UNSW Embryology

Abnormal Development - Viral Infection

© Dr Mark Hill (2011)

Acknowledgements

Introduction

Hepatitus B virions (Image: CDC USA)

Below is a list of some known maternal, then fetal and postnatal infections that impact upon development. Only a very brief overview is given for each virus for more specific details see the listed internal and external links. Viruses cannot reproduce by themselves and therefore infect cells to use the cell machinery to produce more virus. Different viruses have genetic material as single- or double-stranded RNA or DNA. The infectious virus particle is called a "virion" and is the genetic material packed in a protein shell. Viruses come in many genetic sizes, as little as 4 proteins up to 200 proteins.

Viral infections can range in their effects from no discernable impact through to severe impacts on development. Furthermore this may occur either directly by the infection or indirectly by the associated maternal fever and other side-effects of the infection. (More? Maternal Hyperthermia)

Rubella virus "German Measles" infection during pregnancy is one of the most serious causing congenital rubella syndrome with serious malformations of the developing fetus. (More? Rubella)

Viral infections have also recently been in the news with the 2009 novel influenza A (H1N1) "Swine Flu" pandemic. (More? Swine Influenza Virus)

Some early postnatal viral infections can also impact upon development and have been the target for worldwide immunization and eradication. (More? Polio)

Human Immunodeficiency Virus (HIV) leads to AIDS and according to United Nations 2005 data about 38.6 million people had HIV. Of the 17.3 million women infected with HIV, 3.28 million gave birth each year (mostly in sub-Saharan Africa), leading to 700,000 new infections of HIV in children each year. (More? Human Immunodeficiency Virus)

Note also that many cancers can be caused by viruses (papilloma viruses, hepatitis B and C viruses, Epstein-Barr virus and human T-cell lymphotropic virus). Virus-induced cancers account for about 20% of worldwide cancer incidence.

In a few developing countries, and mainly in Africa, at least 3 viruses induce a hemorrhagic fever: Ebola hemorrhagic fever, Marburg virus disease, and Lassa fever.

Page Links: Introduction | Some Recent Findings | Rubella Images | Cytomegalovirus | Herpes Simplex Virus | Hepatitis Virus | Human Immunodeficiency Virus | Influenza Virus | Swine Influenza Virus | Avian Influenza Virus | Lassa Virus | Adenovirus | Prevention | References | WWW Links | Glossary

Related Pages: Herpes Simplex Virus | Rubella | Lassa virus | Polio |

Some Recent Findings

Dating the emergence of pandemic influenza viruses. Smith GJ, Bahl J, Vijaykrishna D, Zhang J, Poon LL, Chen H, Webster RG, Peiris JS, Guan Y. Proc Natl Acad Sci U S A. 2009 Jul 13. PMID: 19597152

"In the 20th century, 3 influenza viruses caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. These pandemics were initiated by the introduction and successful adaptation of a novel hemagglutinin subtype to humans from an animal source, resulting in antigenic shift. ...Our results indicate that genetic components of the 1918 H1N1 pandemic virus circulated in mammalian hosts, i.e., swine and humans, as early as 1911 and was not likely to be a recently introduced avian virus. Phylogenetic relationships suggest that the A/Brevig Mission/1/1918 virus (BM/1918) was generated by reassortment between mammalian viruses and a previously circulating human strain, either in swine or, possibly, in humans. Furthermore, seasonal and classic swine H1N1 viruses were not derived directly from BM/1918, but their precursors co-circulated during the pandemic. Mean estimates of the time of most recent common ancestor also suggest that the H2N2 and H3N2 pandemic strains may have been generated through reassortment events in unknown mammalian hosts and involved multiple avian viruses preceding pandemic recognition. The possible generation of pandemic strains through a series of reassortment events in mammals over a period of years before pandemic recognition suggests that appropriate surveillance strategies for detection of precursor viruses may abort future pandemics."

Cytomegalovirus infection in the human placenta: maternal immunity and developmentally regulated receptors on trophoblasts converge. Pereira L, Maidji E. Curr Top Microbiol Immunol. 2008;325:383-95. Review. PMID: 19067401

"During human pregnancy, CMV infects the uterine-placental interface with varied outcomes from fetal intrauterine growth restriction to permanent birth defects, depending on the level of maternal immunity and gestational age. Virus spreads from infected uterine blood vessels, amplifies by replicating in decidual cells, and disseminates to the placenta in immune complexes."

Rubella Virus

Rubella Virus, transmission electron micrograph (Image: CDC USA)

Rubella virus (Latin, rubella = little red), also known as "German Measles" (due to early citation in German medical literature), infection during pregnancy can cause congenital rubella syndrome (CRS) with serious malformations of the developing fetus. The type and degree of abnormality relates to the time of maternal infection.

(More? UNSW Embryology - Rubella)

Cytomegalovirus

Immunoflourescent detection of Cytomegalovirus (Image: CDC USA)

Viral infection causes systemic infection and extensive brain damage and cell death by necrosis.   References: Cytomegalovirus infection in the human placenta: maternal immunity and developmentally regulated receptors on trophoblasts converge. Pereira L, Maidji E. Curr Top Microbiol Immunol. 2008;325:383-95. Review. PMID: 19067401

Links: Medical Microbiology- Cytomegalovirus | Search Medical Microbiology "Cytomegalovirus"

Herpes Simplex Virus

Herpes Virus, transmission electron micrograph (Image: CDC USA)

Viral herpes simplex infection can cause a systemic infection and extensive brain damage and cell death by necrosis. There is also some evidence which suggests that fetal exposure to herpesvirus infection is associated with pregnancy-induced hypertensive disorders and preterm birth.   (More? UNSW Embryology - Herpes Simplex Virus)

NCBI Bookshelf (external link) Search Medical Microbiology "Herpes Simplex Virus"

Search PubMed: term = Herpes Simplex Virus teratology | embryo infection | fetal infection | neonatal infection

Polio Virus

Poliomyelitis (polio) is a highly infectious viral disease, affecting only humans of any age, but mainly children under the age of 3 (> 50% cases) causing paralysis and death. There are three types (type 1, type 2, and type 3) of wild poliovirus which can invade the nervous system and can cause total paralysis in several hours.

(More? UNSW Embryology - Polio)

Human Immunodeficiency Virus

Human Immunodeficiency Virus, transmission electron micrograph (Image: CDC USA)

The human immunodeficiency virus (HIV) is a retrovirus that causes Acquired Immunodeficiency Syndrome (AIDS). Maternal transmission of HIV can occur perinatally in utero, during labour and delivery, or postnatally through breastfeeding and can be reduced by the use of antiretroviral treatment and avoidance of breastfeeding. Neonatal infection diagnosis can be made by PCR from 6-12 week. UNAIDS, the Joint United Nations Programme on HIV/AIDS, estimated that 38.6 million people had HIV (2005), 17.3 million were women. About 3.28 million pregnant women infected with HIV give birth each year (the majority in sub-Saharan Africa) leading to 700,000 new infections of HIV in children each year. (text modified from Gray and McIntyre, BMJ 2007;334:950-953)

Pubmed Coll O, Suy A, Hernandez S, Pisa S, Lonca M, Thorne C, Borrell A. Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies. Am J Obstet Gynecol. 2006 Jan;194(1):192-8.

Search PubMed: term = Human Immunodeficiency Virus teratology | embryo infection | fetal infection | neonatal infection

Links: British HIV Association Guidelines for management of HIV and hepatitis C coinfection in adults | Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV, 2005 | Guidelines for management of HIV and hepatitis B coinfection in adults | World Health Organization HIV-infected women and their families: psychosocial support and related issues. A literature review. 2003

Hepatitis Virus

Hepatitus B virions (Image: CDC USA)

Hepatitis (inflammation of the liver) is caused in humans by one of 7 viruses (A, B, C, D, E) with the 2 additional F has not been confirmed as a distinct genotype; and G is a newly described flavivirus. "All of these viruses can cause an acute disease with symptoms lasting several weeks including yellowing of the skin and eyes (jaundice); dark urine; extreme fatigue; nausea; vomiting and abdominal pain. It can take several months to a year to feel fit again." (CDC text). Virus particles measure 42nm in overall diameter and contain a 27nm diameter DNA-based core.

Hepatitis Transmission Risk to the Fetus

Hepatitis A

• Fetal transmission of virus occurs with extreme rarity.

Hepatitis B

• Can occur as a consequence of intrapartum exposure, transplacental transmission, and breastfeeding.
• 20%–30% of HBsAg-positive/HbeAg-negative women will transmit virus to their infants.
• 90% of HBsAg- and HBeAg-positive women will transmit virus to their infants.
• Immunoprophylaxis at birth with both HBIG and Hepatitis B vaccine within 12 hours of birth decreases the risk of transmission.
• Passive (HBIG) and active immunization is 85%–95% effective in preventing neonatal HBV infection.
  

Hepatitis C

• The overall risk of transmission is approximately 5%–10% with unknown maternal viral titers.
• All pregnant women with HCV should have viral titers performed.

Data Source: Hepatitis and reproduction. Practice Committee of American Society for Reproductive Medicine. Fertil Steril. 2008 Nov;90(5 Suppl):S226-35. Review. PMID: 19007636

References:

• Hepatitis and reproduction. Practice Committee of American Society for Reproductive Medicine. Fertil Steril. 2008 Nov;90(5 Suppl):S226-35. Review. PMID: 19007636
• Ornoy A, Tenenbaum A. Pregnancy outcome following infections by coxsackie, echo, measles, mumps, hepatitis, polio and encephalitis viruses. Reprod Toxicol. 2006 May;21(4):446-57.
• Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B immunisation in newborn infants of mothers positive for hepatitis B surface antigen: systematic review and meta-analysis. BMJ. 2006 Feb 11;332(7537):328-36.

Search PubMed: term = Hepatitis Virus teratology | embryo infection | fetal infection | neonatal infection

Influenza Virus

Flu is the general term and abbreviation of influenzaviral infections and the possible teratogenic effect of influenza viruses (orthomyxoviruses, "flu") is unclear, with very little evidence directly linking the two events. A relatively recent study was unable to identify any placental transmission of influenza virus during the second and third trimester. Severe maternal infection though may lead to hyperthermia, which has been demonstrated to be teratogenic, particularly in early neural development. (More? Maternal Hyperthermia)

Irving WL, James DK, Stephenson T, Laing P, Jameson C, Oxford JS, Chakraverty P, Brown DW, Boon AC, Zambon MC. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG. 2000 Oct;107(10):1282-9.

"We found no evidence for transplacental transmission of influenza virus or auto-antibody production in pregnancies complicated by influenza infections. There was an increase in the complications of pregnancy in our influenza cohort."

Postnatally, the suggested initial limited neonatal immune system makes postnatal infection dangerous.

References:

Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M. Transmission of influenza A in human beings. Lancet Infect Dis. 2007 Apr;7(4):257-65.

Links: Medline Plus - Flu | Search Medical Microbiology "orthomyxovirus"

Swine Influenza Virus

In 2009 a global pandemic of the novel influenza A (H1N1) or Swine Flu has occurred. At this stage the possible teratogenic effect of this influenza virus should be considered the same as those described for the influenza virus above. The term "Pandemic" refers only to the spread of the virus, not the severity of the infection or potential developmental outcomes. This virus has also been spreading in an unseasonable pattern, that is in the northern hemisphere summer, when typically viral infections increase in the winter period.

H1 refers to one of the hemagglutinin subtypes (H1, H2 or H3) and N1 refers to one of the two neuraminidase subtypes (N1 or N2). Over the last century there have been at least three different human viral pandemic circulating strains H1N1 (1918, 1977), H2N2 (1957) and H3N2 (1968).

Region	Number of Confirmed Cases (10 July 2009 based upon online data)	Number of Confirmed Deaths
USA	37,246	211
Mexico	11,699	121
Canada	9,717	39
UK	9,718	14
Europe	13,667	16

(Table data source: BMJ 2009;339:b2840)

Confirmed infections per million population (July 2009)

• Australia and New Zealand - 462
• Britain - 158
• USA - 118

Australia - H1N1 Influenza 09 (Human Swin Flu) Facts

• Incubation period: maximum = 7 days (3 days would be more common)
• Period of communicability: from 24 hours prior to the onset of symptoms until:
  • adults 12-64 yrs = 7 days
  • adults >65 yrs = 14 days
  • children <12 yrs = 14 days (or until resolution of fever, whichever is longer)
• Means of virus transmission: most likely to be spread from person-to-person by inhalation of
  infectious droplets produced while talking, coughing and sneezing; transmission may also occur
  through direct and indirect (fomite) contact.

Australian State Information

• NSW http://www.health.nsw.gov.au/publichealth/swine_flu.asp
  • Public health offices in NSW Area Health Service Areas can be found at: http://www.health.nsw.gov.au/publichealth/swine_flu.asp
• Victoria http://www.health.vic.gov.au/ideas/diseases/swine-influenza
  • http://www.health.vic.gov.au/pandemicinfluenza/general_practice.htm
• Queensland http://access.health.qld.gov.au/hid/InfectionsandParasites/ViralInfections/swineFlu2009_fs.asp and http://www.health.qld.gov.au/swineflu/html/hc_resources.asp
• WA http://www.public.health.wa.gov.au/2/949/2/swine_flu.pm and http://www.public.health.wa.gov.au/3/952/3/human_swine_flu_health_providers.pm
• SA http://www.flu.sa.gov.au/Swineflu.aspx and http://www.health.sa.gov.au/pandemicinfluenza/
• NT http://www.health.nt.gov.au/Centre_for_Disease_Control/index.aspx and http://www.health.nt.gov.au/Emergency_Management_and_Disaster_Arrangements/Pandemic/index.aspx
• Tasmania http://www.pandemic.tas.gov.au/ and http://www.pandemic.tas.gov.au/what_does_it_mean_to_you/health_sector
• ACT http://health.act.gov.au/c/health?a=da&did=10098808&pid=1240874209 and http://www.health.act.gov.au/c/health?a=da&did=11044035&pid=1242181681
  

(Facts from: Australian Commonwealth Department of Health and Ageing H1N1 Influenza 09 (Human Swine influenza) – Summary Sheet for General Practitioners Current as of 24 May 2009)

UK Information

20 July 2009: Chief Medical Officer's advice to pregnant women
"Some pregnant women who catch the H1N1 (swine) ‘flu virus will develop complications of the infection (including pneumonia) that could put their own and their baby’s health at risk. The risks are greatest in the second and third trimesters of pregnancy. It is too early in the pandemic of influenza to be able to quantify these risks for the individual but most pregnant women who catch the disease are likely to make an uncomplicated recovery...."

Links: WHO - H1N1 Pandemic | USA CDC - H1N1 Flu | Medline Plus - H1N1 Flu (Swine Flu) | GenBank sequences from pandemic (H1N1) 2009 viruses

Avian Influenza Virus

Avian Influenza virion (Image: CDC USA)

In 1997 the first instance of direct bird-to-human spread of influenza A (H5N1) virus was documented during an outbreak of avian influenza among poultry in Hong Kong. The virus caused severe respiratory illness in 18 people (6 died) and there have been subsequent instances of other H5N1 infection. The virus does not typically infect humans, and there is no evidence yet of a direct effect on development.

Lassa Virus

Lassa virions (Image: CDC USA)

Lassa virus of the arenaviridae family, a single-stranded RNA virus. The virus is the causative agent of a hemorrhagic fever and can be transmitted between species (zoonotic). Death rates are high for women in the third trimester of pregnancy. Fetal death (95%) occurs in uterus of infected pregnant mothers. (More? UNSW Embryology - Lassa virus)

Adenovirus

Adenoviruses have a double-stranded linear DNA structure. This virus family is the causative agent of membrane infections in: respiratory tract, eyes, gastrointestinal tract, and urinary tract.

Modified adenovirus is currently used as a research tool to introduce genes into cells in vitro and in animal systems.

Links: Medical Microbiology - Adenoviruses | Search Medical Microbiology "adenovirus"

References:

Gordon JW. Adenovirus gene transfer vector toxicity to mouse embryos: implications for human IVF. Hum Reprod. 2002 Sep;17(9):2380-7.

Coxsackie

Coxsackie B virus are 6 pathogenic enteroviruses with a range of adult illness from mild gastrointestinal to pericarditis and myocarditis. These viruses may cause an increase in early spontaneous abortions and rarely a fetal myocarditis.

Echoviruses

Echoviruses are RNA viruses found in the gastrointestinal tract that belongs to the genus Enterovirus of the Picornaviridae family. These viruses do not seem to damage the fetus.

Mumps

Mumps (epidemic parotitis) is a viral inflammation of the parotid glands, which are the major salivary glands in humans. This viral infection may cause increased early and late fetal death and neonatal mumps. Note that parotid inflammation can also occur during bacterial infections.

Marburg Virus

Marburg virions (Image: CDC USA)

Marburg RNA virus of the filovirus family, causes hemorrhagic fever in both humans and non-human primates and is a very rare. Virus has characteristic "Shepherd’s Crook" shape.

Prevention

For some viral infections there are antiviral medicines and immunizations (vaccines), others have no current direct protection. In general the following public health advice is given in preventing the spread of viruses: Cover your nose and mouth with a tissue when you cough or sneeze and discard after you use it. Wash your hands often with soap and water, or use alcohol-based hand cleaners, after you cough or sneeze. Avoid touching your eyes, nose or mouth. Avoid close contact with sick people. Stay home from work or school if you are sick.

Australian NHMRC Recommendations

The Australian NHMRC (1988) recommends neonates be assessed for follow-up care under the following conditions.

• Birthweight less than 1500g or gestational age less than 32 weeks
• Small-for-gestational-age neonates
• Perinatal asphyxia
• Apgar score less than 3 at 5 minutes
• clinical evidence of neurological dysfunction
• delay in onset of spontaneous respiration for more than 5 minutes and requiring mechanical ventilation
• Clinical evidence of central nervous system abnormalities ie., seizures, hypotonia
• Hyperbilirubinaemia of greater than 350umol/l in full term neonates
• Genetic, dysmorphic or metabolic disorders or a family history of serious genetic disorder
• Perinatal or serious neonatal infection including children of mothers who are HIV positive
• Psychosocial problems eg., infants of drug-addicted or alcoholic mothers.

WWW Links

CDC (USA)

Public Health Training Network Epidemiology and Prevention of Vaccine-Preventable Diseases (viewable Webcasts requires Media Player) |

Advisory Committee on Immunization Practices (ACIP) Recommendations

Royal College of Obstetricians and Gynaecologists (UK)

Infection and Pregnancy - study group recommendations (Jun 2001)

References

Reviews | Articles | Search NCBI Bookshelf | Search PubMed | Glossary

Reviews

Cytomegalovirus infection in the human placenta: maternal immunity and developmentally regulated receptors on trophoblasts converge. Pereira L, Maidji E. Curr Top Microbiol Immunol. 2008;325:383-95. Review. PMID: 19067401

Degani S. Sonographic findings in fetal viral infections: a systematic review. Obstet Gynecol Surv. 2006 May;61(5):329-36.

Ornoy A, Tenenbaum A. Pregnancy outcome following infections by coxsackie, echo, measles, mumps, hepatitis, polio and encephalitis viruses. Reprod Toxicol. 2006 May;21(4):446-57.

Giles ML, Garland SM, Grover SR, Lewin SM, Hellard ME. Impact of an education campaign on management in pregnancy of women infected with a blood-borne virus. Med J Aust. 2006 Apr 17;184(8):389-92.

Kriebs JM. Changing the paradigm: HIV in pregnancy. J Perinat Neonatal Nurs. 2006 Jan-Mar;20(1):71-3.

Bailao LA, Osborne NG, Rizzi MC, Bonilla-Musoles F, Duarte G, Bailao TC. Ultrasound markers of fetal infection part 1: viral infections. Ultrasound Q. 2005 Dec;21(4):295-308.

Slowik MK, Jhaveri R. Hepatitis B and C viruses in infants and young children. Semin Pediatr Infect Dis. 2005 Oct;16(4):296-305.

Articles

Dating the emergence of pandemic influenza viruses. Smith GJ, Bahl J, Vijaykrishna D, Zhang J, Poon LL, Chen H, Webster RG, Peiris JS, Guan Y. Proc Natl Acad Sci U S A. 2009 Jul 13. PMID: 19597152

Revello MG, Zavattoni M, Furione M, Fabbri E, Gerna G. Preconceptional primary human cytomegalovirus infection and risk of congenital infection. J Infect Dis. 2006 Mar 15;193(6):783-7.

Coll O, Suy A, Hernandez S, Pisa S, Lonca M, Thorne C, Borrell A. Prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal anomalies. Am J Obstet Gynecol. 2006 Jan;194(1):192-8.

Search NCBI Bookshelf: prenatal viral infection | Medical Microbiology - prenatal viral infection

Search PubMed: Search May 2006 "prenatal viral infection" 2,710 reference articles of which 441 were reviews.

Search term = prenatal viral infection | rubella virus | Cytomegalovirus | Herpes Simplex Virus | Polio |

Glossary

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers

Where to Next?

You should look at normal development of the effected systems in the embryo. Development Notes

Alternatively, go on to look at Systematic Development of organs and tissues.

Quick Links

System Abnormality Notes ----------------- Heart/Cardiovascular Respiratory Coelomic cavity Gastrointestinal Tract Head and Neck Neural Neural Crest Eye Ear Nose Endocrine Urogenital Musculoskeletal Integumentary

This quick link is to the abnormal development page for each system.

Development Notes ----------------- Menstrual Cycle Week 1 Week 2 Week 3 Week 4 Placenta Serial Images Genes/DNA Molecular Dev Abnormal Dev Postnatal Dev Notes Index

System Notes ----------------- Heart/Cardiovascular Respiratory Coelomic cavity Gastrointestinal Tract Head and Neck Neural Neural Crest Eye Ear Nose Endocrine Urogenital Musculoskeletal Integumentary

Movies ----------------- Movies Quicktime Flash Audio Week 1 Week 2 Week 3 Stage 13 Stage 22 Neural Heart Gastrointestinal Renal Genital Other Embryos

Other Embryos ----------------- All Animals Chicken Fly Frog Mouse Rabbit Rat Worm Zebrafish Guinea Pig

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