Teratogenesis and Infections

1. Teratogenesis and Infections Professor Hassan Nasrat

2. Teratogenesis and Congenital Anomalies The term teratogenesis is derived from the Greek word “Tera” meaning monster. Teratogenesis means study of 'monster making'.

3. Malformations: Alterations in normal development that occur as a result of an intrinsic abnormality in the formation or developmental process. Deformations: Result from an abnormal mechanical pressure on an otherwise normal fetus (e.g., the development of clubbed foot under the pressure from oligohydramnios). Disruptions: Due to the disruption of an otherwise normal developmental process, often due to vascular accidents (e.g., gastroschisis, which is thought to result from a vascular disruption in the fetal anterior abdominal wall).

4. Etiology of Malformations Genetic causes (20 to 25 percent): single gene defects and chromosomal abnormalities Environmental factors “Teratogen” (10 percent): The term “Teratogen” refers to any factor that alters normal intrauterine development includes drugs and environmental exposures, maternal medical conditions, and infectious agents. The potential teratogenic effects of environmental agents are altered by several factors (see later). Unknown (65 to 75 percent):Either genetic factors that have not yet been discovered or combination of genetic and environmental factors.

5. Environmental factors “Teratogen” (10 percent) Environmental factors “Teratogen”:(10 percent). Any factor that alters normal intrauterine development includes drugs and environmental exposures, maternal medical conditions, and infectious agents. The potential teratogenic effects of environmental agents are altered by several factors.

6. Factors that determine the teratogenetic effects • The Developmental stage at time of teratogenic insult • Dose and duration of exposure; most drugs have a threshold dose for teratogenic effects • Species specificity: teratogenic agents may have different effects in different species. As an example, thalidomide is not teratogenic in rabbits, but has devastating effects in humans. • Genetic susceptibility; some individuals may be more susceptible to the genetic effect of some drugs or substances than others • Teratogen characteristics and placental transfer • Drug interaction

8. Proof of Teratogenesis A specific malformation or group of malformations is consistently associated with exposure to the teratogen. The teratogen was present at the time of organogenesis when the anomaly would have to occur, e.g. Phocomelia, was almost nonexistent before the introduction of thalidomide. Experimental animals will develop the anomaly if given the presumed teratogen at the appropriate stage of organogenesis.

9. Maternal and Perinatal Infection in pregnancy

10. Maternal and Perinatal Infection in pregnancy • Infections acquired in utero or during the birth process are significant causes of fetal and neonatal mortality and early and later childhood morbidity. • Causes: • Viruses. • Bacteria. • Mycoplasmas. • Fungi. • protozoa.

12. TORCH Rubella Cytomegalovirus Toxoplasmosis Others (such as syphilis) Herpes

13. What is the prevalence of the infections among pregnant patients? • 2) In those women who get the disease, how frequently does the microorganism reach the fetus? • 3) With what frequency does the microorganism seriously and permanently affect the fetus? And finally what preventive measures and/or treatment are available?

14. Toxoplasmosis • Prevalence and Epidemiology: Is a parasitic infection, the causative agent is Toxoplasma gondii. • Based on serologic studies, approximately 1/3 of women in the reproductive-age are seropositive (i.e. already immune), but there is wide geographical variation. • Maternal-Fetal Transmission of infection • The risk of vertical transmission increases with increasing gestational age at maternal infection. • Estimated to be about: • - 15 percent at 13 weeks • - 44 percent at 26 weeks • 71 percent at 36 weeks

15. Diagnosis of Toxoplasmosis • Clinically: Usually asymptomatic • Maternal diagnosis: • Serology: Assay for specific IgM and IgG antibodies are the most commonly used primarily screening tests but: • IgM antibodies alone does not indicate recent infection since in some women IgM remain positive for years. • The diagnosis can be based on: • A minimum of two blood samples at least two weeks apart show seroconversion from negative to positive toxoplasma-specific IgM or IgG. • A combination of a positive IgM and negative IgG result, with both tests becoming positive two weeks later. • In all cases a reference laboratory should confirm serological diagnosis of acute infection.

16. Prenatal / Fetal diagnosis: • The objective of fetal diagnosis are: • To help decide on initiation of prenatal treatment • Some patients may consider termination of the pregnancy if legally appropriate • Exclusion of fetal infection by prenatal diagnosis can also prevent unnecessary postnatal treatment in children without clinical signs of toxoplasmosis and at low risk of congenital infection. • The methods to be considered for prenatal diagnosis are: • Polymerase chain reaction (PCR) for T. gondii DNA in amniotic fluid is currently the method of choice for diagnosing fetal infection. • Ultrasound for signs of fetal affection but usually reflect late findings ( e.g. ventriculomegaly, intracranial calcifications, microcephaly after 21 weeks). • Fetal blood sampling usually after 20 weeks for IgM specific antibodies or PCR testsing. This method is not used any more because of potential fetal risks.

17. Prevention and treatment in pregnancy • Pregnant women should be advised to avoid contact with cat litter if at all possible. • not to eat rare cooked meat • maintain clean habit of hand washing. • In cases of primary infection during pregnancy the mother should be counseled based on: • There is uncertainty about treatment effectiveness, and the potential risk of treatment. • In addition most infected babies have a good prognosis and, on average, do not differ in their development at three to four years from uninfected children. • If she still opts for treatment the drugs of choice are Spiramycin (1 g orally every eight hours without food) or double agent therapy with Pyrimethamine and sulfadiazine.

18. Syphilis Causative agent: Treponema pallidum, a motile spirochete. Infection occurs in four stages: primary, secondary, latent, and tertiary (or late). It is rare to see pregnant women with tertiary or late syphilis. Maternal infection: Acquired by direct sexual contact with ulcerative lesions of the skin or mucous membranes of infected persons. Maternal-Fetal transmission: occurs through transplacental transmission of T. pallidum from infected mothers with primary or secondary syphilis. Fetal infection can occur at any time during gestation but typically occurs during the second half of pregnancy.

19. Effect on the fetus • Treponema pallidum infection can manifest in: • In The Fetus: • Asstillbirth (24%), neonatal death, and overt infection at birth with features such as hydrops fetalis. • In the newborn: Two-thirds of live-born neonates with congenital syphilis are asymptomatic at birth. • Later in Childhood: Clinical manifestations may appear early (≤2 years of age) or late (>2 years of age)

20. Diagnosis • Direct visualization of the spirochetes: using dark field microscopy or direct fluorescent antibody tests: • Serological tests: • A non-treponemal test: e.g. • VDRL (Venereal Disease Research Laboratory) or • RPR (rapid plasma reagin), is used for screening. • The non specific tests provide quantitative results and are used for screening, which are helpful indicators of disease activity and are used to monitor response to treatment.. • Specific treponemal test: • Microhemagglutination test for T. pallidum (MHA-TP) • Fuorescent treponemal antibody absorption (FTA-ABS). • The specific tests are not quantitative and, once positive, will remain so for life, even after successful treatment.

21. Diagnosis Neonatal diagnosis: Confirmation of neonatal diagnosis is important in order to initiate treatment at early stage. The obstetrician has duty to inform the neonatologist regarding all high-risk cases e.g. if the mother has a history of contact with an individual with primary or secondary syphilis within 90 days of delivery and/or did not receive treatment.

22. Management Management: Penicillin is the only antibiotic currently recommended for syphilis treatment in pregnancy because of its safety, efficacy, and transplacental passage to treat the fetus. Penicillin-allergic women should undergo desensitization first or receive alternative therapy such as ceftrixone. All women with syphilis should be carefully evaluated for other sexually transmitted diseases, in particular HIV.

23. Rubella Diagnosis: Maternal Rubella infection can be subclinical, but it usually manifests 14 to 21 days after exposure with a maculopapular rash that begins on the face and spreads to the neck, trunk, arms, and legs; other signs and symptoms are lymphadenopathy, malaise, arthalgias, and petechiae. Suspectedinfectionshould be documented by specific rubella IgG and IgM measurement or by viral culture of the mother

24. Maternal-Fetal Transmission • In the first trimester: fetal infection 81 %. • Late second trimester: 25 %. • The third trimester: rise again in rate of fetal infection from 35 percent at 27 to 30 weeks to nearly 100 percent for fetuses exposed beyond 36 weeks. • However, the risk of congenital defects after maternal infection is essentially limited to maternal infection in the first 16 weeks of pregnancy.

25. Diagnosis The most common congenital anomalies include: Congenital Rubella Syndrome: The diagnosis of CRS is made in the presence of any of the recognized defects or laboratory data, i.e. Isolation of rubella virus: demonstration of IgM antibody, or a persistently elevated rubella IgG titer that fails to drop twofold dilution per month. Audiologic defects: predominantly sensorineural deafness (60 to 75 %) Ophthalmologic abnormalities (10 to 25 %) particularly cataracts and pigmentary and congenital glaucoma . Cardiac malformations (10 to 20 %) Neurologic sequelae (10 to 25 %) ranging from meningoencephalitis, to behavior disorders and mental retardation

26. Diagnosis Other features include: Intrauterine growth restriction or microcephaly, radiolucent bone disease, hepatosplenomegaly, thrombocytopenia, and characteristic purpura, resulting in the "blueberry muffin" appearance. Late manifestation persistent neuromotor deficits. pneumonitis, diabetes mellitus, thyroid abnormalities, and progressive panencephalitis.

27. Congenital Rubella Syndrome • The diagnosis of CRS is made in the presence of: • A recognized defects defects or. • Laboratory data, i.e., isolation of rubella virus, demonstration of IgM antibody, or a persistently elevated rubella IgG titer that fails to drop twofold dilution per month.

28. Diagnosis A fourfold rise in IgG titer between acute (with the onset of rash) and convalescent serum specimens (two to three weeks later) The presence of rubella specific IgM A positive rubella culture e.g. the virus is generally isolated from the pharynx one week before to two weeks after the rash. Prenatal Diagnosis: currently Rubella specific Polymerase chain reaction (PCR) on CVS samples (rather than amniotic fluid or fetal blood) is the preferred option.

29. Herpes Causative Agent: Genital herpes is usually caused by “Herpes simplex type 2”. Mode of transmission: Contracted by sexual contact. However currently 30% to 50% of genital herpes are caused by herpes simplex type 1, which most often causes oropharyngeal herpes.

30. Clinical Feature and diagnosis Clinical Features: In primary infection: The signs and symptoms are highly variable: include painful genital ulcers, dysuria, fever, tender local inguinal lymphadenopathy, and headache. In some cases the infection can be mild, subclinical, or entirely asymptomatic. In non-primary and recurrent infection: the symptoms and signs (lesions) are milder, and often no symptoms at all.

31. Diagnosis Should be confirmed by one the following tests: (1) Antibodies specific serology testing of IgG and IgM antibodies for HSV type I and II (2) Viral culture: as obtained from active lesions. (3) PCR amplification of viral particle: The choice to testing depends on the clinical presentation.

32. Maternal-Fetal transmission • Congenital fetal and neonatal infection can occur through one of two mechanisms: • The primarily mechanism is via direct contact with infected vaginal secretions during delivery. • Rarely fetal infection occurs via intrauterine transmission from transplacental or ascending infection. • Risk factors for fetal infection include: • Acquisition of HSV infection near the time of labor. • Premature rupture of the membrane. • Use of scalp electrode for fetal monitoring.

33. Risk of Congenital herpes lesions: The risk of congenital infection is 30% to 50% during a primary episode, but less than 1% during a recurrent infection.

34. Treatment • Depends on the type of infection (Primary or recurrent) and the timing in relation to labor. • In primary infection antiviral treatment “acyclovir” (400 mg three times a day) should be offered regardless of the timing of occurrence during pregnancy. • Patient with recurrent lesions should be offered suppressive antiviral treatment from 36 weeks until labor. • Cesarean delivery should be offered as soon as possible to women who have active lesions or, in those with a history of genital herpes or prodromal symptoms at the time of delivery. • If the membranes have already been ruptured for more than six hours, the benefit of CS is less certain.

35. Cytomegalovirus (CMV) • Epidemiology and prevalence: CMV infection is the most common congenital viral infection. • It is estimated that about 1% of live births are infected with CMV. • It is a leading cause of deafness and an important contributor to learning disabilities. • Its prevalence among the general population ranges between 40% and 100 percent depending upon geography and socioeconomic status and age • Approximately 30-50 % of women of the reproductive age group are seropositive.

36. Maternal Infection • Occurs through • Close contact with infected secretions including sexual contact. • Through blood transfusion. • Organ transplantation. • Primary (initial acquisition of virus during pregnancy) • Recurrent (in women who are already seropositive), • Both can result in congenital CMV. • However Preexisting maternal CMV seropositivity is associated with less severe fetal disease, suggesting a protective role of maternal immunity. 

37. Maternal Infection • The risk of seroconversion during pregnancy averages 2.0 to 2.5 percent. • Risk factors for seroconversion during pregnancy: • young maternal age. • having young children at home or at work. • poor hygiene. • and lower socioeconomic.

38. Maternal-Fetal Transmission

39. Diagnosis • Prenatal diagnosis:Depends on multiple approaches which include: • Ultrasonographic markers suggestive, but not diagnostic, of fetal CMV infection includes: Cerebral ventriculomegaly, Microcephaly, hyperechogenic fetal bowel, hepatosplenomegaly, ascites, intracranial calcifications, fetal growth restriction, and placental enlargement. • Confirm fetal infection using PCR technology for amplification of viral DNA and viral culture: In Amniocentesis, and/or cordocentesis (fetal blood sampling) • Viral culture of neonatal urine can confirm the diagnosis after birth.

40. Diagnosis • Diagnosis: Most patients are asymptomatic or have mild generalized symptoms. • Suspected CMV infection should be documented by serology or cultures of the cervix, amniotic fluid, or maternal urine • Serology: is used to diagnose maternal infection and determining past exposure to CMV infection but has limitation in diagnosis of recent infection, because: • The detection of CMV-specific IgM antibodies, suggesting recent seroconversion is not certain because IgM from previous infection can be detected for up to one year. • Even rise in CMV-specific IgG titers (up to four folds) in paired specimens obtained at least two to four weeks apart also suggest recurrent or recent infection.

41. Prevention and treatment • Routine screening of the pregnant population is not currently recommended because present laboratory methods are limited in the differentiation between primary and recurrent infection. • Preventive efforts are based on good hygiene, limiting intimate contact with infected children, and responsible sexual practices. • CMV vaccine is still under development.

42. Human Immunodeficiency Virus Fetal infection: The most serious consequence of HIV infection in pregnancy is fetal infection, resulting in the birth of a congenitally infected newborn. Maternal HIV is not teratogenic or associated with increased fetal loss (except for end-stage disease). With out treatment the risk of fetal transmission is around 30%. The quantity of viral load (HIV-1 RNA) in the mother appears to be a significant risk factor for fetal infection.

43. Management Management: The goals of management in pregnancy are: (1) Identifying the disease (2) Preventing perinatal transmission.

44. Diagnosis of HIV Screening for HIV: In some communities screening with an enzyme-linked immunosorbent assay (ELISA) for HIV is recommended and should be offered to all pregnant women. Women at risk (e.g. those with hemophilia, intravenous drug users, and female partners of infected men) should be screened more than once during the pregnancy. Suspected cases i.e. positive screen tests should be confirmed with more specific tests such as Western blot.

45. Counseling of women with positive HIV test Such cases should best be counseled in a center familiar with HIV treatment and management. Counseling include education about the diseases and its potential consequences, the need for treatment during pregnancy, screening for other family members…etc.

46. Prevention and treatment Prevention of perinatal transmission: All women who are HIV positive should be advised to take antiretroviral therapy “Zidovudine” during pregnancy and delivery to decrease perinatal transmission of the virus. Evidences have shown that Zidovudine administration in HIV-infected pregnant women from 14 to 34 weeks' gestation decreased perinatal transmission from 25.5% to 8.3%.  

47. Mode of delivery is controversial: many experts recommend cesarean section at 38 weeks for women with a viral load greater than 1000 copies per mL. If vaginal delivery is contemplated in women with lesser viral load, artificial rupture of membranes and placement of a scalp electrode onto the fetal head to monitor the fetal heart rate are contraindicated.

48. Care of the newborn: Breast-feeding is contraindicated in HIV-infected women. The newborn should be followed up and tests with specific tests for up to 6 months or one year.

49. Varicella (or chickenpox) The causative agent: Varicella-zoster virus (VZV), is also the causative agent of herpes zoster (shingles). VZV is a member of the herpesvirus family along with herpes simplex types 1 and 2, cytomegalovirus. Transmission: VZV is highly contagious virus transmitted by respiratory droplets or close contact. Primary varicella generally confers lifelong immunity, although there are reported cases of re-infection. VZV remains latent in the dorsal root ganglia and may be reactivated, often associated with impaired cell-mediated immunity.

50. Diagnosis • Depends on: • The typical clinical lesions (erythematous macules, papules, and vesicles rashes). • Serologic tests can help to document acute infection; Specific IgM and IgG antibodies can be detected as early as three and seven days respectively after varicella symptoms. • PCR can identify VZV-specific DNA from vesicular fluid or throat swabs.