A randomized controlled pilot study was conducted in Department of Obstetrics and Gynecology, Guru Teg Bahadur Hospital, New Delhi from July 2012 till June 2013. Prior ethical approval was obtained from the institutional ethical committee. The ctri reference number is REF/2013/01/004495. The funding for the study was through hospital budget. Patients meeting the inclusion criteria were given adequate information about purpose and nature of the study and a written informed consent was obtained from each patient. Detailed history and examination was recorded in the case record performa. Blood investigations and endometrial sampling were done.

Women included were in reproductive age group of 15-45 years, without medical disorders like jaundice, migraine, epilepsy, hypertension or diabetes mellitus, history of thromboembolism, breast or genital tract malignancy, genital prolapse or infections. A total of 60 patients suffering from AUB were recruited for this study and received therapy from single investigator. AUB was defined as any abnormal bleeding from uterus for which no organic pathology of genital tract such as fibroid or adenomyosis is identifiable. They were randomised into two groups (1:1 ratio) based on computer generated random number table by the statistician. First group comprising of 30 women received Nuvaring therapy for three months and the second group (n= 30) received OCPs. In test group, Nuvaring was inserted in the vagina (Initially by the doctor and then patients were taught to insert and remove the ring herself) on the fifth day of the cycle, for next three weeks. At the end of three weeks, it was removed for one week during which withdrawal bleeding occurs. A new ring was inserted after one week of ring free period.

In control group, combined oral tablet containing 30μg EE and 150 μg levonorgesterol (Available as Mala N in government supply, manufactured by Hindustan Latex Ltd.) was started from day 5 of the cycle, one tab daily for 21 days. The black iron tablet which was free of hormone was continued immediately after white tablet for next seven days during which withdrawal bleeding occured. The next packet of Mala N was started immediately after finishing the first packet. In patients, having irregular bleeding, Mala N was started on any day of the cycle, after endometrial sampling was done. Patients was followed up regularly; initially, after one week of starting the therapy and then monthly for three months. Patients were asked to maintain a diary of menstrual pattern, flow, side-effects or any other problem. Menstrual blood loss was recorded as per Pictorial Blood Loss Assessment Chart (PBAC). Withdrawal bleeding was classified as any bleeding/spotting that occurred during ring/pill free period. Ideal bleed (IB) is defined as cycle with a regular withdrawal bleeding in ring or active pill free days of cycle, no early bleed, continuous or irregular bleeding. Any bleeding starting before ring/pill free was termed early withdrawal. Late withdrawal was termed when bleeding continued into the next ring/pill use period. Dysmenorrhea was scored as mild, moderate or severe on the basis of subject’s perception. Patient weight and haemoglobin were measured pre study and post study in all.

Primary outcome measures were change in menstrual cycle pattern and PBAC score. Secondary outcomes included side effects, change in haemoglobin and weight. Data was analyzed by statistical software SPSS 20. Baseline demography and clinical profile were analyzed using unpaired student t-test and Chi-square/ Fisher-exact test. Two factor repeated measures ANOVA, taking time as a repeated factor and groups fixed factor. Sphericity assumption was tested using Mauchty test of sphericity and if assumption was violating Green house Geissen adjustment was applied. Interaction between group and time was also tested. The compliance and side effect profile were compared using Fisher-exact test. Change in Haemoglobin and weight were compared using paired t-test separately for each group. Generalized estimating equation technique with logistic link function using unstructured working correction was applied to find trend of Ideal bleed and late bleed pattern.

During study, 30 women in Nuvaring group and 28 women in OCP group received treatment. Two patients in OCP group opted out of the study in the first cycle itself, due to personal reasons. Baseline demographic and clinical characteristics of subjects are shown in [Table/Fig-1]. All the subjects were multiparae; there were no significant differences in demographic profile between the two treatment groups.

Irregular heavy menstrual bleeding was the most common presentation; PBAC scoring was calculated to quantify menstrual loss and baseline value was compared to subsequent cycles. Also, bleed pattern in each cycle was noted to see the effect of treatment on cycle regularization. Mean PBAC score at the start of study was 214.87 in Nuvaring and 237.57 in OCP group, which was comparable, with no statistically significant difference [Table/Fig-2]. After completion of first cycle, there occurred 50% reduction in PBAC score in Nuvaring group and 44% in OCP group as compared to baseline score. Although significant reduction in PBAC score was observed in subsequent cycles within both the groups but no significant difference in score was found when Nuvaring group was compared with OCP (p-value = 0.194) [Table/Fig-2,3].

[Table/Fig-3]:

Trend of Mean Blood Loss in Nuvaring and OCP.

Beside heavy menstrual flow, irregular cycle was common complaint. Use of hormonal therapy not only improved PBAC score but regularized menstrual cycle. [Table/Fig-4] shows the effect of Nuvaring and OCP on patterns of menstrual flow. There was an improving trend towards Ideal bleed (IB) pattern in subsequent cycles in both the groups. IB pattern in Cycle2 and Cycle3 was significantly higher compared to Cycle1 in Nuvaring and OCP groups (p-value =0.0057, < 0.001 respectively). Incidence of Ideal bleed (IB) was slightly higher for Nuvaring than OCP in all 3 cycles, although no statistically significant difference was there between groups (p-value= 0.286) [Table/Fig-5]. Similarly the incidence of late withdrawal (LB) bleed was lower in Nuvaring than the OCP, however no significant difference was observed between groups (p-value=0.752). There was a decreasing trend of LB in subsequent cycle in both the groups. Breakthrough bleed was higher in all cycle of OCP group ranging from, 7%-14%, whereas only 1/ 30 women reported breakthrough bleed in Nuvaring group in cycle 3.

[Table/Fig-5]:

Patterns of menstrual flow. Cycle-wise menstrual pattern

[Table/Fig-6] shows that more number of women in Nuvaring group were satisfied with treatment (29/30) and recommended its usage as compared to OCP group (23/28); however the difference in number was not statistically significant. Compliance was better in Nuvaring group; because of once-a-month insertion, all women completed the study compared to 28 women in OCP group. 8/28 women (28%) discontinued in OCP group after 3 month of therapy, main reason being poor compliance and breakthrough bleed where as 3/30 women (10%) in Nuvaring discontinued and reason being persistence of dysmenorrhea. No major side effects were encountered during 3 month therapy in any of the group; however minor side effects were seen more in OCP users; but the difference was not significant statistically. Two cases of Nuvaring expulsion was reported, however no coital difficulty or irritation was reported by user or her partner.

[Table/Fig-7] Persistent severe dysmenorrhoea was seen in 7% of Nuvaring and 3.5% of OCP group after 3 month of therapy, whereas persistent mild to moderate dysmenorrhoea was seen in 23.3% of Nuvaring and 10.7% of OCP users. No significant change from baseline values was found in haemoglobin level and body weight at the end of study period in both groups [Table/Fig-8].

Nuvaring has been found comparable to OCPs for contraception usage. Nuvaring may be the contraceptive of choice in patients who wish to avoid inconvenience of daily pill intake, those with busy schedule and frequent travelling. Because of vaginal route of administration, it allows steady and continuous release of hormone, resulting in stable serum concentration. This is responsible for good cycle control and less systemic side effects [7,8]. It is one of the best contraceptives for women suffering from AUB. The return of ovulation after stopping Nuvaring usage is generally in 3-4 weeks and it does not cause long term infertility. Various treatments for AUB include tranexamic acid, progestogen only pills, OCPs, GnRH analogues etc, depending on the patient profile. Earlier only the oral route was available but now with the advent of new technology, other options like parenteral, subdermal, nasal, and intravaginal route are also available.

In the present study, PBAC score improved from baseline score of 214.87±86.29 to 87±42.29 in Nuvaring group and 237.57±86.29 to 74.75±51.58 in OCP group after the completion of 3 month therapy. Both Nuvaring and OCP were found to significantly reduce menstrual blood loss within group; however no significant difference was found when PBAC score reduction was compared between groups. Incidence of ideal bleed in each cycles were higher in Nuvaring group compared to OCP group, which provides evidence that cycle control was better with Nuvaring group. Besides good cycle control and decrease in PBAC score, break through bleeding was noticed only in one cycle out of total 90 exposed cycles in Nuvaring user, compare to 10 cycles of 84 exposed cycles in OCP group. This observed low incidence of breakthrough bleed and good cycle control with Nuvaring was earlier reported by Milsom et al., Roumen et al., Oddsson et al., Ahrendt et al., [7,9–11]. Low incidence of breakthrough bleed with Nuvaring may be explained by its continuous, steady and precise dosing, resulting in stable serum concentration [1,4].

OCP have been widely prescribed for treatment of dysmenorrhoea and chronic pelvic pain. However literature shows conflicting reports. Vercellini et al., & French in 2005 in their study reported significant decrease in dysmenorrhea in OCP user. Whereas Proctor et al., found evidence insufficient to conclude on effectiveness of OCP in treating dysmenorrhoea [12–14]. In our study, 47% women in Nuvaring and 35.6% women OCP group reported dysmenorrhoea at start of study. Post 3 month therapy, dysmenorrhoea was seen in 30.3% of Nuvaring and 10.5% of OCP group. Thus both the drugs were found to be effective in treating dysmenorrhoea with OCP being superior, although difference was not significant statistically. In present study no major hormone related side effects was seen, where as minor side effects such as headache, GI upset were seen in both groups. Nausea was commonly encountered minor side effect in OCP group; Six out of 28 women reported nausea in OCP group, compare to none in Nuvaring group. Similarly mood swings were reported only in OCP user; 25% women in OCP group complained of mood swings while on therapy compared to none in Nuvaring group. Incidence of headache was also higher in OCP group compared to Nuvaring group. 14% women in OCP group complained of headache compared to 6% in Nuvaring group, however difference was not significant statistically. An open label, non comparative study reported 5.8% headache in Nuvaring user, which was similar to our study [8]. Two women in Nuvaring group complained of expulsion of ring. No coital dysfunction was reported in Nuvaring user. No significant changes in body weight and haemoglobin level were found in both groups as an effect of hormone therapy. Current trial found Nuvaring to be as effective as OCP for treating AUB in carefully selected patients, though sample size and short duration of study were limiting factors.

Present study shows Nuvaring to be as effective as OCP for symptom control in abnormal uterine bleeding. Side effects were minor, few and high rates of patient satisfaction were observed. The convenience of once- a- month administration motivated majority of patients to continue therapy even after the study period, for dual benefit of contraception as well as AUB treatment. Dysmenorrhoea was relieved more in OCP users, though difference was not statistically significant.