Condyloma acuminatum (CA) is a highly contagious sexually transmitted disease (STD) caused by sub-types of the human papillomavirus (HPV). Genital warts often occur in clusters and can spread into large masses in the genital or penile area.1 Patients suffering from CA during pregnancy represent a special risk group. These cases are typically characterized by fast-growing warts, reduced tolerability, and poor compliance to treatment, especially when the warts spread into the cervix and/or vaginal wall. Traditional therapeutic approaches, such as carbon dioxide laser, highfrequency electric ion treatment, microwaves, surgery, and topical corrosive substances, usually result in ulcer formation and local infection within the genital track area.2,3 Moreover, the pain induced by various physical treatments might lead to uterine contraction, or may even induce abortions. Podophyllotoxin and other cytotoxic drugs may have adverse effects on the fetus. Physical treatments and topical corrosive substances are not recognized as safe practices in pregnant women. Topical use of 5-aminolevulinic acid (ALA) in combination with photodynamic therapy (PDT) is a novel treatment that has evolved in recent years. It has demonstrated a higher clearance rate of warts, lower recurrence rates, and a favorable safety profile. In addition, it has the advantage of a shortened healing period and less damage to local tissue integrity.4,5 In our study, ALA-PDT was used since 2009 in five pregnant women with CA, and achieved satisfactory therapeutic results.
Five pregnant patients with the complaint of CA presented to the Outpatient Dermatology Department of our hospital between October, 2009 and May, 2011. All patients provided written informed consent for the study. The five individual cases are outlined below.
Patient one was 31 years old, diagnosed with cervix and vulva CA in December, 2009 at day 38 of gestation at out-patient Department of Gynecology & Obstetrics. CA was confirmed by acetic acid white experiment. Multiple verrucous papules were observed in the vagina, vaginal wall, and cervix by the Dermatology Department. The patient realized the advantages of photodynamic therapy, and strongly requested to use it without considering abortion, long-term fertility problems, or other relevant risks.
Patient two was 32 years old, and presented in March, 2010 at 16 weeks of gestation with the complaint of perianal verrucous for two months. The patient was diagnosed with genital neoplasm two months earlier. She received cryotherapy twice and laser treatment once, but suffered recurrence. Her admission history includes 7-8 perineum and perianal warts, cristated-like, with diameters of 0.2-0.8 cm. CA was confirmed by acetic acid white experiment.
Patient three was 32 years old, and presented in July, 2010 at 13 weeks of gestation with the complaint of multiple neoplasm in her vagina and cervix. This was confirmed to be CA by pathological biopsy in another hospital. Routine examination was completed in our Outpatient Department, and 20-30 warts were seen spreading around the vulva, vagina, and cervix, with diameters of 0.3-0.8 cm. The patient was willing to take the relevant risks of PDT on the fetus. All lesions disappeared after two administrations of PDT. PDT was performed at total of three times in this patient.
Patient four was 31 years old, and presented in February, 2009 at 12 weeks of gestation with the complaint of massive CA warts in the nympha and vagina for two weeks. The biggest wart was found in the nympha, and had a diameter of 1.5 cm, confirmed by acetic acid white experiment. The larger warts vanished after two administrations of PDT; all warts disappeared after four administrations of PDT (telephone review only).
Patient five was 25 years old, and presented in May, 2011 at 25 weeks of gestation with complaint of CA in vagina. Routine examination was performed in our outpatient department, and 6-10 warts with diameters of 0.5-1.5 cm were observed. Warts were cristated and cauliflower-like, and confirmed by acetic acid white experiment.
Materials and instruments
ALA hydrochloride powder for topical use was purchased from Shanghai Fudan-Zhangjiang Company, with specification of 118 mg.
An XD2635AB photodynamic laser (Guilin Xingda photoelectric medical equipment Co., Ltd.) was used for treatment with emission of the semiconductor laser at a wavelength of 635 nm. The instrument was equipped with a special laser probe; the laser spot was adjustable according to the size of the target lesion. The laser was also equipped with a cylindrical fiber and disposable plastic cover.
After routine cleaning of the operation area, the lesion area was covered with cotton containing 20% ALA solution and warped by plastic film (except the cervix) for at least 3 hours, all in dark places during the process of ALA treatment. The targeted area was exposed after 3 hours of ALA treatment and then irradiated with a helium neon laser at 100-150 J/cm2. Additional therapy was performed based on results one week after initial treatment. For each patient, three to four treatments were performed at intervals of 7 to 15 days.
Responses were deemed “complete” if 100% of the lesions disappeared; “partial” in cases of 50%-100% clearance; and “poor” when clearance was <50%.6
The clearance rate of genital warts was 100% after four administrations of PDT (Table 1). The lesions of patient 1 disappeared after three administrations of PDT (Figure 1). All lesions of patient 2 disappeared after one administration of PDT with excellent healing. PDT was administered two additional times to prevent recurrence (Figure 2). All lesions of patient 3 were eliminated after two administrations of PDT and treatment was performed at total of three times in this patient. The larger warts of patient 4 vanished after two administrations of PDT (Figure 3); all warts disappeared after four administrations of PDT (telephone review only). The lesions of patient 5 disappeared after twice PDT administrations; three times of treatments were performed in total.
No severe adverse events were reported in any patient. All 5 pregnancies resulted in healthy live birth without delivery complications. Therapeutic efficacy for patient 1, 2 and 4 is demonstrated in Figures 1-3 respectively.
CA is a sexually transmitted infection caused by HPV, and humans are the only host of HPV.7 There are six different outcomes of HPV infection: (1) automatic removal of virus; (2) latent infection; (3) subclinical infection; (4) visible benign rash; (5) precancerous lesions; and (6) HPV-induced tumor. High recurrence rates are one feature of CA, mostly due to latent and subclinical infections of HPV.
CA in pregnancy is characterized by rapid growth of warts and more severe adverse responses to treatments compared with non-pregnant patients. The main reasons for this might be due to hindered immunity during pregnancy,8 alteration of hormones (e.g., elevated progesterone levels), increased vaginal discharge which results in a more moist local environment, and others. Ultimately, however, the warts on many patients often reduce or completely disappear after termination of pregnancy, even without treatment.9
The treatment of CA in pregnancy is challenging: without therapy, CA in pregnancy can result in HPV infection of the fetus, and newborns can be infected with HPV during vaginal delivery. However, the active treatment of CA in pregnancy can sometimes lead to abortion or preterm delivery.10
Traditional therapies for CA include operation, laser, electrocautery, cryotherapy, and/or trichloroacetic acid treatment. In addition to a high recurrence rate, these approaches are usually accompanied by severe bleeding, local bacterial infection, ulcer formation, pain, premature birth, and abortion.11
Invented recently, PDT-ALA is a novel approach that has achieved favorable therapeutic efficacy in non-pregnant patients. ALA for topical use is an FDA-approved class C reagent, and is the precursor of hemoglobin. Endogenous ALA exists in trace amounts in cells under normal conditions, and has no photosensitivity itself. Exogenous ALA is selectively absorbed by HPV-infected cells which are highly proliferative12 and converted into prophyrins such as protoporphyrin IV. PDT is the combination of photosensitizer and semiconductor laser treatment. The semiconductor laser is the essential light source to activate the photosensitizer, with a wavelength of 635 nm penetrating less than 5 mm deep. The size of a normal cervix is 3-4 cm in length and 1-3 cm in diameter, thus PDT has very little chance to directly affect an intrauterine fetus. Prototype ALA is mainly excreted from the urine within 6 hours if administered via injection or orally. Protoporphyrin IX can be cleared from the body within 24 hours; therefore, there is no accumulation of drug in tissue, and it can be performed repeatedly. In addition, the most favorable advantage of PDT is that it abolishes subclinical infection of HPV and decreases recurrence rates of CA from 80%-90% to 10%.13,14 It is especially effective for CA of the urethral orifice and urethra.15
PDT is safe for pregnant women in principle. However, it has not been thoroughly assessed and evaluated neither domestically nor internationally. Thus, the risk regarding infertility is unknown as yet. Although there are reports of ALA-PDT on CA located on various parts of the bodies of non-pregnant patients,16,17 there is lack of reports specifically on pregnant patients.
Medication for pregnant women has been challenging to clinicians. There is very little documentation of medication on pregnant women because few of them are willing to participate in clinical trials. Although there is a placental barrier between mother and fetus that prevents drug absorption, the blockade function of the placental barrier is much weaker than the cerebrospinal fluid barrier. The majority of drugs administrated to a mother can enter into fetal blood circulation. At this time, there is no absolute nontoxic drug available for the fetus when the mother is in the need of medication. Improper medication can cause severe teratogeny or stillbirth. On the other hand, withholding treatment may negatively affect the health of both the mother and the fetus. ALA was reported to be nontoxic and non-mutagenic in mouse model experiments. In mouse models, continuous intraperitoneal injection of ALA 100 mg/kg during mating and pregnancy had no adverse effects on fertilization and reproductive capability. It was also confirmed in a rat model for treating extrauterine pregnancy by Glinert et al,18 that PDT had no adverse effects on uterine and reproductive capability. In this study, all patients and their families expressed their wishes of treating and curing CA and experiencing a healthy birth by following clinical doctor's suggestions, such as caesarean operation to prevent CA infection during vaginal delivery. All subjects the risk of any complications during ALA-PDT, such as spontaneous abortion and stillbirth. All five pregnant patients were treated three or four times with PDT, and all warts disappeared. There was no obvious pain or discomfort during the treatment. All five pregnancies resulted in smooth delivery and healthy newborns. Outpatient visits or telephone follow-up has lasted more than two years at this point, and no recurrence has been found.
Based on our reported five cases, PDT is plausible for CA in pregnancy, and is characterized by good tolerance and low recurrence. Since the long-term effects on the fetus remain unclear, it is still recommended to terminate pregnancy first and cure CA. If CA is mild and warts are located only in the vulva, it is possible to treat CA at that time, or after delivery. In this situation, cesarean section should be considered as a strong recommended to avoid newborn HPV infection during vaginal delivery.
In summary, PDT-ALA is an efficacious and safe therapeutic option for CA in pregnancy. The proposed therapy must be thoroughly evaluated in a prospective study before it can be recommended for routine use in clinical practice.
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