J Pediatr Adolesc Gynecol (2009) 22:25e31Original StudiesComparative Performance of a Combined InjectableContraceptive (50 mg Norethisterone Enanthate Plus 5mgEstradiol Valerate) and a Combined Oral Contraceptive(0.15 mg Levonorgestrel plus 0.03 mg Ethinyl Estradiol)in Adolescents ´Ramiro C. Molina, MD, MPH, Jorge Z. Sandoval, MD, Adela V. Montero, MD, Pamela G. Oyarzun, ´ ´MD, Temıstocles G. Molina, BS, and Electra A. Gonzalez, SW, MScCenter for Adolescent Reproductive Medicine, Faculty of Medicine, University of Chile, Santiago, ChileAbstract. Study Objective: To compare in a regular non- Keywords. Injectable monthly contraceptive—clinical trial experience the efﬁcacy, acceptability, and con- Contraception in high risk adolescentstinuation rates of an injectable contraceptive containing 50mg norethisterone enanthate plus 5mg estradiol valerate(IC) and an oral contraceptive containing 0.15 mg levonor-gestrel plus 0.03 mg ethinyl estradiol (OC), among adoles-cent users. Introduction Design: A total of 251 adolescents ages 14e19 were fol-lowed during 12 months. The IC group (124 subjects) was Prevention of the ﬁrst pregnancy in adolescents isstudied for 1044 cycles and the OC group (127 subjects) a challenge for health care professionals. Lack of sex-was studied for 1368 cycles. The users were not assigned ual education, poor reproductive health care, limitedin a random selection. Information was collected from clin- access to contraception at this age, and the heteroge-ical records. Groups were compared using Pearson chi- neous cultural patterns of earlier fertility are the mainsquare, odds ratio (95% conﬁdence interval), t-test, and barriers.1 Another difﬁculty is inadequate access toproportion difference test. Results: The IC group had signiﬁcant differences in acceptable contraceptive methods for this age group.baseline social risk, conﬁdence, psychiatric problems, con- Hormonal oral contraceptives and condoms are thesumption of alcohol, and number of sexual partners. At 12 most widely known methods among teenagers inmonths, the IC group showed signiﬁcant decrease in weight Chile. However, they are not well informed aboutand increase in hypermenorrhea. In the OC group, dysmen- injectables.2orrhea decreased, and hypomenorrhea and regular cycles Clinical experience with adolescents shows that or-were signiﬁcantly more frequent. One pregnancy occurred al contraceptives containing low doses of estrogensin the OC group (Pearl Index: 0.88). Final continuation (35 mg or less) do not have adverse effects on health,rates at 12 months were 41.9% and 37.8% for IC and are highly effective with proper use, and induce excel-OC, respectively. lent cycle control. There are some problems, however, Conclusions: The monthly injectable is a recommended with oral contraceptive (OC) use: the chance of miss-contraceptive option for adolescents, especially for thosefacing psychosocial risk factors. ing a pill, non-compliance, and the difﬁculty in con- cealing the use of this method. Follow-up in our Center showed 60 % discontinuation rates during the ﬁrst year among adolescents using the pill to pre- vent the ﬁrst pregnancy.2 Other factors that put adolescents at risk are: early This study has been funded by the Faculty of Medicine, University ofChile, Santiago, Chile. sexual initiation associated with mental health prob-Address correspondence to: Ramiro Molina Cartes, MD, Casilla lems, poor communication with their families, pro-Postal: 70.011-7 Independencia. Santiago, Chile.; E-mail: miscuity, and consumption of tobacco, alcohol, firstname.lastname@example.org or drugs.3Ó 2009 North American Society for Pediatric and Adolescent Gynecology 1083-3188/09/$34.00Published by Elsevier Inc. doi:10.1016/j.jpag.2008.07.010
26 Molina et al: Comparison of Injectable and Oral Contraceptives For some adolescent populations, the ideal contra- respectively, had discontinuation. These subjects wereceptive method would be a reversible one, for which not included in the ﬁnal analysis.continuation does not depend on the user. Intra- Since most consulting adolescents at the Centeruterine devices (IUD) fulﬁll these requirements. In choose OC, in order to have similar size of compari-Chile, however, physicians are reluctant to use IUDs son groups, within a week of the IC user’s ﬁrst visit,in young nulligravid women and some adolescents we selected a matching OC user for each IC user,are reluctant to undergo IUD insertion.2 Implants whose age was within a year of the IC user’s age.could be another contraceptive choice for this group. Participants did not show differences regardingTheir use, however, may not be easy to conceal and age, activity, referral source to the Center, schoolingthe cost is higher. A third possible method would be and school grades. Routing interviews at the Centerthe injectable containing depomedroxyprogesterone revealed that only 17% of the parents were aware ofacetate (DMPA). Although some authors have their daughters being sexually active. In Chile, pre-expressed concern regarding the use of DMPA in scribing contraceptives to adolescents between 14teens due to loss of bone mineral density (BMD), and 18 years old is permitted by the National Guide-complete recovery of BMD occurs within 12 months lines on Fertility Regulation of the Ministry of Health,of contraceptive discontinuation in teenagers.4,5 The without permission of the parents.7 Contraceptive pro-World Health Organization (WHO) has recently rec- vision to women and men in this age group at theommended that use of DMPA should not be restricted Center was approved by the Ethics Committee ofin teenagers.6 The objective of this prospective obser- the Faculty of Medicine, University of Chile on Sep-vation cohort, nonclinical trial study was to compare tember, 14, 2000, when the Chilean law changed, in-two groups of hormonal contraceptive users under creasing the age of voluntary coitus from 12 to 1419 years of age: one using a monthly combined estro- years old.7gen-progestin injectable (IC) and the other using an All adolescents had the chance to be interviewedoral contraceptive. All subjects were nulligravidas thoroughly and privately. PAP smear and ultrasoundpreventing ﬁrst pregnancy. examinations were performed as necessary. Blood pressure was monitored by the physician using a mer-Materials and Methods cury manometer and body weight taken by a trained nurse using a SeccaÓ balance scale, calibrated everyThe study was conducted at the Center for Adolescent day with a metal block of 1 kg. The body weight wasReproductive Medicine, Faculty of Medicine, Univer- taken without shoes and with light dress. All informa-sity of Chile in Santiago (CEMERA). Nulligravids tion was kept conﬁdential. Participants received coun-were adolescents from lower-middle and low income seling on human sexuality, contraception, sexuallylevels, who had not previously used hormonal contra- transmitted infections, and HIV. IC, OC, and condomsception, except two that changed from OC to IC were provided at no charge. Information was regis-because of intolerance during the recruitment period. tered on special ﬁles recording information relatedOur team was staffed by trained specialists in pediat- to the family, mental health and gynecological as-ric and adolescent gynecology, a social worker, pects. IC users returned for monthly injection becausepsychiatrist, psychologist, family counselor, midwife, the facilities and free of charge at the Center. Forand nutritionist. visits, the IC and OC users returned every two to three For this non-clinical trial study, recruitment months or at any time, if she needed consultation, al-extended from September 1998 to March 2005. After ways free of charge. Follow-up by phone or homereceiving a detailed counseling and information about visits was not performed, so as to comply with strictcontraception, the decision whether to use IC or OC conﬁdentiality.was made by the adolescents: 206 adolescents The injectable selected was a combination of 50mgrequested injectables and 224 requested OCs. They norethisterone/5mg estradiol valerate. The oral con-were not assigned by a random selection to IC or traceptive selected was a combination of 0.15 mg lev-OC contraception, but those adolescents with risk fac- onorgestrel/0.03 mg ethinyl estradiol. Both methodstors received a special counseling to use an injectable were donated by Schering of Chile and provided tocontraceptive. adolescents free of charge. There were no payment However, many did not return to the clinic after or special incentives for professionals or other person-receiving the ﬁrst injection or OC package (82 and nel in this study.97, respectively). Consequently, 124 subjects were The objective of the study was to analyze the efﬁ-followed in the IC group and 127 in the OC group, cacy, safety, acceptability and continuation rates ofinvolving 1044 and 1368 months of observation, re- a monthly injectable and an oral contraceptive.spectively. At the end of the second month of observa- Data were continuously registered. Groups weretion, 29 and 26 subjects in the IC and OC groups, compared using Pearson chi-square, odds ratio
Molina et al: Comparison of Injectable and Oral Contraceptives 27(OR), and 95% conﬁdence interval, t test and propor- One pregnancy occurred in the OC group withtion difference test.8e10 a Pearl Index of 0.88. No pregnancies occurred in the IC group. The Center provides health services to young peo-Results ple up to 19 years old. Beyond that age, they are re- ferred to adult outpatient clinics within the PrimaryAs shown in Table 1, adolescents have more than one Heath Care System. This explains the discontinuationrisk factor. Social risk, absolute necessity of privacy of 0.81% of IC and 2.36% of OC group. Therefore,to use contraception and psychiatric problems were real discontinuation rates were 58.10 % for IC andsigniﬁcantly higher within the IC group users (OR: 62.24 % for OC, without including aging out, this last5.4, 3.6 and 18.7 respectively) Adolescents at social administrative reason for discontinuation.risk were those experiencing serious personal or fam-ily problems, including troubles with the law or resid-ing at special juvenile homes, where they were Discussionreferred to the Center by a juvenile court judge. Ado-lescents with the need for absolute privacy to use con- Although this study was a 12-month study, new ado-traceptives were those with an extreme lack of lescents are still being seen as part of daily clinical ac-communication with their very traditional parents. tivities at the Center. At the beginning, adolescentsPsychiatric, neurological, and neurodevelopment dis- who choose the monthly IC were those with associ-orders included depression, anorexia nervosa/bulimia, ated high risk factors. Clinical experience revealedepilepsy, and one with low IQ. The IC subject with that many adolescents at low risk also asked for80e90 IQ discontinued at 6 months of observation, monthly IC, encouraged by other clients of the Centerbecause of decision of the parents. IC users showed since this was a conﬁdential method. On the last eval-a greater proportion of alcohol and cocaine abuse, uation at 2007, out of the total new adolescent users atand a higher number of sexual partners. the Center, 50% choose monthly injectables. Other health characteristics and physical ﬁndings A study comparing a monthly combined injectablewere similar in both groups. At 3, 6, 9, and 12 months of 50 mg noresthisterone enanthate and IUD in pre-of observation, no differences were found in IC and menopausal women showed no differences in spinalOC users on normal change of blood pressure and bone density after two years of observation.11 Otherweight gain. The proportion of dysmenorrhea was sig- studies on hormonal replacement therapy with a com-niﬁcantly higher with IC at 3, 6, 9, and 12 months (Ta- bination of norethisterone acetate and estrogens haveble 2). Although not shown in the table, breast shown an increase in bone mineral density.12e15tenderness was also higher in IC users and signiﬁ- However, there is no information regarding nore-cantly higher at months 3 and 9. thisterone enanthate in adolescents. Available infor- Regarding the menstrual cycle, the proportion of mation shows that low dose oral contraceptiveshypermenorrhea was higher in IC users at months 3 containing 0.02mg ethinyl estradiol have no effectand 6, the incidence of hypomenorrhea was higher on bone resorption in young women. Gestodene isin IC at all intervals. Amenorrhea was higher in the capable of reducing bone resorption.16IC group, but with no signiﬁcant differences. Spotting This study revealed that blood pressure and bodywas also higher in IC at months 3, 6, and 9. From the weight were slightly higher but insigniﬁcantly, inlast line of the table it can be seen that irregularity of OC users and they remained within the normal range.menstrual cycles on IC users, reached 35%, 21%, The difference in body weight was higher in OC users19%, and 22% at months 3, 6, 9, and 12 of observa- at months 9 and 12 of observation; no body weighttion, as compared to 4%, 4%, 0%, and 0% among changes were observed in IC users as previouslyOC users at the same intervals. In summary: cycle dis- reported in a Colombian open study.17turbances are higher in IC users. The incidence of dysmenorrhea, in two different Table 3 shows the discontinuation rates. At month studies with monthly combined injectable of 50 mg12, including all subjects with 3 or more months of noresthisterone enanthate, was 6.5% and 9.83 % re-observation, rates were 58.9% and 64.6% for IC and spectively at month 12.18,19 In our study, the inci-OC users, respectively. The difference (5.7%) was dence of dysmenorrhea reached 41% among ICnot signiﬁcant (P O 0.05). Loss of follow-up was users and 14% among OC users at month 12. Thisthe main cause of discontinuation, followed by per- study showed a higher incidence of breast tendernesssonal reasons and medical indications. There was (12% and 14%) at months 6 and 12 than the one re-a signiﬁcant difference between IC and OC at month ported by other investigators (1.1 % and 4%) for the12, with higher and signiﬁcant cycle disturbances in same periods of observation.18 The proportion of dys-IC users. menorrhea and breast tenderness is higher in this
28 Molina et al: Comparison of Injectable and Oral ContraceptivesTable 1. Risk Factors Associated with Contraceptive Choice IC OC TotalRisk Factors N % N % N % Pe OR (95%)Factors Detected Yes 71 57.3 121 95.3 192 76.5 .0001 0.07 (0.02e017) No 53 42.7 6 4.7 59 23.5Social Risk Yes 42 33.9 11 8.7 53 21.1 .0001 5.4 (2.5e11.9) No 82 66.1 116 91.3 198 78.9Absolute Privacy Yes 32 25.8 11 8.7 43 17.1 .0001 3.67 (1.7e8.2) No 92 74.2 116 91.3 208 82.9Psychiatric Morbidity Yes 16 12.9 1 0.8 17 6.8 .0001 18.7 (2.8e788.8) No 108 87.1 126 99.2 234 93.2Medical Morbidity Yes 2 1.6 1 0.8 3 1.2 .61c 2.07 (0.1e122.8) No 122 98.4 126 99.2 248 98.8HOC Intolerance Yes 2 1.6 0 0.0 2 0.8 .24c No 122 98.4 127 100.0 249 99.2Others Yes 2 1.6 0 0.0 2 0.8 .24c No 122 98.4 127 100.0 249 99.2a P value of corrected c2 test (**) 95% conﬁdent limitsdHOC: Hormonal oral contraceptives.cNot signiﬁcant.eP signiﬁcant ! .005.study, because both mild and severe cases were preparation of 50 mg noresthisterone enanthate usersconsidered. the proportion of irregular bleeding was 33.3% and In Phase III WHO clinical trials, irregular bleeding 20% for the same period of observation.20 In 38 ado-in monthly combined injectable of 50 mg noresthis- lescents using the same monthly injectable contracep-terone enanthate users over 18 years varied from tive and followed for one year, the abnormal bleeding34.6% at 3 month of use to 14.6% at month 12.19 In was 26.2% and 28.9% at 3 and 12 months respec-another recent study of monthly combined injectable tively.21 Our ﬁndings of irregular cycles was higherTable 2. Menstrual Patterns and Irregular Cycles in Adolescent IC and OC users at 3, 6, 9 and 12 Months of Follow-up 3 months 6 months 9 months 12 monthsMenstrual Pattern N % N % N % N % P*Total cases observed 196 100.0 141 100.0 98 100.0 52 100.0 NSInjectable contraceptive 95 48.5 70 49.6 43 43.9 23 44.2Oral contraceptive 101 51.5 71 50.4 55 56.1 29 55.8Hypermenorrhea 11 5.7 3 2.1 1 1.0 0 NS IC 10 10.5 3 4.3 1 2.3 0 OC 1 1.0 0 0 0Hypomenorrhea 9 4.6 6 4.3 3 3.1 3 5.8 NS IC 8 8.4 5 7.1 3 6.9 3 13.0 OC 1 1.0 1 1.4 0 0Amenorrhea 1 .5 0 1 1.02 1 1.9 NS IC 1 1.1 0 1 2.3 1 4.3 OC 0 0 0 0Spotting 16 8.2 9 6.4 3 3.1 1 1.9 NS IC 14 14.7 7 10.0 3 6.9 1 4.3 OC 2 1.9 2 2.8 0 0Regular cycles 159 81.1 123 87.2 80 81.6 47 90.3 IC 62 65.2 55 78.6 35 81.4 18 78.3 0.03 OC 97 96.0 68 95.8 55 100.0 29 100.0a P 5 Proportion Difference Test; *P # 0.05, NS 5 Not signiﬁcant.
Molina et al: Comparison of Injectable and Oral Contraceptives 29Table 3. Discontinuation rates by Reasons of IC and OC users at 3, 6, 9, and 12 Months of Follow-up Total accumulative 3 months 6 months 9 months 12 months 1 e 12 monthsDiscontinuation Reasons n % n % n % n % n % P*Pregnancy 1 0 0 0 1 ——— IC 0 0 0 0 0 0 0 0 0 0 OC 1 0.8 0 0 0 0 0 0 1 0.8Personal Reasons 7 6 3 2 18 0.84 IC 3 2.4 3 3.1 2 2.7 1 1.6 9 7.3 OC 4 3.1 3 2.9 1 1.3 1 1.7 9 7.1Cycle Disturbance 3 1 1 0 5 0.06 IC 3 2.4 1 1.0 1 1.4 0 0 5 4.0 OC 0 0 0 0 0 0 0 0 0 0Breast 0 0 0 1 1 ———Tenderness/Headache 0 0 0 0 0 0 1 1.6 1 0.8 IC 0 0 0 0 0 0 0 0 0 0 OC 0 0Lost to Follow-up 35 37 18 16 106 0.46 IC 19 15.3 18 18.4 4 5.4 8 12.9 49 39.5 OC 16 12.6 19 18.6 14 18.2 8 13.8 57 44.9Medical Indications 4 3 9 4 20 0.52 IC 1 0.8 1 1.0 5 6.8 1 1.6 8 6.5 OC 3 2.4 2 2.0 4 5.2 3 5.2 12 9.4Over 19 years 1 2 0 1 4 0.63 IC 0 0 1 1.0 0 0 0 0 1 0.8 OC 1 0.8 1 1.0 0 0 1 1.7 3 2.4Total Discontinuation 51 49 31 24 155 0.42 IC 26 21.0 24 24.5 12 16.2 11 17.7 73 58.9 OC 25 19.7 25 24.5 19 24.7 13 22.4 82 64.6Total Continuation(**) 200 151 120 96 96 0.42 IC 98 79.0 74 59.7 62 50.0 51 41.1 51 41.1 OC 102 80.3 77 60.6 58 45.7 45 35.4 45 35.4*P signiﬁcant ! 0.05, corrected chi-square test (Total accumulative 1e12 months).(**) 124 and 127 initial cases of IC and OC respectively.at 3 months with 34.6% and lower at 21.7% at 12 the discontinuation rate was 48% at one year.21 In ICmonths of observation in IC users, but signiﬁcantly and OC groups, reasons for discontinuation were sim-lower in OC users, with 4.0% and 0% of irregular cy- ilar to other studies with adult IC. Loss to followcles for the same period of observation. These ﬁnding up (39.5% and 44.9% for IC and OC users), was high-with OC are very similar to those of untreated adults er in comparison with the adult studies, but similarwith contraceptives, where the irregular bleeding was to adolescent studies where the proportion was4.5% and 8.6% at the 3 and 12 month of follow up.22 38.4%.17,18,21 This ﬁnding was expected, due to theThese ﬁndings conﬁrm that bleeding irregularity im- well-known behavior of adolescents regarding contra-proved with OC use, but it did not with IC use. ceptive use, especially of those who are preventing the The higher irregular cycles of adolescent IC users ﬁrst pregnancy.might be related to the pubertal development stage There are differences in the continuation rates ofof this group, since 50% of users were under 16 years contraceptive users in clinical trials and regular clini-and 11% of users under 14 years. It is generally ac- cal programs. In one study in the USA, with 5178cepted that 43% of irregular cycles may occur during DMPA users, 57% returned for a second administra-the ﬁrst year after menarche. This percentage de- tion; 63% of those who returned for their secondcreases to 20% after ﬁve years.23e25 Discontinuation injection went on to receive a third. The overallrates at month 12 were 58.9% and 64.6% for IC and one-year continuation rate was 23%.26 In one otherOC users, respectively. In the Colombian and Latin study in Cairo, Egypt, nearly 70% of injectable usersAmerican adult studies of monthly combined inject- had stopped using their chosen method after one year,able of 50 mg noresthisterone enanthate discontinua- compared with 34% of IUD users and 10% of implanttion rates were lower: 45.1 % and 17.9% at the end users.27 In the Philippines the continuation rates ofof the ﬁrst year respectively, varying from 9.7% to contraceptive users were compared by quality of care.49.5% among the six participating countries in the With low-quality, the discontinuation of use waslast study.17,18 In the study of 73 adolescents IC users 45%, with medium-quality it was 38%, and with
30 Molina et al: Comparison of Injectable and Oral Contraceptiveshigh-quality it was 23 %.28 Based on Demographic ´ 8. Canavos GC: Probabilidades y Estadıstica: Aplicaciones yand Health Survey in six countries, the cumulative ´ Metodos. Editores McGraw-Hill/Interamericana 1988;12-month probabilities of discontinuation per 100 333e8, 350.episodes of method use, by country and by Pill ´ ´ 9. Siegel S: Estadıstica No Parametrica: Aplicada a las ´ ciencias de la conducta. Mexico, Editores Trillas 1970;and Other Modern Method were: Morocco: 35,1 130e7and 49,8 ; Tunisia: 32,2 and 41,4 ; Egypt: 36,5 and ´ 10. Martinez Oliva L: Cancer y ambiente. Bases epidemiolog- ´58,7 ; Ecuador: 37,0 and 62,4; respectively. In Indone- ´ ´ icas para su investigacion y control: Metodos epidemiolo- ´sia: 26,2 and 24,9 for pills and injectable. In Thailand: ´ gicos. Mexico, Editores Metepec, 1990; 57e59.36,2 and 36,6 for pills and injectable.29 11. Kessuru E, Etchepareborda JJ, Wikinski R, et al: Premeno- After analysis of 11 studies that assessed programs pause contraception with monthly injectable Mesigynain the USA, and that assessed policies were found. with special emphasis on serum lipid and bone density pat-The intervention generally had positive albeit short- tern. Contraception 2000; 61:317term effects on contraceptive use; none reduced 12. Arabi A, Garnero P, Porcher R, et al: Changes in bodypregnancy rates. Programs that gave women a contra- composition during postmenopausal hormone therapy:ceptive during the visit were the most effective at a 2 year prospective study. Hum Reprod 2003; 18:1747 13. Rubinacci A, Peruzzi E, Modena AB, et al: Effect of lowincreasing method use. Advance provision of emer- dose transdermal E2/NETA on the reduction of postmeno-gency contraception increased the likelihood of its pausal bone loss in women. Menopause 2003; 10:241use and did not affect regular contraceptive use.30 14. 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