptable alternative. Penicillin is preferred due to its narrow spectrum of activity. Five million units of penicillin G is given as the loading dose. This is followed with 2.5–3.0 million units every 4 hours until delivery. The dose of ampicillin is 2 g loading followed by 1 g every 4 hours. Increased resistance of GBS isolates to second-line therapies has been noted. Susceptibility testing should be ordered in patients who are allergic to penicillin. Cefazolin is recommended for patients that are not at high risk for anaphylaxis. Two grams are given intravenously followed by 1 g every 8 hours. If the patient is a high risk of anaphylaxis, treatment would depend on the susceptibility of the isolate. Clindamycin (900 mg IV every 8 hours). Erythromycin is no longer an acceptable alternative for penicillin allergic women at high risk for anaphylaxis. Patients at high risk of anaphylaxis with unknown susceptibility or resistance to clindamycin, should be treated with vancomycin. The dose of vancomycin is 1 g every 12 hours until delivery. It must be emphasized that vancomycin is reserved for patients at high risk for anaphylaxis.[77] Women with intact membranes who present with threatened preterm delivery and unknown GBS status should receive IAP until GBS culture results are available. If GBS is negative, or the patient is not in true labor, IAP may be discontinued and re-screening should be done at 35–37 weeks.[78]
Listeriosis IV ampicillin and gentamicin (for both mother and newborn) *Avoidance of soft cheeses
  • Avoidance of potentially contaminated water and food: See “Food and water safety” in food poisoning.
  • Nationally notifiable condition: Listeriosis must be reported to the local or state health department.[79]
Tuberculosis * recent converters should be treated with isoniazid, 300 mg/day, starting after the first trimester and continuing for 6–9 months. Women younger than 35 years of age with a positive PPD of unknown duration should receive isoniazid, 300 mg/day, for 6 months after delivery.
  • Patients with active disease should be started on treatment immediately on diagnosis, with dual-agent therapy for 9 months. Isoniazid 300 mg/day, combined with rifampin, 600 mg/day, is the standard. Ethambutol, 2.5 g/day, may be substituted in case of resistance. Pyridoxine (vitamin B6) supplementation, 50 mg/day, is essential for all patients receiving isoniazid. None of these medications are known to have adverse effects in pregnancy. Breastfeeding is considered safe during maternal treatment as long as the infant is not receiving antituberculous therapy. Infants born to women with active tuberculosis should receive isoniazid prophylaxis (10 mg/kg/day) until maternal disease has been inactive for 3 months. [80]
Prophylaxis is not recommended for women older than 35 years of age in the absence of active disease because of concern about hepatotoxicity.
Syphilis Therapy is indicated in the gravida with a positive FTA-ABS of recent onset, and the drug of choice is penicillin. [81] The regimen recommended is the same as in the nonpregnant woman. For early syphilis, a single dose of 2.4 million units of benzathine penicillin G is recommended. Some recommend a follow-up dose 1 week later, particularly in the third trimester. For late-stage syphilis (more than 1 year of duration), three doses are recommended. For the patient allergic to penicillin, treatment with penicillin after oral desensitization is recommended. This should be done in a facility that has appropriate provisions for resuscitation, if needed. [82] *Maternal screening in early pregnancy
  • Nationally notifiable condition: Congenital syphilis and syphilitic childbirth must be reported to local or state health department.[83]
Gonorrhea current recommendations include one of the following regimens:
  • Ceftriaxone, 125 mg IM, single dose
  • Cefixime, 400 mg orally, single dose
  • Spectinomycin, 2 g IM, single dose (for patients who cannot tolerate a cephalosporin).

In addition, treatment for Chlamydia should be administered because of the likelihood of coinfection. [84] Disseminated infection in the newborn requires high-dose treatment, and ophthalmic infection should be treated both locally and systemically.

Prevention of perinatal infection is best accomplished by careful maternal screening and treatment.[85]
Mycoplasmas The treatment for the pregnant woman and the neonate is clindamycin for Mycoplasma hominis and erythromycin for M. pneumoniae and Ureaplasma urealyticum.[86] These associations have not been conclusively established, and, consequently, treatment should be used only if there is reasonable evidence for causality in a given situation.[87]
Chlamydia Recommended treatment for pregnancy includes the following:[88]

Erythromycin base, 500 mg, or erythromycin ethylsuccinate, 800 mg orally four times daily for 7 days Amoxicillin, 500 mg orally three times daily for 7 days Azithromycin, 1 g orally as a single dose

The question of maternal screening and prophylactic treatment to prevent neonatal infection is unsettled. As diagnostic studies have become more readily available, screening has become more practical. The decision to routinely screen a prenatal population should probably be based on a determination of the specific population prevalence.[89]
Salmonella Treatment is chloramphenicol, despite the existence of some resistant strains. Alternate antibiotics are ampicillin or amoxicillin (combination of trimethoprim and sulfamethoxazole is useful for resistant strains but avoided in pregnancy if possible). Aspirin should be avoided because patients with typhoid are extremely sensitive and severe hypothermia may result. Hornick RB: Nontyphoidal salmonellosis. [90] Prevention is best accomplished by sanitation and hygienic processes and the control of faulty food processing. [91]
Trichomonas vaginalis Because of evidence of a possible relationship between vaginal trichomoniasis and adverse pregnancy outcomes, metronidazole, 2 g orally as a single dose, can be given after the first trimester.[92]
Malaria Perhaps the most likely consideration is a pregnant woman who must travel to an endemic area.3 Chloroquine phosphate, 500 mg once a week starting 1 week before the trip and continuing for 6 weeks after, is the recommendation. This can be safely given to pregnant women. [93]
Zika virus *Avoidance of travel to ZIKv endemic areas during pregnancy.
  • The use of N,N-Diethyl-meta-toluamide, which has been recommended in pregnancy to prevent ZIKV infection,85 long sleeves and pants or permethrin-treated clothing, and use of mosquito nets and window screens if living in or traveling to an endemic area.
  • If living in an endemic area, areas of standing water (such as tires, buckets,planters, etc) should be eliminated because they are a breeding area for mosquitoes.
  • All pregnant women and their partners should receive counseling on prevention measures including avoidance of mosquito bites and sexual transmission.
  • If a couple has a male partner and he travels to an area with ZIKV, they should use condoms or abstain from sexual activity for 6 months (even in the absence of symptoms).
  • If a female travels to an area with risk of ZIKV, condoms or abstinence from sexual activity for 8 weeks (even in the absence of symptoms) is recommended.
  • If a pregnant patient and her partner travel to or live in an area with ZIKV, condoms should be used each time the couple has sex for the remainder of pregnancy, or they should abstain from sexual activity. [94]


Prevention

Minimizing the risk of transmitting a maternal infection to a fetus is often a major concern for parents. The first step is identifying possible maternal infections. Proper prenatal care in many cases allows for early diagnosis and thus early treatment of certain infections, thus improving the newborn's prognosis [95]

A woman's nutritional status may contribute to her ability to fight off infections, particularly in cases of malnutrition . A well-balanced diet rich in nutrients such as folic acid , calcium, iron, zinc, vitamin D, and the B vitamins is recommended for pregnant women. Mothers are recommended to eat approximately 300 additional calories day (above and beyond a normal non pregnancy diet) to support the fetus's growth and development [96]

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