As counted by the Centers for Disease Control and Prevention (CDC), anogenital human papillomavirus (HPV) is the most common and widespread sexually transmitted infection. Eight out of 10 sexually active people will be infected with more HPV strains(1). The prevalence of the identified HPV infection in European women from the general population is estimated to be 14%, with a peak in the age groups represented by adolescents and females in their early 20s, affecting women during their gestational period(2,3).
More than 200 distinct types of human papillomavirus have been identified, and at least 40 subtypes can infect the genital area. In most cases, HPV infection is asymptomatic and resolves spontaneously within two years. In persistent infection, low-risk HPV strains can cause benign proliferative lesions, while high-risk strains infection can progress, over at least ten years, to precancerous lesions and malignancies of the cervical uterus, anal, oropharynx and penile tissue(4).
During pregnancy, external anogenital warts (condyloma acuminata) are the most common manifestation of HPV infection. During this period, the proliferation and growth of warts accelerate, being frequently followed by a spontaneous regression of lesions in the puerperium(5). The mother’s immune system is highly adaptative, going through various changes at every stage of gestation, keeping a balance between the allogeneic fetus and immunocompetence against any pathogens. The physiological increase in local estrogen and glycogen in the genitals during pregnancy, in addition to the immune disorders inherent in pregnancy, favors the proliferation of the HPV(5,6).
Condyloma acuminata (anogenital warts)
HPV types 6 or 11 are the etiologic factor for the majority of anogenital warts. Other types of human papillomavirus that have been isolated in genital warts are HPV 2, 40, 42, 43, 54, usually as co-infections with HPV 6 or 11. The infection with one type of HPV does not prevent the infection with a different type, 5% to 30% out of mucosal HPV infections being caused by multiple strains of the virus. HPV types 6 and 11 have also been associated with conjunctival, nasal, oral and laryngeal warts(7,8).
Anogenital warts present as flat, papular, pedunculated or cauliflower-like growths of pink, grey or brown colouring, on perineal and anogenital skin and/or mucous membranes. Anogenital warts are frequently multiple, asymmetric and polymorphic and can occasionally cause bleeding, pruritus, increased vaginal secretions, obstruction of the birth canal and neonatal infections. These type of skin lesions decrease the quality of life, as they can be intractable to treatment, may regenerate spontaneously or remain in remission for a long period(9).
During pregnancy, condyloma acuminata can have a rapid development of the perineal and anogenital lesions, especially during weeks 12 and 14 of gestation. HPV seems to actively replicate due to the rising estrogen levels, decreased cellular immunity and increased vascularisation and blood flow in the genital area due to pregnancy. Anogenital warts that develop during pregnancy are usually located near the vaginal opening, cervix and the vaginal wall, and are more difficult to treat because of ulceration and infections risks. Furthermore, they are fragile and pruriginous and can easily cause bleeding(7,10). They may sometimes become very large, particularly when new warts develop during pregnancy. There have been cases of giant condylomas – also known as Buschke-Löwenstein tumors – reported during pregnancy, that grow to such an extent, that they obstruct the birth canal. Caesarean delivery is indicated for women who may suffer from labor dystocia or excessive bleeding during vaginal delivery associated with condyloma acuminata(11-13).
Risk of vertical transmission
The transmission of HPV from mother to offspring has been reported by several studies. The virus may infect the fetus during pregnancy, through transplacental or perinatal transmission, or by nursing after delivery(14,15). The vertical transmission is due to the microtears in fetal membranes or through the placenta if the mother has genital HPV infection. Studies have demonstrated that HPV (low- and high-risk) can cross the placenta and reach the fetus, with a detection rate of HPV-DNA in the placental samples varying from 0% to 42.5%(14). HPV-DNA has been detected both in amniotic fluid and the umbilical cord(15). The risk of transmission of the same HPV type present in the maternal genital tract is four times higher when the umbilical cord blood tests positive for the same HPV(16).
The way of delivery (vaginal or caesarean section) does not seem to influence the neonatal infection rate. Caesarean delivery may be considered when the birth canal is obstructed, in case of premature rupture of membranes or when high viral load is suspected. Breastfeeding should not be restricted if the mother is found to be infected with HPV(10,17).
Generally, the newborn becomes clear of the HPV infection after the first year of life; nevertheless, neonatal anogenital, oral or conjunctival HPV lesions can develop. The infection with mucosal HPV 6 and 11 may cause recurrent respiratory papillomatosis in children, which is a rare and severe respiratory disease(18).
There is currently no curative antiviral treatment available for HPV infection. Most treatment options for condyloma acuminata require physical destruction of the infected cells. The surgical or medical treatment choice depends on the location, number, dimension, type of wart and on the compliance to treatment. During pregnancy, the treatment options are limited, as the standard systemic treatment is teratogenic(8).
The preferred method to treat anogenital warts during pregnancy is the surgical treatment, that consists of electrocautery excision, curettage, scalp excision under general or local anaesthesia, cryotherapy, and using a CO2 laser. Cryotherapy is considered the first line of treatment; it uses nitrous oxide or liquid nitrogen directly on the lesions. Small lesions can be treated during pregnancy with trichloroacetic acid (TCA) applied sparingly, with limited efficacy(10,19).
Podofilox® (podophyllotoxin) and sinecatechins are topical treatment options that should not be used during pregnancy. Podophyllotoxin is an antimitotic drug, toxic to the mother, but also teratogenic; it can cause malformations of the ear, heart and extremities of the fetus. Despite the low risk of teratogenicity, the use of imiquimod should be avoided, as the current data are insufficient.
The removal of warts during pregnancy can be considered, despite the fact that the resolution might be incomplete or poor until pregnancy is complete(10,20).
Condyloma acuminata during pregnancy poses a dilemma for the clinician; untreated it may affect the fetus, whereas the treatment options are limited due to lack of eloquent clinical trials.
Researchers have recently discovered a link between the strains of beta HPV in the oral cavity and the increased risk to develop head and neck cancer. Also, it is very important to understand if viral DNA of HPVs is pathogenic for infants or if it is only a transient infection and without the possibility to cause a real disease in the future(21).
Prevention plays a key role. Achieving high vaccination rates among young girls and implementing a programme of gender-neutral vaccination can help reduce the vertical HPV transmission and, implicitly, the incidence of juvenile recurrent respiratory papillomatosis. In Australia, the national vaccination programme started in 2007 and extended to boys in 2013(22,23), while in the 19 EU countries, the national vaccination programme was introduced from 2012(24). HPV vaccines that prevent HPV 6 and HPV 11 related anogenital warts are available in Romania from 2008 (Gardasil/Silgard® – Merck & Co., Inc., tetravalent vaccine) and from 2020 (Gardasil 9® – 9-valent vaccine). The Romanian Ministry of Health promotes a school-based immunization campaign, providing free vaccines for 10- to 11-year-old girls(25,26).