1. Infection of the foetus and newborn Professor M. Cafferkey Consultant Microbiologist, The Rotunda

2. Consequences of Infection l Consequences to the infected host »acute manifestations, chronic infection, other sequelae l Vertical Transmission »mother to infant l Horizontal transmission »family, others people, healthcare workers

3. Intrauterine Infection Infections in pregnancy are common: Which infections, if acquired in pregnancy, may harm the foetus ?

4. Definitions l congenital »contracted in utero l perinatal »from completion of 28 weeks gestation until 1-4 weeks after birth l postnatal l neonatal

5. Intrauterine & Perinatal Infection l infection diagnosed in utero l congenital infection, symptomatic or asymptomatic at birth l acquired around the time of birth and manifest later

6. Effect of Maternal Infection upon the foetus l no evidence of damage l subclinical infection without evidence of damage l abortion l foetal death l stillbirth l death in infancy l intrauterine growth retardation (IUGR) resulting in low birth weight (LBW) l congenital defects l late onset of congenital disease or defects

7. Congenital and Perinatal Infection 1.Diagnosed in utero 2.Congenital infection may be asymptomatic or symptomatic at birth 3.Infection acquired around the time of birth may manifest later

8. Common Infecting Agents l Viruses l Bacteria l Protozoa l Rickettsiae/Chlamydiae l (Fungi are very very rare, as a cause of intrauterine infection – an increasing cause of late-onset neonatal sepsis)

9. Intrauterine & Perinatal Infection Diagnosed in utero Parvovirus B19 Manifest at Birth Toxoplasma gondiiRubella CytomegalovirusVaricella/Zoster Treponema pallidumhepatitis B hepatitis CHIV

10. Intrauterine & Perinatal Infection Acquired around the time of birth and symptomatic later Herpes simplexhepatitis B hepatitis CHIV Group B  haemolytic streptococci E. coli (+)Listeria monocytogenes Chlamydia trachomatis Neisseria gonorrhoea

11. Torch Syndrome Toxoplasma Others (Varicella/Zoster & Tr. pallidum Rubella CMV Herpes simplex These agents are grouped together “for convenience”

12. Prevention l Requires a knowledge of the route and mechanisms of infection, and the period of transmission of infection to the foetus/neonate

13. Intrauterine and Perinatal Infection Mechanisms: l Intrauterine »Blood borne transplacental infection »Ascending infection l During delivery l Postnatal infection »breast milk »cross infection »the environment

14. Period of transmission

15. Intrauterine Infection: What you should know l The risk posed by the agent to the foetus l Timing of infection in relation to risk l Frequency of Damage l Nature of Damage l Availability of diagnostic tests l Whether treatment is available l Preventive measures

16. Protect the mother: Protect the foetus l Education l Medical »standard precautions »screening - Bacteruria ? »Serological screening »Screening for GBS carriage (controversial outside North America and AUS)

17. A ntenatal screening - Definition of screening: l The systemic application of a test or enquiry l to identify individuals at sufficient risk of a specific disorder to benefit from further investigation or direct preventive action, l among people who have not sought medical attention on account of symptoms of that disorder

18. Antenatal Screening: Justification l Will give information “for action” to prevent or reduce the adverse consequences of the infection l Treatment or prophylactic measures will usually be instituted Problems with screening for infection: it gives a “snapshot” in time l Women remain at risk of acquiring infection during the pregnancy - ? Repeat tests l A woman may be in the “window period” before signs of the infection appear

20. Examples of types of Congenital Infection - Included in routine antenatal screening programmes? YESNO Rubella CMV HBVherpes simplex HIV parvovirus B 19 Syphilis

21. Congenital Infection: specific examples

22. Rubella An RNA togavirus l 1938viral aetiology suggested l 1941McAlastair Greig suggested an association between maternal rubella, congenital heart disease and cataracts l 1962virus isolated l 1969live vaccine developed

23. Timing of infection: Risk of damage Infection at l 0-8 weeks 80% detectable defects l 9-12 weeks 52% detectable defects l 13-20 weeks 16% ? l 20+ weeks no increased risk

24. Rubella: Nature of Damage Rubella Syndrome l PDA l Cataracts l Hearing deficits l Encephalitis l Interstitial pneumonia l Sensory abnormalitis: Eye/Ear l Bony radiolucencies Expanded Rubella Syndrome l Small for Gestational age l Microcephaly l PDA l Pulmonary Stenosis l Hepatosplenomegaly/ lymphadenopathy

25. Congenital Rubella l Retinopathy with retinal degeneration in the region of the macula and characteristic clumping of pigment

26. Rubella l Routine infant immunisation, now as MMR at 15 months and 4 years l Routine screening test in pregnancy - a convenient time to screen healthy normal women l Women who are non-immune are offered vaccine postnatally l [pre-conceptual screen, premarital screen]

28. Cytomegalovirus The most common congenital infection worldwide; predominantly due to primary maternal infection

29. CMV retinitis l Haemorrhages, sheathing of blood vessels and white fluffy areas of retinal infiltration

30. Congenital CMV l The most common congenital infection worldwide; rate estimated at 0.5 to 2.5% l 95% are asymptomatic at birth, 10-15% may develop symptoms later l Microcephaly, hydrocephaly l periventricular cerebral calcification l deafness, cerebral palsy l Seizures l microphthalmia l chorioretinitis, blindness l interstitial pneumonia l petechiae/purpura l anaemia, HSM, lymphadenopathy

31. Congenital CMV l Prevention - there is no proven preventive intervention l Treatment - There is limited evidence that treatment of infants with neurologic symptoms, with ganciclovir iv x 6 weeks, may help, however when the drug is stopped the viral load increases again

32. Congenital toxoplasmosis

33. Toxoplasmosis Toxoplasma gondii l The cat is the primary host l Other animals and birds l 24% of Irishwomen have antibody indicating previous infection l Human infection is believed to result from eating undercooked infected meat or handling infected soil or cat litter

34. Congenital Toxoplasmosis l Classic triad »hydrocephalus, intracranial calcification & chorioretinitis l non-specific signs »hepatosplenomegaly, jaundice »thrombocytopenia, »growth retardation, rash

35. Congenital Toxoplasmosis l Retinal scar with surrounding pigment

36. Sequelae l Only 10% of infected babies are clinically symptomatic at birth l The most common clinical sequel is chorioretinitis »by the age of 20, 60-85% have had chorioretinitis which may be unilateral or bilateral l Deafness, low IQ

37. Treatment of CT l In utero diagnosis and treatment »France, Austria, Switzerland »few controlled studies »Meta-analysis “5 studies showed that antenatal treatment was effective, four that it was not” Wallon et al., BMJ, 1999, 318, 1511-4 l Postnatal diagnosis and treatment »treatment for the entire first year of life will improve outcome McLeod and the Toxoplasma Study Group

38. Treponema pallidum

39. Congenital syphilis l Foetal death and miscarriage l Stillbirth l Congenital infection which may be asymptomatic at birth and manifest later

40. Congenital Syphilis l Most likely to occur if a mother has untreated primary infection in this pregnancy l The risk of transmission decreases with subsequent pregnancies

41. Rash - congenital syphilis

42. Congenital syphilis l discrete macular lesions similar to those seen IN secondary syphilis

43. Congenital syphilis l Interstitial keratitis

44. Positive treponemal serology l Treat mother unless previous treatment and serological response has been documented l Repeat serology monthly l Screen for other STDs l Partner referral to GUM/ID service l Assess infant »Dependant on maternal results and treatment, X-rays and CSF exam may be required in infant l Treat the infant in virtually all cases »one dose, 10 days, 14 days regimen dependant on circumstances

45. Listeriosis Listeria monocytogenes l A zoonosis l soft cheeses, pate l Infection in utero may result in stillbirth or a live infant with congenital infection l Uncommon, however it the third most common organism causing Early Onset neonatal infection

46. Maternal or Neonatal Listeriosis l Prevalence in Ireland unknown l Rotunda 1993 – 2001: »approximately 58,000 births »two mothers with L. monocytogenes septicaemia, and 1 mother with a clinical diagnosis of listeriosis: c. 1 in 20,000 »no cases of neonatal sepsis with L. monocytogenes

47. Parvovirus B19 l “Slapped Cheek Syndrome” or Fifth Disease l A common febrile exanthematous infection of childhood l Symptoms include a “lacy” rash, influenza- like symptoms and arthropathy l Some 50% of women of child-bearing age are immune

48. Parvovirus B19 l When acquired by a non- immune pregnant woman the transmission rate to the foetus is about 33% l anaemia, cardiomyopathy, hepatic dysfunction, hydrops foetalis - foetal death may occur l Diagnosis by specific IgM l Exchange transfusion in utero is appropriate therapy in severe cases

49. Parvovirus B19 l “B19 multiples in the bone marrow where it is cytotoxic for erythroid progenitor cells; this results in temporary arrest of erythropoiesis” - this effect is not typically seen in the normal child or adult l Severe anaemia is most frequent with infection of the foetus and in individuals with chronic haemolytic anaemias such as sickle-cell disease l myocarditis occasionally reported

50. Varicella zoster virus l Infection in the first 20 weeks may result in the congenital varicella syndrome l The risk of CVS with chickenpox in the first 20 weeks is approx. 2% l Acute varicella in the time period from 2 days before to 5 days after delivery is associated with a high risk of severe disseminated varicella in the newborn

51. Varicella zoster l In general, exposure to zoster, or the appearance of maternal zoster does not lead to foetal infection

52. Varicella zoster: Prevention l Specific VZ immunoglobulin if administered within 96 hours of exposure will usually modify the illness l If administered up to 9 days there may be attenuation

53. Varicella zoster: Prevention l The principal reason for VZIG administration in pregnancy is to modify the illness in the mother; there is little evidence that it will influence the development of the congenital varicella syndrome

54. Varicella zoster: Prevention l If a mother has chickenpox in the time period 2 days before to 5 days after delivery, the infant should be given VZIG and carefully observed; if any lesions develop, iv aciclovir should be given

55. Perinatal Viral infection l Cytomegalovirus l herpes simplex l hepatitis B l human immunodeficiency virus

56. Herpes simplex l The principal risk of transmission is with primary maternal infection at the time of delivery l The risk is smaller with recurrent herpes at time of delivery

57. Prevention of neonatal herpes l Recognition l Elective section in primary herpes at term or <4 hours after membrane rupture l Some obstetricians would also recommend elective section when recurrent genital herpes is present at term

58. Primary herpes of the cervix

59. Herpes simplex l Recognition of primary herpes can require a high index of suspicion l type 1 infection typically produces less severe symptoms and relatively little local manifestation compared with type 2 infection l the infection may be confined to the cervix

60. Hepatitis B

61. l Chronic HBV infection with persistence of HBsAg occurs in »up to 90% on infants infected vertically, »30% of children 1 to 5 years old infected after birth »in 5 to 10% of older children, adolescents and adults with HBV infection

63. Hepatitis B l The development of the carrier state following vertical transmission has been estimated to  the risk of chronic liver disease x20 times & hepatoma x86 times l In addition, horizontal transmission of the infection may occur in childhood; est. that vaccinating one child protects 3 others

64. HBV: Perinatal Transmission l Baby should receive Hepatitis B vaccine l Administration of HBIG will further reduce the risk of transmission

65. HBV: Prevention of vertical transmission l Routine linked antenatal HBV testing would be cost-effective because of the morbidity prevented by identifying carrier mothers and giving immunoprophylaxis to their infants l This is the case even in areas of low endemicity such as all of N Europe

67. Hepatitis C l Most transmission is around the time of birth l Rotunda studies: Vertical transmission rate = 6.7% l Outcome - may become chronic carriers l Identify mothers at risk

68. Human Immunodeficiency Virus

69. HIV - Vertical Transmission l perinatal in most cases l transmission rate 15 - 25% l Role of Caesarean section in reduction of transmission in some cases

70. HIV - Vertical Transmission l transmission can be decreased by approximately 2/3 by administration of anti-retrovirals »to the mother in pregnancy (po), in labour (iv and po) & »to the infant for the first 4 weeks (po) - this is post-exposure prophylaxis

71. HIV - Antenatal testing Unlinked testing indicated that only 25-50% of HIV+ women were identified Routine anti-HIV testing introduced Rotunda January 1998 National programme commenced April 1999, based on the Rotunda model

72. HIV l >90% of cases of paediatric HIV are due to vertical transmission l prevention is dependent on identification of infected mothers and »antiretroviral therapy, antepartum and intrapartum with post-exposure prophylaxis to the infant »caesarean section in selected cases

73. Chlamydia trachomatis l Acquisition occurs in some 50% of infants born vaginally to infected mothers and in some delivered by CS with intact membranes l The nasopharynx is the common site of primary multiplication in the infant »conjunctivitis in 15-50% »pneumonia in 5 - 20%

74. Chlamydia: Prevention l Opportunistic screening of women “at risk” »DNA detection methods suitable for use on urine specimens l UK DOH recommendation »All women attending STD clinics »single women < 25 years »women with multiple sex partners »women with a new sex partner

75. Neonatal Sepsis

76. Perinatal infections: in the hospital l sepsis l meningitis l pneumonia l urinary tract infection l conjunctivitis l omphalitis l otitis media

77. Perinatal infections: in the community l skin infections  omphalitis l bronchiolitis  pneumonia l diarrhoeal disease l otitis media l urinary tract infection l conjunctivitis (orbital cellulitis) l sepsis l meningitis

78. Diagnosis of Neonatal Sepsis l Difficult l Signs are Subtle and Non-specific »respiratory distress »lethargy »poor feeding »jaundice »vomiting & diarrhoea

79. Risk Factors l Maternal History »Traumatic delivery »Prematurity »Maternal Peripartum Sepsis »Prolonged Rupture Of Membranes

80. Risk Factors »Prolonged Rupture Of Membranes –ROM >24 hours:Infection rate of 1/100 –ROM with Chorioamnionitis: Infection rate of 10/100 –Irrespective of the time interval, membrane rupture - delivery, infection rates are 5 times higher in infants born before term

81. Characteristics Early-Onset l Within first 24 hours, range (0 - 6d) l Fulminant, Multisystem, Pneumonia frequent l Mortality rate of 15- 50% Late-onset l at 3 to 4 weeks, range 7d to 3 mo l Slowly progressive, l Focal; Meningitis frequent l Mortality rate of 10- 20%

82. Neonatal sepsis “The big three” l Group B strep l E. coli »and other Gram negative bacilli such as Proteus, Klebsiella l Listeria monocytogenes Others including: l Staph aureus l coagulase- negative staphylococci l Candida species l Pseudomonas l Enterobacter

83. Neonate with pneumonia and empyema due to E. coli

84. 20 day old infant osteomyelitis due to E. coli following early-onset sepsis

85. Neonatal sepsis: problems Difficulties with making a laboratory diagnosis l Mother had antibiotics l Infant has received antibiotics l Small sample size, especially in the premature or growth retarded infant l Frequent isolation of “normal flora”

86. Neonatal Sepsis l Many neonatologists/units perform screening swabs l ear swab, umbilical swab, gastric aspirate, in addition to blood culture

87. GBS infection - Prevention l Early-Onset GBS infection is primarily an intra-uterine infection l Therefore it may be prevented by intrapartum chemoprophylaxis l In Late-Onset GBS infection the route of entry is unclear l This is not amenable to prevention by chemoprophylaxis

88. Group B streptococcus l Historically the case-fatality rate has been estimated to be 5-20% for neonates and 15-32% for adults l Fatality rate in early-onset sepsis in the most recent studies was 6%. This reduction in rates may be because of advances in neonatal care

89. GBS Epidemiology l Reservoir - Gastrointestinal tract l The genitourinary tract is the most common site of secondary spread l Colonisation rates may vary by geographical area, race and age l In most populations studied 10-30% of pregnant women were colonised

90. GBS Epidemiology l Neonatal disease: “1 to 4 cases /1,000 live births” l USA 1990, multistate surveillance 1.8 cases /1,000 live births l In general, Early-onset accounts for >75% of neonatal cases

91. GBS Surveillance l GBS disease in infants less than 90 days of age UK and ROI l Results of Year 1 –67% < 7 days –Overall 0.73/1,000 LB; 0.48 EO, 0.25 LO –ROI total 0.63/1,000; 0.34 EO, 0.29 LO –Overall EOS sepsis 62%, pneumonia 28% –Overall LOS meningitis 42%, sepsis 41%

92. RSV Bronchiolitis l Seasonal l more severe in infants with respiratory compromise l prevention l avoid crowds and handling!! l RSV IG, Who to treat ???

93. Rotavirus gastroenteritis l Common worldwide l may be very severe l Prevention: vaccine now withdrawn because of unexpected side effect - increased incidence intussusception

94. Control & Prevention of Congenital, Perinatal & Neonatal infection

95. Control & Prevention General Medical l precautions with clinical examination l use of standard / universal precautions when coming into contact with blood or secretions that may contain blood

96. Prevention of congenital and perinatal infection l Serological screening in pregnancy »Rubella, syphilis, Hepatitis B, HIV: “routine” »Hepatitis C: in certain groups Q VZV l Handwashing »CMV, toxoplasmosis l Modification of “at risk” behaviour »Blood borne viruses »Sexually transmitted infection

97. Prevention of congenital and perinatal infection l Avoidance of certain foods »pate, soft cheeses, undercooked meats l Screening for GBS carriage is performed in USA and AUS »from 35 weeks »intrapartum penicillin in carriers and those who deliver earlier (not screened) l Active herpes at term - avoid vaginal delivery