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Three Part Question

In [a girl with labial adhesions] is [oestrogen cream] an [effective treatment to induce labial separation]?

Clinical Scenario

A 4-year-old girl presents with low-grade pyrexia and dysuria. A urine dipstick test shows positive results for leucocytes and nitrite, suggesting urinary tract infection. On examination, you notice partial adherence of the vulval labia minora. Her mother reports that the girl has intermittently had discomfort in the genital area over the last year. While waiting for the results of the urine microscopy, you remember that one of your colleagues has mentioned treating labial adhesions with oestrogen creams in the past. You wonder whether there is good evidence to support their use in this condition.

Search Strategy

Cochrane and Pubmed
Cochrane Library using the terms "labial adhesion AND treatment", "labial adhesion AND management" and "labial adhesion and oestrogen/estrogen" as well as three alternative terms for labial adhesion ("labial fusion", "labial agglutination", "synechia vulvae") in combination (AND) with "treatment", "management", "oestrogen" and "estrogen". No relevant results.
PubMed (1975–2006) using the same search terms (no limits set). Search date: 21/05/06. Search outcome: a total of 207 matches for all searches combined—147 articles in total.

Search Outcome

Cochrane 0 relevant articles
Pubmed Only three were relevant (leung, Muram, Aribarg).
In addition, we retrieved and evaluated publications that were cited as references in the three articles found in the initial literature search. This method identified two more relevant articles (Khanam, Capraro).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Leung et al, 2005,	20 girls aged 2–38 months treated with oestradiol cream (0.625 mg/gwt) twice daily In all patients fusion covered at least 50% of the vaginal opening. Duration of treatment variable depending on response (range 1–3.5 months/mean 2.4 months). Follow-up variable (range 2.5–4 months)	Prospective case series – single centre (level 4)	Separation of labia,Recurrence rate	All patients responded to treatment(100%/95% CI, 83.9% to 100%)	Petroleum cream/Vaseline was used topically bd for 1 month after separation occurred. Side effects: breast enlargement in one patient (transient), vulval pigmentation in five patients (transient) No recurrence during follow up Relatively short follow-up period (true recurrence rate may be higher)
Aribarg 1975,	25 girls aged 2 months to 2 years treated with 0.01% dienoestrol cream once daily(all classified as severe cases). Control group of 5 girls treated with bland cream only Duration of treatment was variable,depending on response (1 week to a maximum of 8 weeks). Follow-up over at least one year	Case series – single centre (level 4)	Separation of labia,recurrence rate	Treatment was successful in 22 children (88%/95% CI, 69.8% to 95.6%). Only one patient (4.5%) had recurrence during follow up The five girls in the control group showed no improvement, but were subsequently successfully treated with oestrogen cream	Frequent side effect: vulval pigmentation (transient). One child had vulval erythema. No systemic side effects observed
Khanam et al, 1977,	75 girls aged 3 months to 4 years. 50 were treated with oestrogen cream (0.01%dienoestrol) and 25 had surgical separation electively. Complete fusion was present in 80% of patients (60/75).Duration of treatment: 2–8 weeks	Prospective case series – single centre (level 4)	Separation of labia,Recurrence rate	Treatment was successful in 90% (95% CI, 78.6% to 95.6%) of patients treated with oestrogen cream and in 60% (95% CI,40.6% to 76.6%) of those treated with surgery alone.	Side effects not reported. Daily frequency of oestrogen application not mentioned. No details about follow up given (true recurrence rate may be higher)
Capraro and Greenberg, 1972,	50 girls aged 2 months to 14 years treated with oestrogen cream. 60% of patients had complete fusion of the labia minora. Oestrogen cream was applied twice a day for 2–4 weeks	Prospective case series – single centre (level 4)	Separation of labia,recurrence rate	47/50 had adequate follow-up. 42/47 (89%/95% CI, 77.3% to 95.3%) had good response. Some cases required manual separation of the remaining fine adhesions	Petroleum jelly, bland baby ointment or cortisone cream was used topically for several weeks after separation occurred. Proportion of patients requiring manual separation of remaining adhesions not clear Side effects: three patients had breast tenderness (transient) and three patients had vulval pigmentation (transient). No details about follow up given (true recurrence rate may be higher)

Comment(s)

Labial adhesion, also termed labial agglutination, labial fusion and synechia vulvae, is not a rare condition and has been reported to occur in up to 1.8% of female prepubertal patients (Leung). It mainly affects girls < 5 years of age, with a peak incidence around the age of 13–23 months. Although most patients are asymptomatic, some experience complications such as local inflammation, dysuria, urinary tract infection and obstruction. About 80% of labial adhesions resolve spontaneously within 1 year, Pokorny and persistence after the onset of puberty is very rare. Management options range from reassurance for asymptomatic patients to surgical treatment of severe cases and cases resistant to conservative treatment. Most authors agree that manual or surgical separation should only be performed under general anaesthesia to limit emotional and psychological trauma. Conservative treatment with oestrogen creams as first-line intervention is the preferred option of most authors in this field. However, the studies that we were able to identify in our search supporting this approach consisted exclusively of case series (level 4), and no randomised trials seem to have been undertaken. In the five studies listed in the table, the success rate of topically applied oestrogen cream ranged between 46.7% and 100% (95% confidence intervals (CI) are in parentheses). It is not entirely clear as to why the success rate reported by Muram was considerably lower than in the other four studies, all of which reported success rates around 90%. One reason could be because that this study was undertaken at a tertiary referral centre and predominantly moderate to severe cases with dense fibrous adhesions (61.4% of the study population) were referred to the author. Secondly, these patients received oestrogen cream for only 10–14 days, which may have contributed to the failure of the treatment. In contrast, in all other studies, oestrogen cream was applied for a minimum of 1 month, unless separation had occurred earlier. On the basis of the results of these studies, it seems worthwhile to persist with the conservative treatment for a few weeks, unless complications occur. This may explain the complete success in all cases reported by Leung et al, who treated their patients conservatively for up to 3.5 months. Regarding the preferable frequency of the application, there is little certainty. Two studies did not give details on frequency of application, one study used a once daily regimen whereas the remaining two used a twice daily regimen. All five studies aimed at investigating recurrence rates. Recurrence rates were reported to be between 0 and 11.6%. However, follow-up was rather variable and limited in all but one study reported by Aribarg, where patients were followed up for the duration of at least 1 year. Thus, the true recurrence rate may be considerably higher. However, the study reported by Muram found that the recurrence rate in patients treated conservatively was lower than in the group of patients who underwent manual separation or surgery. Leung et al, who reported no recurrences during the follow-up period, emphasise the importance of maintaining genital hygiene to prevent inflammation and re-adhesion, but also recommend the use of topical petroleum-based cream once separation has occurred. The reported side effects in all five studies, consisting of breast tenderness or enlargement, vulval pigmentation and erythema, were all mild and transient. Although some experts (Muram) recommend watchful waiting in asymptomatic children with labial adhesions, others (Leung) believe that treatment is mandatory as labial adhesions have been found to predispose to asymptomatic bacteriuria and urinary tract infections. In the case series published by Capraro and Greenberg, 14% of the patients had developed urinary tract infection. The authors reasoned that the causality was unclear and postulated that urinary tract infections may predispose these patients to develop labial adhesions; conversely, labial adhesions could lead to urinary outflow obstruction, which may predispose them to acquire urinary tract infections. Ultimately, the decision on treatment lies with the parents and the child, who should be guided to make an informed choice in the light of existing evidence. Despite the weaknesses of these studies, it seems appropriate to use topical oestrogen cream for a period of several weeks in children with labial adhesions, particularly because no major side effects have been reported. In agreement with many other authors, (Leung, Ariburg, Capraro, Schroeder) we think that surgical intervention should be reserved for symptomatic patients resistant to conservative management and patients who present with urinary retention. A randomised placebo-controlled trial evaluating a variety of oestrogen creams with different active ingredients—that is, estriol v conjugated oestrogen v diethylstilbestrol—would be desirable as this could identify the most effective formulation and could also establish with greater certainty the proportion of spontaneous resolution in this group of patients. However, this seems unfeasible given the sample sizes that would be required. A trial merely comparing a single oestrogen cream with placebo assuming a difference in success rate of 10%—that is, 90% resolution with oestrogen cream v 80% spontaneous resolution—would require 219 participants in each group (Fisher's exact sample size estimation for two independent groups/power 80%/alpha = 0.05). For a trial comparing the effectiveness of two oestrogen creams, assuming the difference was as small as 5%, one would need to recruit 474 participants into each treatment group (Fisher's exact sample size estimation for two independent groups/power 80%/alpha = 0.05). Thus, conducting a high-quality cohort study, which would clarify these uncertainties at least partially, could be the only feasible alternative.

Clinical Bottom Line

Topical treatment with oestrogen creams is effective in most patients and can be used safely to treat symptomatic prepubertal girls with labial adhesions (grade C). Treatment may be required for several weeks to achieve separation of the labia minora (grade C). Controversy exists on whether treatment is indicated in asymptomatic cases (grade D). Surgical intervention should be reserved for severe cases resistant to conservative management and girls presenting with urinary retention (grade D).

References

1. Leung AK, Robson WL, Kao CP, et al. Treatment of labial fusion with topical estrogen therapy. Clin Pediatr (Phila) 2005;44:245–7.
2. Muram D. Treatment of prepubertal girls with labial adhesions. J Pediatr Adolesc Gynecol 1999;12:67–70.
3. Aribarg A. Topical oestrogen therapy for labial adhesions in children. Br J Obstet Gynaecol 1975;82:424–5
4. Khanam W, Chogtu L, Mir Z, et al. Adhesion of the labia minora - a study of 75 cases. Aust N Z J Obstet Gynaecol 1977;17:176.
5. Capraro VJ, Greenberg H. Adhesions of the labia minora. A study of 50 patients. Obstet Gynecol 1972;39:65–9.
6. Leung AK, Robson WL, Tay-Uyboco J. The incidence of labial fusion in children. J Paediatr Child Health 1993;29:235–6.
7. Pokorny SF. Prepubertal vulvovaginopathies. Obstet Gynecol Clin North Am 1992;19:39–58.
8. Schroeder B. Pro-conservative management for asymptomatic labial adhesions in the pubertal child. J Pediatr Adolesc Gynecol 2000;13:184–5.
9. Leung AK, Robson WLM. Labial fusion and urinary tract infection. Child Nephrol Urol 1992;12:62–4.