HPV and PREGNANCY Arsenio Spinillo,, MD

HPV and PREGNANCY Arsenio Spinillo,, MD University of Pavia, Department of Obstetrics and Gynecology, IRCCS Fondazione Policlinico San Matteo di Pavia

Human Papilloma Virus HPV is a member of the Papovaviridae family of double-stranded DNA, that includes more than 200 types, 35 infect the anogenital tract.

HUMAN PAPILLOMA VIRUS Member of the papovavirus family. Virus that displays epithelial tropism. Without a lipoprotein envelope, it s capsid contains 72 sub-units units organized in a icosaedric structure. It contains a double- stranded DNA.

Prevalence of infection Female population of American colleges: Clinical condilomatosis 1% Subclinical lesions 4% Positive HPV-DNA 10% Positive antibodies for previous infection 60% No actual or previous infection 25%

HPV INFECTION AND CERVICAL CANCER OF THE UTERUS In the last 20 years it has been proven the causal association between HPV and cervical cancer The risk of lung cancer in a white male smoker is 8 times higher compared to non smoker The risk of cervical cancer among HPV-16 positive women is 434 times higher compared to the HPV 16 negative

Cervical cancer Magnitude of the Problem 500,000 new cases identified each year 80% of the new cases occur in developing countries At least 200,000 women die of cervical cancer each year Cervical cancer is the third most common cancer worldwide YET - Cervical cancer is a preventable disease

CERVICAL CANCER: EXTENT OF THE PROBLEM IN ITALY Incidence 1-10/100001 10/10000 women Approximately 3500 new cases each year 60000 new cases of preneoplastic lesions 3% of cervical cancer cases are diagnosed during pregnancy

HUMAN PAPILLOMA VIRUS Through hybridization techniques more than 200 different types of HPV were isolated and identified with alphabetical order. Among these, 35 present tropism for the anogenital area. HIGH RISK 16, 18 Certainly Oncogenic High grade CIN Squamous Ca MEDIUM RISK 30,31,33,35, 45,51,56 Probably Oncogenic Medium-high grade CIN LOW RISK 6, 11 Non oncogenic Genital Warts

HPV-associated Conditions HPV 16, 18 Cervical cancer - High/low grade cervical abnormalities Anal, Vulvar, Vaginal, Penile Head and neck cancers HPV 6, 11 Low grade cervical abnormalities Genital warts RRP Estimated % 70% 30%-50% 10% 10% 90% 90%

Prevalence of HPV lesions (Pavia) (986 biopsies during 3 years) 80 70 60 50 40 30 20 10 0 6 11 16 18 All CIN 1 CIN 2-3 HPV 6/11 25% of CIN 1 HPV 6/11 and 16/18 55% of CIN 1 HPV 16/18 63% of CIN 2-32 HPV 6/11 and 16/18 72% of CIN 2-32 Spinillo et al; Multiple human papillomavirus infection and high grade cervical Intraepithelial neoplasia among women with citologycal diagnosis of atipical squamous cells of undetermined significance or low grade squamous intraepithelial lesions; Gynecologic Oncology 113 (2009) 115-119

PRENEOPLASTIC LESIONS (PAVIA) (936 biopsies) 60 40 20 0 60 40 20 0 Multiple NO 16-18 CIN 1 CIN 2-3 CIN 1 CIN 2-3 Multiple infections in low grade lesions are 38% and in the severe lesions 58%. In multiple infections, virus different from 16-18 18 are present in 44% of low grade and in 31% of the high grade lesions. Spinillo et al; Multiple human papillomavirus infection and high grade cervical Intraepithelial neoplasia among women with citologycal diagnosis of atipical squamous cells of undetermined significance or low grade squamous intraepithelial lesions; Gynecologic Oncology 113 (2009) 115-119

Viral latency A latent infection can only be diagnosed by nuclear acid amplification techniques techniques. Routine diagnostic test include: HYBRID CAPTURE II (HC 2) POLYMERASE CHAIN REACTION (PCR) INNO-LIPA

Subclinical HPV s form The viruses presence can be diagnosed only with cytological survey or colposcopic examination and biopsy. Cervix (dysplasia / planum warts) Vagina (vain / planum warts) Vulva

Cervical HPV infection:

Categories for Pap test results: Normal results: If no abnormal cells are seen, then the test result is normal. If only benign changes are seen, usually resulting from inflammation or irritation, then the test result is normal. Abnormal results: Atypical cells of undetermined significance (ASCUS, AGUS). Low-grade squamous intraepithelial lesions (LSIL) or cervical intraepithelial neoplasia (CIN) 1. These are mild, subtle cell changes, and most go away without treatment. High-grade grade squamous intraepithelial lesions (HSIL) or CIN 2 or 3. Moderate and severe cell changes which require further testing or o treatment. Carcinoma.

Clinical HPV s lesions Are defined those forms in which HPV S infection is clinically recognizable. The clinical aspect of viral productive infection is known as condyloma.

Clinical Significance of Representative HPV Types Genotype Disease Association 1 Plantar warts 2, 4, 29 Common warts 3,10,28,49 Flat warts 6, 11, 42 Genital warts; laryngeal papillomas 16, 18, 31, 33, 35, Anogenital dysplasias, neoplasms 39, 45, 51, 52, 56 58, 59, 68 Photo credit: http://www.telemedicine.org/warts/fig4b.htm

Genomic Organization The viral genome is divided in 3 regions: Early Late Regulatory

E2 (Regulator of DNA replication and RNA transcription) E1 e E2 encode proteins with regulatory control on the cell-division cycle. Early Region E1 (Viral DNA Replication factor)

E6 inactivates tumor suppressor p53 by inducing its degradation causing apoptosis blockage. Early Region E6 (p53 degradation) E7 (disrupts cell cycle) E7 binds to RB family proteins inducing cell replication

Functional Assignments of Viral Late Proteins L1 Major capsid protein Late Region L2 Minor capsid protein

When a cell suffers DNA injury or damage, p53 protein activates the transcription of genes like p21 (CIP1/WAF1) or GADD45, effecting a delay in the cell s entry into the S phase until DNA repair is accomplished. Alternatively, p53 may induce apoptosis by activating genes such as bax 1 and the fas receptor gene. The inactivation of p53 by the E6 oncoprotein, therefore, results in the deregulation of the cell cycle and allows cellular mutations to occur.

The binding of the E7 oncoprotein on prb provides a complementary function. The binding releases transcription factor E2F that activates the expression of genes that stimulate DNA synthesis in the cell. If earlier E6 action had freed the same cell from p53 control, that cell survives into the S phase with a damaged DNA and, through E7 action, is able to replicate the HPV DNA.

HPV S PREVALENCE AND PREGNANCY 0,3-5 5 % with an underestimated prevalence in the general population. Physiological period of viral active replication. T immusuppressive state. Progestative state interacts with DNA s regulatory elements. Risk of progression of productive and preneoplastic lesions.

Cervical cancer and pregnancy Pregnancy represents a opportunity to diagnose cervical cancer during preconception check up Check-up Speculum exam PapPap test

Pap-test allows do identify this spot.

Who should have a pap smear?

Cervical cancer and pregnancy The incidency of anomalous pap-test during pregnancy is 5-8%. 5 Younger age is associated with an increasing rate of SIL during pregnancy. SIL during pregnancy + 1,3% Microinvasive Carcinoma + 0,015%

1. Adapted from Baseman JG, Koutsky LA. J Clin Virol. 2005;32S:S16-S24. Natural History from HPV Infection to Cervical Cancer 1 Undetected Cellular Changes HSIL * LSIL Cervical Cancer Oncogenic HPV Infection of the Cervix ** LSIL & HSIL Median Age of Event: Early 20s Early to mid 20s Mid to late 20s 40s to 50s *LSIL = low-grade squamous intraepithelial lesion **HSIL = high-grade squamous intraepithelial lesion

ANOMALOUS PAP-TEST MANAGEMENT DURING PREGNANCY AJOG 2008

ANOMALOUS PAP-TEST MANAGEMENT (L-SIL) DURING PREGNANCY American society for colposcopy and cervical pathology, 2007

Colposcopy in pregnancy

ANOMALOUS PAP-TEST MANAGEMENT DURING PREGNANCY Perform colposcopy + viral typization + in case of lesions biopsy check Perform colposcopy + viral typization + in case of lesions biopsy check (2B) Treatment revaluation not earlier than 6 wks from delivery

INTRAEPITHELIAL LESIONS MANAGEMENT DURING PREGNANCY CIN s treatment during pregnancy is not recommended, this is because the risk of CIN s progression from 2-2 3 to microinvasive carcinoma is low and the post partum regression rate is high. Follow up in patients with diagnosed CIN1 is recommended ed Treatment of CIN1 during pregnancy is not acceptable ACOG LEVEL B

LEEP during pregnancy LEEP can be justified before 16th week of pregnancy but not above 20th week, with endocervix depth not superior to 10 mm sufficient to exclude microinvasion, in all extensive H-SIL cases or with uncertain colposcopic signs for microinvasion ( atypical vessels ).

STAGE AT DIAGNOSIS PREGNANT NOT PREGNANT FIGO I 69-83% FIGO II 11-23% FIGO III 3-8% 3 FIGO IV 0-3% 0 FIGO I 42% FIGO II 35% FIGO III 21% 3% FIGO IV 2%

Condylomas & pregnancy I-II II trimester Destructive or excisional treatment for small and medium size lesions. Not recommended Imiquomod,, 5fu, Podofillina.. III trimester The treatment is recommended when the lesion s size allows treatment and consequent normal vaginal delivery.

Perinatal trasmission

PERINATAL TRASMISSION DIRECT: - During passage through the birth canal -At birth by contact with infected maternal secretion -During C-section C by ascendant infection after PROM INDIRECT: By contact with contaminated objects INTRAUTERINE (During fecundation with infected sperm, by ascendant infection, transplacental infection)

Trasplacentar transmission The viruses life cycle is 18 days, which means that its presence in birth specimen is either contamination or intrauterine infection. Intrauterine infection than can occur with premature rupture of membrane but also transplacentally.

Trasplacental trasmission of HPV. Rombaldi RL et Al. Virology J 2008 (5)106 This a prospective study to evaluate transplacental transmission. Placenta s samples have been take via biopsy, tampons, centrally and peripherycally,, on the fetal and on the maternal side. The identification rate of the placenta is 24.5% and transplacental transmission has been 12.2 %.

Infection s Regression Several investigations reported negativization of HPV S presence in newborns between 6 and 12 months. Maybe there could be maternal Ab transplacental passage that neutralize the virus, or contamination at the time of birth with maternal infected cells.

HPV results in mother and infant included in tha prospective study.

HPV results in mother and infant included in tha prospective study. LOW CONCORDANCE

Conclusion HPV persistence in infants is a rare event. The substantial HPV positivity observed in children born to HPV-negative mother (16,9% vs 19,7% in child of HPV positive mothers) suggest that vertical tgrasmission may not be the sole source of HPV infection in children. Horizontal mother-to to-child trasmission may play a role.

A= att sex B&C= abuso sospetto o provato D= autoinoculazione E= trasmissione interfamiliare F= Possibile trasmissione verticale G= causa sconosciuta Sirijanen et al 2000

Sirijanen et al 2000

Recurrent respiratory papillomatosis (RPP) Benign and very rare pathology that occurs in children below 5 years that causes stridor aphonia and blockage of air pathways. It is more aggressive and recurrent than the adults type Repeated laser treatments are required It is associated with HPV-6 6 e 11 Infection transmission could be non-sexual and/or perinatal

RRP: Operative Procedures Derkay, C. Task Force on recurrent respiratory papillomas Arch Oto H+N, December 1995

HPV and RRP: Transmission Clinically apparent HPV infection noted in 5% of pregnant women in US 1/3 of children born to mothers with condyloma have nasopharyngeal swabs positive for HPV 1:400 children born to mothers with active condyloma will develop RRP RRP in 7 every 1000 women with genital warts

Factors contributing to RRP Child immune status : unable to manage HPV with appropriate T Cell response Time in birth canal Viral load in birth canal Local trauma

In conclusion there is insufficient data to recommend generalized c- section in HPV positive mothers.

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