Infections of the Fetus and Newborn Infant

References: The Centers for Disease Control document- http://www.cdc.gov/nchstp/dstd/Stats_Trends/1999Surveillance/99PDF/Surv99Master.pdf

Remington, JS and Klein, JO. 1995. Infectious Diseases of the Fetus & Newborn Infant. W.B. Saunders Company. Philadelphia, PA. ISBN: 0-7216-6782-1

Introduction 

Live births in the U.S. in 1998 (the latest data available) increased by 2% to 3,941,553. This was the first increase in live births since 1990. The birth rate rose slightly in 1998 to 14.6 births per 1000 total population. The fertility rate which relates births to the number of women of child-bearing age rose 1% to 65.6 births per 1000 women of 15-44 years of age. The incidence of infections among these 3.9 million live births is unknown. However, approximate numbers can be extrapolated from selected studies. About 1% of all newborn infants excrete CMV. Up to 15% of infants are infected with Chlamydia trachomatis. About 33% of infants infected with C. trachomatis develop conjuntivitis with one sixth developing pneumonia. One to 8 infants per 1000 live births develop bacterial sepsis. Congenital or perinatal infections with HSV, Toxoplasma gondii, and VZV occurs in about 1 infant per 1000 live births. Unfortunately, the sequelae of infection with HSV, T. gondii, and VZV are usually severe. The incidence of perinatally acquired HIV is 25% in children born to HIV positive women. There are about 200 pediatric HIV infections per year. There were 14.3 cases of congenital syphilis per 100,000 live births in 1999.
 

Important Points to Remember Concerning Congenital Infections.

1. The time to provide information to mothers about these infections is before pregnancy begins, because this is the best time for preventive measures.
2. The first trimester is usually the most dangerous time for the mother to acquire these infections, because there is a greater risk of the fetus being affected.
3. Infection in the mother can often be accompanied by very trivial symptoms, or even none at all, so the condition is not usually diagnosed.
4. Infection in the mother does not always mean the baby will be affected.  For many infections, the baby is more at risk at particular stages of pregnancy (for example, first trimester for Rubella, at delivery for HSV).
5. Some infections can be avoided by the mother through simple measures, such as immunization (Rubella, VZV) during childhood and before pregnancy.  Some infections are treatable (ex. syphilis is treated effectively with penicillin).

Bacteria
Treponema pallidum, Mycobacterium tuberculosis, Salmonella typhosa, Listeria monocytogenes, Campylobacter fetus, Borrelia burgdorferi.

Fungi
Candida albicans

Parasites
Toxoplasma gondii, Plasmodium spp., Trypanosoma cruzi.

The more common organisms causing congenital infections include:
CMV, HSV, Erythrovirus (Parvovirus) B19, Rubella, Hepatitis B virus, HIV, VZV, Treponema pallidum, Toxoplasma gondii.

Pregnant women are exposed to the infections in the community and are also more likely to be exposed to infections associated with young children. These children are often sick and represent a significant additional factor in exposure to infectious diseases. The vast majority of infections in pregnant women involve the upper respiratory tract and the gastrointestinal tract. These infections usually resolve spontaneously or resolve after treatment with antimicrobial agents. Such infections remain localized and have no effect on the developing fetus. However, if the infecting organism invades the bloodstream, infection of the fetus may ensue. The most common means of infection of the fetus is via the bloodstream. Less common means of infections include: extension of infection in adjacent tissues and/or organs, or as a result of invasive procedures for diagnosis and therapy of fetal disorders (ex. monitors, sampling fetal blood, intrauterine transfusions).

Results of infection of the embryo and fetus
Infection of the embryo or fetus can result in: death and resorption of the embryo, abortion and stillbirth of the fetus, and live birth of a premature or term infant who may or may not be normal. The effects of in utero infection appear in the live-born infant as low birth weight, developmental abnomalies, congenital disease or none of these. Infections acquired in utero may persist after birth and cause significant abnormalities soon after birth or may not be recognized for months or years.
 

	Effect of Infection on the Fetus and Newborn Infant
Organism or disease	Prematurity	In utero Growth Retardation and Low Birth Weight	Developmental Anomalies	Congenital Disease	Persistant Postnatal Infection
Viruses
Rubella	-	+	+	+	+
CMV	+	+	+	+	+
HSV	+	-	-	+	+
VZV	-	(+)	+	+	+
Enteroviruses	-	-	(+)	+	-
Hepatitis B	+	-	-	+	+
HIV	(+)	(+)	(+)	+	+
Erythrovirus B19 (Parvovirus B19)	-	-	-	+	-
Bacteria
Treponema pallidum	+	-	-	+	+
Mycobacterium tuberculosis	+	-	-	+	+
Listeria monocytogenes	+	-	-	+	-
Campylobacter fetus	+	-	-	+	-
Salmonella typhosa	+	-	-	+	-
B. burgdorferi	-	-	-	+	-
Parasites
Toxoplasma gondii	+	+	-	+	+
Plasmodium spp.	(+)	+	-	+	+
Trypanosoma cruzi	+	+	-	+	-

+ = evidence for effect; - = no evidence for effect; (+) = association of effect with infection has been suggested and is under consideration.

Rubella and Treponema pallidum infections have been discussed previously. Refer to those lectures to refresh your memories.

Toxplasma gondii
Toxoplasmosis is mainly acquired from cat feces or eating undercooked meat.  The infection may be asymptomatic or produce only mild symptoms in the mother.  Infection early in the pregnancy may cause the death of the fetus and abortion;  infection later can cause fetal damage, stillbirth or a liveborn infant with damage to the brain and body organs.
Infection in the mother does not always cause congenital disease in the baby.  Overall, the rate of transmission is about 50% and is dependent upon the stage of the pregnancy during which the maternal infection developed.  The risk of fetal infection is fifteen, forty-five and seventy per cent during the first, second and third trimesters respectively.  In contrast the risk of fetal damage resulting in spontaneous abortion or symptomatic disease at birth is greatest if infection occurs early in pregnancy.

While severe disease is seen in 80% of infants delivered to mothers who acquired the infection in the first trimester, only 50% of infants are symptomatic at birth if the maternal infection was acquired in the second trimester.  Although maternal infection in the third trimester rarely results in fetal damage, neurological injury and chorioretinitis may appear months or years later.  Symptomatic babies are born with hydrocephalus, chorioretinitis and cerebral calcification.

Treatment of the mother with spiramycin appears to reduce the incidence of vertical transmission by 60%.

Cytomegalovirus
Cytomegalovirus (CMV) is the most common cause of in utero infections.  About 50% of women of child-bearing age remain susceptible to CMV infection and 1% of women who are susceptible at the beginning of pregnancy will acquire a primary infection during pregnancy.  Unlike rubella, fetal damage may follow primary infection, or rarely recurrent infection, at any stage of pregnancy.  Risk of fetal infection is greatest (30-40%) during primary maternal infection.  Nevertheless, only 10% of infants born with congenital CMV are symptomatic at birth.  These more severely affected infants are more likely to have been exposed to a primary maternal infection during the first trimester.  Most (80-90%) infants who are symptomatic at birth (hepatosplenomegaly, jaundice, petechiae and microcephaly) and another 10% of infants with asymptomatic infection at birth develop late complications such as deafness, intellectual disability, or seizures.

Herpes Simplex Virus
Most studies have revealed a large number of HSV infections in women. 30-40 percent of all adults are seropositive. One in 5 pregnant women has had a HSV-2 infection. In utero infections of the fetus are rare. The most severe infections will result in a triad of symptoms:

1. skin vesicles or scarring,
2. eye disease (chorioretinitis along with other eye findings such as keratoconjunctivitis), and
3. microcephaly or hydranencephaly. Less severe infections will result in fewer symptoms.

The most common route of infection occurs during delivery (intrapartum). Infection with HSV in the infant is almost invariably symptomatic and frequently lethal. Infants who are infected intrapartum and postnatally can be divided into 3 different catagories:

1. disease localized to the skin, eye, or mouth;
2. encephalitis with or without skin, eye, or mouth involvement;
3. disseminated infection that involves multiple organs, including the CNS, lung, liver, adrenals, skin, eye, and /or mouth.

Erythrovirus (Parvovirus) B19
A very common viral infection of children that if symptomatic results in Erythema infectiosum (Slapped cheek syndrome; fifth disease). It infects and lyses human erythroblasts. Only 5% of children under 5 years of age are infected but by the time they are 5 years old 20-40% of them are infected. By age 50-75% of the people are seropositive. A seronegative pregant women can become infected and the infection can infect the fetus in utero. Sixty to 70% of the women of child bearing age are susceptable to infection however, only 1.1% of those susceptable women exposed to the virus are infected. Perinatal and intrapartum infections are very rare. Infections in utero can result in fetal death (rare), nonimmune fetal hydrops (uncommon), birth defects (eyes, CNS), and prematurity.

Hepatitis B virus
Can be acquired in utero and perinatally. Most infections are asymptomatic. Unfortunately, asymptomatic infections in the infant are much more likely to develop into chronic hepatitis and hepatocellular carcinoma. Symptomatic infants may have hepatomegaly, splenomegaly, jaundice, and/or icterus.

Varicella Zoster Virus
Quite rare. About 5 cases/10,000 births. More fetal deaths occur if the fetus is infected in the 1st or 2nd trimester. Congenital infections can result in eye abnormalities (chorioretinitis, cataracts) and skin scars.
 

	Clinical Manifestations of Neonatal Infection Acquired In Utero or at Delivery Microorganism
Clinical Sign	Rubella virus	CMV	HSV	Toxoplasma gondii	Treponema pallidum	Streptococcus agalactiae (Grp B) or E. coli
Hepatosplenomegaly	+	+	+	+	+	+
Jaundice	+	+	+	+	+	+
Adenopathy	+	-	-	+	+	-
Pneumonitis	+	+	+	+	+	+
Skin Lesions Petechiae/purpura	+	+	+	+	+	+
Vesicles	-	+	++	-	+	-
Maculopapular exanthems	-	-	+	+	++	-
CNS Lesions Meningoencephalitis	+	+	+	+	+	+
Microcephaly	-	++	+	+	-	-
Hydrocephalus	+	+	+	++	-	-
Intracranial calcifications	-	++	-	++	-	-
Paralysis	-	-	-	-	-	-
Hearing deficits	+	+	-	-	+	-
Heart lesions Myocarditis	+	-	+	+	-	-
Congenital defects	++	-	-	-	-	-
Bone lesions	++	-	-	+	++	-
Eye Lesions Glaucoma	++	-	-	-	+	-
Chorioretinitis or retinopathy	++	+	+	++	+	-
Cataracts	++	-	+	+	-	-
Optic atrophy	-	+	-	+	-	-
Microphtalmia	+	-	-	+	-	-
Uveitis	-	_	-	+	+	-
Conjunctivitis or keratoconjunctivitis	_	_	++	-	-	-

- = either not present or rare in infected infants; + = occurs in infants with infection; ++ = special diagnostic significance for this infection.

Efficiency of Transmission of Some of the Microorganisms from Mother to Fetus
The efficiency of transmission varies depending on the organism and the trimester of pregnancy. In utero transmission of the Rubella virus and Toxoplasma gondii occurs only as a result of a primary infection, whereas CMV and HIV in utero infections have occured for multiple pregnancies.

The risk of congenital infection with Rubella is high in the first trimester (90% before 11 weeks gestation), then declines to 25% at 23-26 weeks, and then rises to 67% after 31 weeks. Infection in the first 11 weeks is uniformly teratogenic however no birth defects occur in infants infected after 16 weeks.

The frequency subclinical congenital Toxoplasma gondii infection is lowest in the first trimester (14%), increases in the second trimester (29%), and is at its highest in the third trimester (59%).

Congenital CMV infections can result from both primary and recurrent infections. One to 4% of women have a primary infection during pregnancy. Forty percent of these women transmit the virus to their fetus. Five to 15% of the infants have signs of CMV disease. Congenital infection due to recurrent CMV is 0.5 to 1% and fewer than 1% of the infected infants have clinically apparent disease.

The transmission of HIV infection in utero is estimated to be about 25%. Infants at risk for congenital infection are those born to symptomatic women who have more advanced disease or who have low CD4 T lymphocyte counts.

The newborn infant is initially colonized on the skin and mucosal surfaces (e.g. nasopharynx, oropharynx, conjunctivae, umbilical cord, external genitalia). In most infants the organisms proliferate on these sites without causing any illness. A few infants may be infected by direct extension (e.g. sinusitis and otitis from the nasopharynx). Invasion of the bloodstream may then occur. The umbilical cord is an common portal of entry for systemic infection. Microorganisms may also infect the infant through abrasions or skin wounds.

Infants who develop sepsis may have certain risk factors that predispose them to infection. These factors include low birth weight, premature or prolonged rupture of maternal membranes, septic or traumatic delivery, fetal anoxia and maternal peripartum infection. Male infants are also more likely to develop sepsis during the newborn period.

Bacteria
Common: Streptococcus pyogenes (Group A Streptococcus), Streptococcus agalactiae (Group B Streptococcus), Enterococcus spp. (group D Streptococcus), Escherichia coli, Neisseria gonorrhoeae, Listeria monocytogenes, Chlamydia trachomatis
Uncommon: Staphylococcus aureus, alpha hemolytic Streptococci, various gram negative rods (ex. Proteus, Salmonella), Haemophilus spp., Bacteriodes spp., Veillonella spp.

Viruses
Common: CMV, HSV (type 2), Hepatitis B virus
Uncommon: HIV

Fungi
Common: Candida albicans
Uncommon: Coccidioides immitis

Parasites
Uncommon: Toxoplasma gondii, Trichomonas vaginalis
 

Streptococcus pyogenes (Group A Streptococcus)= sepsis, pneumonia, meningitis
Streptococcus agalactiae (Group B Streptococcus)= sepsis, pneumonia, meningitis
Enterococcus spp. (group D Streptococcus)= Urinary tract infections, sepsis
Escherichia coli= sepsis, meningitis, pneumonia
Neisseria gonorrhoeae= Opthalmia neonatorium, sepsis
Listeria monocytogenes=  Late onset= sepsis, meningitis, diarrhea
Chlamydia trachomatis= pneumonia and/or conjunctivitis
CMV= Usually asymptomatic
HSV (type 2)= encephalitis= has a high mortality rate.
Hepatitis B virus= Usually asymptomatic, but can have symptoms similar to adults.
Candida albicans= mucocutaneous (common; thrush) and lung (rare) infections

Many infections in pregnant women and newborns are difficult or impossible to diagnose on clinical grounds. Asymptomatic or subclinical infections are commonly seen with the agents that commonly cause congenital infections. The vast majority of women infected during pregnancy have no symptoms. Only 50% of women infected with Rubella present with rash. Very low numbers of pregnant women have signs and symptoms of CMV mononucleosis. The number of women presenting with signs and symptoms of Toxoplasma gondii infection are less than 10%. The genital lesions associated with HSV and syphilis may go unrecognized.

Some organisms may infect a person more than once and when such happens during pregnancy the fetus can also be infected. Reinfections are typically associated with waning host immunity. Fetal disease has been noted following re-exposure of immune mothers to vaccinia, variola, and rubella viruses.

Microbes capable of persisting in the mother as a chronic asymptomatic infection can also infect the fetus. The following chronic infections have resulted in fetal disease: malaria, T. gondii (only happens when the mother is immunocompromised), syphilis, hepatitis, herpes zoster, and HSV. Congenital CMV and HIV infections have been observed in infants from consecutive pregnancies of the same mother.

Acute infection immediately before conception may result in infection of the fetus. Congenital rubella has occurred in the fetus in cases in which the mother was infected 3 weeks to 3 months before conception.
 

Giving HIV positive pregnant women AZT during pregnancy and delivery followed by treatment of the newborn significantly lowers the chances the newborn will be infected. Discouraging breastfeeding of the newborn in HIV (especially symptomatic mothers and mothers with low CD4 T cell counts) and Hepatitis B infected mothers will lower the child's chances of being infected following birth.

Treat pregnant women that are culture positive for Group B Streptococcus during labor and delivery. Treat the eyes of newborns with erthromycin to prevent opthalmia neonatorium.

Immunizations for Rubella, Hepatitis, and VZV should be given to women thinking of trying to become pregnant if they are seronegative. Live viral vaccines should be give 3-6 months before conception. Please note it is too late to give live viral vaccines to a seronegative woman that is already pregnant. No live attenuated viral vaccine should be given to a pregnant woman for fear of causing congenital infections.