Congenital_and_Perinatal_Infections.docx. Олена Костянтинівна Редько

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1 Congenital_and_Perinatal_Infections.docx Олена Костянтинівна Редько 2014

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3 Ключові терміни: 3 Зміст Ключові терміни: 3

4 Ключові терміни: 4 Ключові терміни: Hepatitis B, Infections in the newborn infant can be classified as congenital or perinatal, Questions, Syphilis, congenital rubella syndrome, congenital toxoplasmosis, cytomegalovirus, immunodeficiency virus (HIV) infection, neonatal herpes simplex virus (HSV) infection, parvovirus B19 Congenital and Perinatal Infections Questions What physical findings in Case 1 suggest this infant has a congenital infection? How does a congenital infection differ from an infection that is acquired perinatally? What are the most common causes for congenital infection? True/False: A term infant with a normal physical exam and no risk factors for infection may have congenital infection Periventricular calcifications in the brain are seen with which congenital infection? Diffuse calcifications? True/False: An infant born to a woman with recurrent herpes infection is at higher risk for developing herpes neonatorum than one born to a woman with primary herpes infection at the time of delivery? Administration of what agents can prevent 95% of perinatally acquired hepatitis B infections? True/False: Breastfeeding should be encouraged in all mothers who are HIV positive, but do not have AIDS. Case 1 You are asked to attend the precipitous vaginal delivery of an estimated 33 week gestation infant whose estimated fetal weight is 1800 grams. Mother is a 26 year old gravida 5, para 4 woman who was admitted in active labor 45 minutes ago. She did not seek prenatal care with this pregnancy, but reports no medical problems during the pregnancy. She denies tobacco, alcohol and illicit drug use. Mother's blood type is O+, antibody negative. All other prenatal labs are pending. Prior to delivery, mother received one dose of ampicillin only. Membranes are ruptured at the time of delivery revealing clear amniotic fluid. At delivery, you receive a small, but vigorous male infant and bring him to the warming table. He is quickly positioned, dried, and stimulated. He is pink with good respiratory effort and his heart rate is 150 beats per minute. You note his skin is mildly jaundiced with raised red/purple lesions. You allow the mother to bond briefly with the infant and inform her that because you suspect the infant has a congenitally acquired infection, you are transferring him to the special care nursery for a more detailed examination and further management. Exam: VS T 37.5, P120, RR 40, BP 60/36, oxygen saturation 100% in room air. Ballard exam: weeks gestation. Growth parameters: weight kg (<5%ile for 38 weeks, 50%ile for 33 weeks), length 44cm (<5%ile for 38 weeks, 50%ile for 33 weeks) and head circumference 31.5 cm (5%ile for 38 weeks, 50%ile for 34 weeks). He is a small, thin male infant with little subcutaneous fat, who is in no acute distress. His skin is mildly jaundiced with the "blueberry muffin" appearance of diffuse raised red/purple lesions and petechiae. His anterior fontanelle is soft, but full. His sclerae are mildly icteric. The abdomen appears distended and protuberant, but it is soft and non-tender. A firm liver edge is felt 4 cm below the right costal margin and the spleen is felt 3 cm below the left costal margin. The remainder of the examination is unremarkable. On admission, you order a CBC with differential, liver function tests, fractionated bilirubin levels and a urine culture for CMV. The CBC is remarkable for moderate anemia (Hct = 30%), thrombocytopenia (50,000) and atypical lymphocytosis (10%). Both SGOT (210 mu/ml) and direct serum bilirubin (8

5 Ключові терміни: 5 mg/100ml) are elevated. Three hours after birth, the infant develops generalized tonic-clonic seizures that stop after administration of 20mg/kg of phenobarbital. Cranial ultrasound done the next morning reveals periventricular calcifications and generalized brain atrophy. These findings are most consistent with congenital cytomegalovirus infection. To complete the workup you consult ophthalmology to evaluate the patient for chorioretinitis. Case 2 A former 31-week premature male infant is now four weeks old and nearly ready for discharge from the intermediate nursery. At birth, he was delivered at an outlying hospital via emergent caesarean section for placental abruption to a 25 year-old G1 female with negative serologies and an otherwise unremarkable prenatal course. At the time of delivery, he required resuscitation and was transfused with O negative blood in the delivery room for a hematocrit of 15%. After stabilization, he was transferred to your facility where he has done well for the past month. Today, he has had a sudden deterioration in his respiratory status accompanied by hypotension. Exam: VS T 36.0 rectal, P 178, RR 90, BP 40/23, oxygen saturation 84% on RA. Growth parameters are all at the 50% for 35 weeks' gestation. He is a pale, mottled premature male infant in moderate to severe respiratory distress. His skin is mildly jaundiced. His mucous membranes are pale. He has nasal flaring with intercostal and subcostal retractions. He is tachypneic with coarse breath sounds. His heart has an increased rate, but regular rhythm. His pulses are barely palpable in his extremities and his capillary refill is 4-5 seconds. His abdomen is soft, but no bowel sounds are present. The remainder of the examination is unremarkable. Suspecting nosocomial bacterial infection, you perform a CBC, blood culture, urinalysis, and spinal tap. Antibiotics for nosocomial infection are started. Initial urine and CSF studies are normal. CBC is remarkable for an elevated white count with lymphocytosis. The baby has moderate anemia (Hct = 32%) and thrombocytopenia (platelets = 30,000). Chest x-ray shows new diffuse symmetric infiltrates bilaterally. Tracheal aspirate shows moderate WBCs but no organisms on gram stain. After 48 hours on antibiotics, there has been no improvement in his clinical condition. The infant remains intubated on high ventilator settings and dopamine for persistent hypotension. His blood, urine, tracheal aspirate and CSF cultures are all negative for growth. You wonder about CMV infection in light of his pneumonia, shock and history of blood transfusion at the time of delivery and send his urine for CMV culture. Two days later, his urine culture is found to be positive. Case 3 A young mother rushes into the emergency department with a baby swaddled in her arms. She reports that earlier today, her one week old son developed a low grade fever that she attributed to overbundling. However, throughout the course of the day, his interest in feedings has diminished and he is now difficult to arouse. There is no history of vomiting, breathing difficulties, URI symptoms, diarrhea, or change in bowel and bladder pattern. She denies excessive weight loss as the infant was seen by his primary care physician yesterday. His birth history is noncontributory: he was born at 39+ weeks gestation via normal spontaneous vaginal delivery to a 23 year-old G1 female who had good prenatal care. Prenatal labs are unremarkable. Mother denies any history of sexually transmitted diseases or abnormal Pap smears. There was no history of prolonged rupture of membranes or maternal fever. Apgar scores were 9 and 9 at 1 and 5 minutes. Birthweight was 3750 gms (75%ile). The infant had an unremarkable hospital course and was discharged home on day 2 with mother. Today's exam: VS T 39.0, HR 160, RR 40, BP 75/52, oxygen saturation 95% in room air. Growth parameters: weight kg (75%ile), length 50 cm (50%ile) and head circumference 35.5 cm (>50%ile). He is a well developed, well nourished term male infant who appears sleepy and lethargic. When he does awake, he is difficult to console and displays a weak, high pitched cry. He is pale, but in no acute distress. He has mild facial jaundice, but no other skin lesions. His anterior fontanelle is soft, but full. Mucous membranes are moist. The abdomen is soft and non-tender. The liver edge is felt 2 cm below the right costal margin and the spleen tip is palpated just below the left costal margin. Neurologically, the infant has decreased tone throughout his extremities and he is difficult to arouse. You order a complete sepsis workup consisting of a CBC with differential, blood culture, urinalysis, urine culture, and cerebral spinal fluid for glucose, protein, cell count with differential, gram stain, and culture. You obtain an extra tube of CSF to be held in the lab. IV access is obtained and the infant is immediately given ampicillin and gentamicin. IV fluids are also started in light of his decreased level of consciousness and poor appetite. Prior to transfer to the pediatric wards, the patient develops rhythmic right-sided tonic-clonic movements. After administering IV phenobarbital, the seizures stop. You then order IV acyclovir and call the lab to run PCR for herpes simplex virus and enterovirus on the extra tube of CSF. This clinical presentation is consistent with a perinatal infection, possibly due to herpes simplex virus. Infections in the newborn infant can be classified as congenital or perinatal. It is important to make this distinction as the clinical presentations, causative organisms, diagnostic approaches, treatments and long-term considerations differ for these two groups. A congenital infection is an infection seen in the newborn infant that was acquired transplacentally during the first, second, or early third trimester. In contrast, a perinatal infection is acquired either around the time of delivery or during the first week of

6 Ключові терміни: 6 extrauterine life. The incidence of congenital infection in the fetus and newborn infant is relatively high at %. The most common causative agents are rubella virus, cytomegalovirus (CMV), Toxoplasma gondii, Treponema pallidum, human immunodeficiency virus (HIV), human parvovirus B19 and Epstein-Barr virus (EBV). Despite the diversity of these organisms, many produce similar syndromes in the newborn infant. Common manifestations of congenital infections include growth retardation, hepatomegaly, splenomegaly, jaundice (secondary to direct hyperbilirubinemia), hemolytic anemia, petechiae and ecchymoses, microcephaly, hydrocephaly, and pneumonitis. However, the majority of affected infants are entirely asymptomatic. The incidence of congenital rubella syndrome is 0.5 per 1000 live births. Infants are usually born small for gestational age. Common clinical findings include: purpura, thrombocytopenia, hepatosplenomegaly, cardiac defects, eye defects (glaucoma and cataracts), pneumonia and meningoencephalitis. Diffuse purpuric lesions on the skin resembling a "blueberry muffin", represent cutaneous extramedullary hematopoietic tissue that may be seen in this and other congenital infections. Congenital Rubella: Retinopathy Blueberry muffin Congenital Rubella: cataracts Congenital rubella infection can be diagnosed with an elevated anti-rubella IgM titer in the perinatal period or high anti-rubella IgG titers throughout the first year of life. Virus can also be isolated from a throat swab, CSF or urine. Common long term problems seen in infants with congenital rubella include communication disorders, hearing defects, mental and/or motor retardation, microcephaly, learning

7 Ключові терміни: 7 deficits, balance and gait disturbances, and behavioral problems. Although live attenuated rubella virus vaccine is available to prevent the disease, there is no specific therapy for congenital rubella. Annually, approximately 40,000 infants are born with congenital CMV infection in this country. Twelve percent of these infants will die and more than 90% of survivors will suffer late complications, most commonly sensorineural hearing loss. Congenital CMV infection may be the result of a newly acquired maternal infection or a reactivated old maternal infection. Although less common, newly acquired maternal infection poses a much higher risk of severe disease and a worse prognosis. Ninety percent of infected newborns are surprisingly asymptomatic at birth. However, those that are symptomatic are small for gestational age and often present with petechiae, ecchymoses, thrombocytopenia, jaundice, direct hyperbilirubinemia, anemia, hepatosplenomegaly, elevated SGOT, microcephaly, seizures and chorioretinitis. The diagnosis of congenital CMV infection is best made by isolating the virus in urine culture. Periventricular calcifications can be seen on cranial ultrasound. Of the affected infants that survive the neonatal period, 1/3 will have hearing loss, one third will have neuromuscular disorders (seizures or spasticity) and a few will have vision problems secondary to chorioretinitis. Although there is no specific therapy for congenital CMV infection, trials examining the effectiveness of ganciclovir, alpha interferon and CMV immune globulin are underway. The incidence of congenital toxoplasmosis infection varies with geographic location and local dietary habits. Maternal toxoplasma infection is usually due to ingestion of tissue cysts found in raw or undercooked meats or consumption of water or other foods containing oocysts from infected cats. Congenital infection with Toxoplasmosis gondii occurs during maternal parasitemia. In the neonate, the primary focus of toxoplasma infection is in the central nervous system, leaving necrotic, calcified cystic lesions dispersed within the brain. Less commonly, similar lesions can be found in liver, lungs, myocardium, skeletal muscle, spleen and other tissue. Approximately 85% of infants with congenital infection have normal examinations and are asymptomatic. Those infants that exhibit illness at birth frequently present with fever, hepatosplenomegaly, jaundice, rash and pneumonitis. The classic triad of toxoplasmosis, chorioretinitis, hydrocephalus and intracranial calcification occurs in only a small proportion of symptomatic patients. Congenital toxoplasmosis, Hydrocephalus chorioretinitis Post-mortem appearance of brain. Irregular areas of calcification in the lateral ventricles are seen in this brain of a seven-week-old child dying of toxoplasmosis. Mental disorders and blindness are common in children who survive. Abnormal laboratory findings include anemia, thrombocytopenia, eosinophilia, and abnormal CSF studies. Seizures, mental retardation, spasticity, and relapsing chorioretinitis are common long-term complications of congenital toxoplasmosis, even if not present at birth. Prenatal diagnosis is made between 20 and 26 weeks by detection of IgM anti-toxoplasma antibodies and on isolation of the parasite from fetal blood or amniotic fluid. Antenatal ultrasound can suggest the diagnosis of congenital toxoplasma infection when bilateral, symmetric ventricular dilatation, intracranial calcifications, increased placental thickness, hepatomegaly and ascites are noted. Postnatal diagnosis is also made by detection of anti-toxoplasma IgM antibodies in the infant's serum. Treatment, antenatally and postnatally, consists

8 Ключові терміни: 8 of pyrimethamine and sulfadiazine. Spiramycin may also be used, if available. Historically, prognosis in untreated infants is poor. However, with recent advances in antenatal diagnostic capabilities and available medical therapies, the frequency of major neurologic sequelae has decreased. Syphilis is caused by the spirochete Treponema pallidum. Transplacental transmission usually occurs during the second half of pregnancy. Сongenital syphilis Genital and perianal lesions typical of early congenital syphilis Most infants born to mothers with primary or secondary syphilis have congenital infection; though only half of those who are infected are symptomatic. Because congenital syphilis is associated with significant neurodevelopmental morbidity, it is imperative that both maternal status and infant risk for syphilis be checked in all pregnancies. Early features of congenital syphilis include hepatosplenomegaly, skin rash, anemia, jaundice, metaphyseal dystrophy, periostitis and CSF abnormalities including elevated protein and mononuclear pleocytosis. However, in some cases, the infant is asymptomatic and may not develop any signs or symptoms of congenital infection for weeks or months. "Snuffles" is obstruction of the nose with initial clear discharge progressing to purulent or sanguineous discharge. It is seen in infants with congenital syphilis usually after the newborn period. Detection of IgM-FTA-ABS (fluorescent treponemal antibody absorption) in the newborn's blood is the most reliable method of diagnosing congenital syphilis. However, this test is not always positive early on in life, thus repeat testing at 3 to 4 week intervals is frequently indicated. Treatment for both the pregnant mother and baby is penicillin G. Despite antibiotic therapy, it is recommended that infants undergo repeat blood and CSF testing during the first 12-15

9 Ключові терміни: 9 months of life until negative or stable low titer levels are achieved. Vision, hearing and developmental evaluations are also indicated before three years of age in infants with congenital syphilis. One to two-thirds of adults in the United States are seropositive for human parvovirus B19. However, the overall risk of fetal infection from human parvovirus B19 is low. Fetal infection with the virus can result in neonatal no immune hydrops fetalis and fetal aplastic crisis (i.e., severe anemia resulting in high output congestive heart failure and hydrops), but has not been shown to cause congenital anomalies. No immune hydrops fetalis B19 is known to have an affinity for progenitor erythroid cells in the bone marrow. This affinity most likely produces bone marrow aplasia that may lead to congestive heart failure and no immune hydrops fetalis. The diagnosis of B19 infection can be made either serologically (anti-human parvovirus B19 IgG and IgM levels) or by viral culture. Antenatal treatment of infected infants with hydrops includes fetal transfusion and maternal digitalization. No specific antiviral treatment is currently available. Perinatally acquired infections are those that are acquired either around the time of delivery or during the first week of extrauterine life. Common pathogens include bacteria, such as group B streptococci, E. Coli, and Listeria (covered elsewhere in this text), herpes simplex virus, hepatitis viruses and human immunodeficiency virus. Infants with perinatally acquired viral infections are often normal at birth, developing illness later in life. A few pathogens like cytomegalovirus (CMV) can cause both congenital and perinatally acquired infection in the newborn with striking contrasts in presentation.

10 Ключові терміни: 10 Сongenital cytomegalovirus infection Ecthyma gangrenosum Homozygous The infant in Case 1 presents with growth restriction, anemia, thrombocytopenia, extramedullary hematopoiesis, and intracranial calcifications, all indicative of a chronic process; namely, congenital CMV infection that was transmitted transplacentally during the first or second trimester of pregnancy. In contrast, the infant in Case 2 acquired CMV infection after birth resulting in illness several weeks later. Perinatally, CMV can be transmitted through breast milk or vaginal secretions. Premature infants however, are particularly susceptible to transmission through transfusion of blood products. The resulting syndrome is characterized by shock, pneumonitis and lymphocytosis as described above. The role of ganciclovir in perinatally acquired CMV infection is unclear. The majority of neonatal herpes simplex virus (HSV) infection is acquired from the maternal genital tract with an incidence of approximately 1 case per 3500 live births. However, infection may also be acquired after birth from mother or other persons with non-genital tract lesions (e.g., oral herpes, herpetic whitlow) following close contact with the infant or handling. Primary maternal infection is associated with a 50% risk of perinatal/neonatal infection, while a risk of <5% is seen with recurrent maternal infection. Of note, active HSV lesions are present at the time of delivery in only 1/3 of mothers of affected infants. Several defects in cellular immune function contribute to neonatal susceptibility to HSV. Perinatally acquired HSV infection results in massive coagulation necrosis of the liver, lungs, adrenal glands and brain. Most infants are asymptomatic at birth, developing illness during first 1 to 2 weeks of life. Clinical illness can be characterized as being localized or disseminated. Disseminated illness can be further described as those with and those without central nervous system involvement. Systemic symptoms of disseminated HSV infection usually present towards that end of the first week of life, including poor feeding, lethargy, fever, irritability, and seizures with rapid progression to hypotension, disseminated intravascular coagulation, apnea and shock. Skin vesicles are present in less than half of patients. With antiviral therapy, 15-20% of patients die and 40-55% of survivors suffer longterm neurologic impairment. Localized disease may involve the central nervous system alone, the central nervous system and skin, eyes, and oral mucosa or only the skin, eyes and oral mucosa. Except in cases of isolated viral encephalitis, HSV is readily recovered in culture from scrapings of skin vesicles, blood, cerebrospinal fluid, conjunctivae, respiratory secretions, and urine. Once neonatal HSV infection is suspected, antiviral therapy should be started immediately. Parenteral acyclovir is the treatment of choice for herpes neonatorum. Treatment duration varies depending on whether the infection involves the CNS and/or is disseminated. Despite antiviral therapy, overall outcome for survivors is poor. More than half of infants who survive disseminated disease will develop microcephaly, spasticity, paralysis, seizures, deafness, or blindness. Those with skin involvement may be subject to recurrent vesicular outbreaks for several years. Of note, HSV can also be transmitted in utero during the first or second trimesters of pregnancy. Those fetuses that are not stillborn or spontaneously aborted demonstrate a syndrome similar to other congenital viral infections like CMV. Treatment is supportive as acyclovir has no proven benefit for these infants. The most important of the hepatitis viruses for the general pediatrician is Hepatitis B. The virus is found primarily in the liver parenchyma, but can be found in circulating blood from a few days to many years. Regardless of maternal acute or chronic infection, the virus rarely crosses the placenta, thus perinatal/neonatal infection is most likely acquired from infected maternal blood encountered during the delivery process. Overall, there is 60-70% chance of transmission during delivery if mother has an acute infection at that time. Mothers may also be carriers which still has a risk of transmission to the newborn.

11 Ключові терміни: 11 In the U.S., hepatitis B surface antigen (HBsAg) carriage rate is relatively low, about 0.1%. However, rates may be as high as 15% in Taiwan and parts of Africa. At birth, infected infants are asymptomatic. By 2 to 6 months of age, liver enzymes are often elevated and infants are antigen seropositive. Occasionally, infection may present with jaundice, fever, hepatomegaly and anorexia, followed by complete recovery or chronic active disease. Approximately 95% of perinatally acquired HBV infection can be prevented by early active and passive immunoprophylaxis of infants born to HBsAg positive mothers. Infants born to HBsAg positive mothers should receive the initial dose of hepatitis B vaccine and hepatitis B immune globulin (HBIG) within 12 hours of birth (given at separate injection sites). Infants born to unscreened mothers should receive their first hepatitis B vaccine within 12 hours of birth while awaiting maternal blood test results. If the mother should be found to be HBsAg positive, HBIG should be given within the first week of life. All infants should complete the hepatitis B immunization series by 6 months of age. Infants born to HBsAg positive mothers should be tested for anti-hbsag antibodies and HBsAg 1 to 3 months after the third dose of vaccine is given to determine those who may be chronically infected and those who may require additional doses of the vaccine. Breastfeeding by an HBsAg positive mother has not been shown to cause hepatitis B infection in infants. Once seen exclusively in children who had received blood products, pediatric human immunodeficiency virus (HIV) infection is now overwhelmingly the result of perinatal transmission. There are three distinct modes of transmission of human immunodeficiency virus (HIV) from mother to fetus. Congenital HIV infection results from the transplacental transmission of virus during early pregnancy. Intrapartum transmission may occur following exposure of the infant to mother's blood or as a result of maternal-fetal transfusion during the delivery. Perinatal infection with HIV can occur either during the birthing process or shortly after birth through breastfeeding. Risk factors associated with perinatal HIV transmission include maternal viral load (plasma and genital tract), primary infection of late stage HIV, low CD4 count, STDs/other co-infections, pre-term delivery, increasing duration of rupture of membranes, placental disruption, invasive fetal monitoring (eg. scalp probes), vaginal delivery and lack of AZT prophylaxis. The transmission rate from mother to infant is approximately 20-30%. However, recent studies have shown that for select HIV-infected women, zidovudine (AZT) may decrease transmission to 8% of their infants. Maternal treatment with AZT in combination with elective cesarean section delivery prior to rupture of membranes and the onset of labor has shown further reduction of the transmission rate to 2%. Infants with congenital infection present in a similar fashion to other congenital infections and may also exhibit craniofacial abnormalities. Infants with perinatally acquired infection are usually asymptomatic at birth (8). To maximize the opportunity to prevent perinatal transmission of HIV infection, maternal HIV status should be determined during the first trimester of pregnancy. Anti-retroviral therapy should be started in those found to be HIV positive. During labor and delivery, AZT, 2mg/kg should be administered IV during the first hour, then 1mg/kg per hour until delivery. The infant should then be started on AZT syrup, 8-12 hours after birth, 2mg/kg QID until 6 weeks of age when the infant's HIV status can be determined. Detection of HIV antibody by ELISA or Western blot in the newborn is complicated by transplacental passage of maternal IgG and should not be performed before 18 months of age. Detection of HIV DNA by PCR is the preferred test for diagnosis of HIV infection in infants. Testing should be performed at birth, then at 1-2 months of age, and a third time between 3 and 6 months of age. Any time an infant tests positive, a second repeat specimen should be obtained immediately to confirm the diagnosis of HIV infection. Viral culture for HIV can also be done; however, issues of cost, regional availability and delay in reporting results make it less useful than HIV DNA by PCR. Umbilical cord blood should not be used for testing. If neither PCR or viral culture are available, detection of the p24 antigen may be used to assess HIV infection status in infants older than one month, though sensitivity is lower than the other two tests. The diagnosis of HIV infection in an infant is made with positive results on 2 separate specimens using HIV nucleic acid detection, HIV p24 antigen test, or HIV isolation by culture. An infant with at least 2 negative HIV virology tests from separate specimens, 1 of which was performed at 1 month of age and 1 of which was performed after 4 months of age can be considered "not infected with HIV". Finally, because transmission of HIV through breastmilk has been reported, counseling to discourage breastfeeding should be provided to all mothers who are HIV positive. Answers to questions Small for gestational age, microcephaly, jaundice, pale skin, petechiae, blueberry muffin spots, hepatomegaly, and splenomegaly A congenital infection is an infection seen in the newborn infant that was acquired transplacentally during the first, second, or early third trimester. A perinatal infection is acquired either around the time of delivery or during the 1st week of extrauterine life Rubella virus, cytomegalovirus (CMV) Toxoplasma gondii, Treponema pallidum, human immunodeficiency virus (HIV), human parvovirus B19 and Epstein-Barr virus (EBV) True Periventricular calcifications are seen in congenital CMV while diffuse calcifications in the brain are seen in congenital toxoplasmosis False

12 Ключові терміни: Hepatitis B vaccine and hepatitis B immune globulin False