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	Child And Adolescent Gynecological Services In Primary Care Sexual Function And Sex Hormones In Women With Premature Menopause Living Conditions And Maternal And Child Health Hormonal Contraception Cohort Study Cost Estimate For Pregnant Women Regarding Attendance At Prenatal Care Services In Three Havana Municipalities, Year 2000

HORMONAL CONTRACEPTION COHORT STUDY

Beatris Macías Peacok, BSc [1] [1]
Yaimarelis Saumell Nápoles, BSc [2] [2]
Radamé Padró Estrada, MD [3] [3]
Francisco Soto Soto, MD [4] [4]

ABSTRACT:  A preliminary observational descriptive longitudinal pharmacological surveillance cohort study was conducted between November, 1998 and June, 1999 of 97 patients using oral hormonal contraceptives (Cohort 1) and 97 using intrauterine contraceptive devices (Cohort 2), who were served by the 30 de Noviembre Community Teaching Polyclinic in Santiago de Cuba.  Both cohorts included approximately the same amount of women by age group and color.  We found drug interactions in 28 of the women (28.9%).  In Cohort 1, there was a predominance of endocrine and metabolic adverse reactions (74.3%), especially weight gain (81.8%).  In Cohort 2, only gynecological adverse reactions were found, with a preponderance of uterine colic (62.2%).  In Cohort 1, 27.8% of patients reported beneficial effects besides contraception.  The incidence rate of all reactions found was calculated.  The incidence rate of gynecological reactions was lower in Cohort 1 (0.41) than in Cohort 2 (0.76).  In our study subjects, the relative risk of developing adverse reactions with the use of oral contraceptives in a six-month period was 0.54; and the attributable risk –0.35.

Introduction

Statistical reports show that hormonal contraceptives are extensively used worldwide.  Over 150,000,000 women are reported to have taken oral hormonal contraceptives some time in their lives.  Furthermore, 64,000,000 women are currently using them.  The main reasons for such widespread acceptance are due to their high effectiveness as reversible contraceptives, and uncomplicated use and distribution.  Despite widespread acceptance and advantages of oral contraceptives over other methods, various side effects have been reported.  Among the most worrisome are cardiovascular disorders and tumor induction or growth.

Yet, the incidence of side effects remains relatively low, especially when we take into consideration that the use of contraceptives prevents 100,000 hospitalizations annually, and that  approximately 500,000 women die each year from conditions related to  pregnancy, delivery, or abortion complications.  The aforementioned facts have motivated  researchers from several countries to conduct pharmaco-epidemiological studies on the use of hormonal contraceptives, aimed at optimizing treatment and increasing effectiveness.(1)(2)   

In Santiago de Cuba Province, since the implementation of Family Planning Program in 1997, various studies have been carried out on contraceptives used by women.  However, no cohort or pharmacological surveillance studies on hormonal contraceptives had been reported.  This is why we proposed  this study.

Objectives

General

Study the onset and behavior of adverse reactions linked to the use of hormonal contraceptives in women seen at one family planning service.

Specific

• Describe drug interactions found in the cohort of women using oral hormone contraceptives.
• Assess the adverse reactions found.
• Calculate the adverse reaction incidence rate in the cohorts studied.
• Calculate relative risk and attributable risk related to the use of hormone contraceptives during the period studied.

Methods 

General Characteristics of the Study

A preliminary observational descriptive longitudinal pharmacological surveillance cohort study was conducted in the health area served by the 30 de Noviembre Community Teaching Polyclinic in Santiago de Cuba, between November 1998 and June 1999.

Sample Characteristics and Information Gathering

Our study included all female patients of childbearing age who lived in the health area served by this polyclinic.  We made a non-random selection of 194 women between the ages 15 and 40.  A population of 97 women using oral hormonal contraceptives (Cohort 1) was identified, as well as another of 97 women who were using intrauterine contraceptive devices instead (Cohort 2).

Among the women in Cohort 1, one group was taking Triquilar and another group Microgynon, both containing levonorgestrel (LN) and ethinyl estradiol (EE).  Triquilar is a triphasic drug containing variable doses of hormones, according to the phase of the menstrual cycle.(3)

Triquilar

Microgynon is a monophasic pill (same dose all through the menstrual cycle) containing 0.15 mg of levonorgestrel and 0.03 mg of ethinyl estradiol.  In both cases, patients took one pill a day, for 21 days, starting on the first day of their menstrual cycle; for the remaining 7 days, they took a pill containing ferrous fumarate only.(2)  In Cohort 2, we included women who used any kind of intrauterine contraceptive device (inert or bioactive).

Since our sample selection was non-random, we leveled up both cohorts to avoid the biases commonly found in this type of study.  We chose one patient from Cohort 1, and one from Cohort 2 with similar characteristics with regard to age and color.  In our study, we considered three age groups (15-22; 23-31; 32-40) and three skin colors (white, mestizo, and black) common in the Cuban  population.  From the cohort of women taking oral contraceptives, we excluded patients with predisposing factors for the use of such drugs (family or personal history of cardiovascular disorders, circulatory disorders, cerebrovascular disorders, hypertension, diabetes, migraine, liver disorders, and neoplasms) as well as patients that transferred to another cohort.(3)

On their first visit to the Family Planning service, Cohort 1 data such as name, age, skin color, home address, and contraceptive used, as well as other information necessary for our study, was collected.  These patients were reassessed 3 and 6 months into the study; that is, after the first and second treatment cycles.  This reassessment was also carried out in the Family Planning service.

General data for patients in Cohort 2 was obtained from their medical records, kept in their corresponding family doctor’s office.  Based on this data, we carried out recruiting visits to the patients’ homes and asked them to go to their family doctor’s office to be weighed during the week following recruitment.  The reassessment of these patients was conducted at their respective family doctor’s office, 3 and 6 months into the study. 

The data obtained during our research was entered on a survey form designed for this study.  This survey form included a detailed questionnaire aimed at properly identifying each adverse reaction in all patients in both cohorts.

Procedures

To describe the drug interactions suffered by our subjects during the study, we took into consideration concurrent use with the contraceptives of drugs belonging to other pharmacological groups, for no less than a week, and which are known to interfere with the effectiveness of oral hormone contraceptives.  The names of these medications, as well as the pharmacological group to which they belong, were registered on the corresponding patient survey form.  Subsequently, we evaluated the patient’s adverse reactions to determine whether they were clinical manifestations indicative of drug interaction resulting from the drug combination reported.

The assessment of the adverse reactions detected during treatment in both cohorts was carried out based on the patient’s report during reassessment.  We also determined the number of patients satisfied with the contraceptive they were using, and analyzed the beneficial effects, other than contraception, found during our study.

To calculate the incidence or the risk of occurrence of adverse reactions by organs and systems, we applied the standard methodology used in cohort studies, as the following table shows:

Where:

a ->     Number of patients exposed to oral hormonal contraceptives who had adverse reactions related to the system studied during the period studied.

b->      Number of patients exposed to oral hormonal contraceptives who did not develop adverse reactions.

c->      Number of patients not exposed to oral hormonal contraceptives (using intrauterine devices) who had adverse reactions .

d->      Number of patients using intrauterine contraceptive devices who did not develop adverse reactions during the period studied.

The incidence or the risk of developing adverse reactions for patients exposed to these drugs (Ie) were calculated for each bodily system affected by these adverse reactions (n).  We used the following equation:

                    a
       Ie  = -------
                 (a+b)

The incidence or risk of developing adverse reactions for women not exposed to oral contraceptives (In) were calculated using the following equation:

                    c
        In  = ------- 
                 (c+d)

To fulfill the fifth aim of our study, we used the same methodology.  The relative effect (or relative risk) (RR) of the population studied from the use of oral hormonal contraceptives, during the time studied, was calculated using the following equation:   

                    Ie     [a/(a+b)]
        RR = ---- = -----------   
                   In     [c/(c+d)]

The differences in rates and attributable risks (AR) related to the use oral hormonal contraceptives were calculated using the following equation:

    AR = Ie - In = [a/(a+b)] - [c/)c+d)].(4)

Data Processing  

The data obtained was introduced into a database using EPI INFO software, on a Pentium PC.  For the analysis of the results, we used percentage as the review measure, and the chi square statistical test, with a significance of p<0.05.

Results and Discussion

Sociodemographic Characterization of Cohorts

In our study, each cohort consisted of 97 women, approximately equal with regard to age group and skin color, as shown in the following tables:

Table 1. — Distribution of patients by age group in both cohorts

Table 1 shows that in both cohorts there was a prevalence of women in the age group 23-31.  In the cohort of women using oral contraceptives, there were 59 patients in this age group (50.9%); and in the cohort of women using intrauterine devices, there were 57 (49.1%).

Table 2. — Distribution of patients by skin color in both cohorts

A predominance of mestizo people was found among our study subjects, 47 (51.1%) in Cohort 1, and 45 (48.9%) in Cohort 2 (Table 2).

Drug Interactions Found in the Study

Drug interaction was found in 28 women in Cohort 1 (Table 3).  However, clinical manifestations that could reduce the effectiveness of the treatment were found in only 2 women, who had increased production of cervix mucus—a non-risk reaction not endangering the patient’s life.

Table 3. — Distribution of women in Cohort 1 by type of drug interaction found

Table 4 shows the medications that, used with oral hormone contraceptives, caused drug interactions. 

Table 4. — Medications found to cause drug interactions during our study

 Source: Compendium of Pharmaceutical and Specialties (CPS)(1)

All these drug interactions can reduce the effectiveness of oral hormonal contraceptives, and result in hemorrhage, increased production of cervical mucus, or unwanted pregnancy.  These adverse reactions take place in the pharmacokinetic phase.(1)

Adverse Reaction Assessment

The assessment of the adverse reactions found during our study showed that in Cohort 1, these reactions affected various bodily systems (Table 5), while in Cohort 2, they included gynecological disorders only.

Table 5.- Distibution of patients in both cohorts by adverse reaction

In the cohort of patients who used oral contraceptives, the side effects most commonly found were endocrine and metabolic disorders (74.3%).  The predominance of this type of disorder is due to the exogenous hormones contained in the pills, which alter the levels of endogenous hormones, resulting in endocrine and metabolic disorders.  Adverse cardiovascular reactions appeared in only three women in this cohort (4.1%) and were the least common side effects found in our study.  This can be explained by the fact that this side effect usually occurs in long-term treatment.  The onset of such adverse reactions early in treatment requires a reevaluation of the patient’s personal medical history, in search of predisposing factors.(2)

In the cohort of women who used intrauterine contraceptive devices, adverse reactions consisted of gynecological disorders only (100%), whose incidence was higher than in Cohort 1 (54.1%).  Studies conducted in Cuba and other countries show the high incidence of gynecological side effects in women using intrauterine contraceptive devices. (5)(6)(7)(8)(9)  Intrauterine devices are foreign bodies whose mechanism is based on their direct contact with the endometrium. This increases the risk of developing local adverse reactions.  These adverse reactions are also greatly dependent on external factors, such as the skill of the specialist who places the device in the woman’s uterus, as well as the patient’s cultural environment.(2)

The incidence of adverse reaction in other bodily systems was much lower, although it is important to list them, as well as their frequency of occurrence in each case.

 Among the endocrine and metabolic disorders found in Cohort 1, weight gain prevailed (Table 6).

Table 6. — Metabolic disorders found in the cohort of women using oral contraceptives

The result obtained was statistically significant (p<0.05).  However, the distribution of women by the amount of weight gained showed no statistical significance (p>0.05) (Table 7).  In this case, 45 women experienced weight gain, with a higher incidence in the group of women whose weight gain was less than 1 kilogram (64.4%).

Weight gain in women using oral contraceptives is commonly reported among the adverse reactions caused by these medications. (10)(11). Numerous authors say that this side effect results from the action of estrogens—anabolic agents that cause retention of salts, water, and other elements, thus increasing body mass and, ultimately, body weight.(12) (13) (14)

Table 7. — Weight gain in Cohort 1 women

Table 8 shows the gastrointestinal adverse reactions found during our study in Cohort 1.  These appeared in 40 women (p<0.05), which indicates a correspondence between the use of oral contraceptives and the development of this type of adverse effect. 

Table 8. — Gastrointestinal adverse reactions in Cohort 1

Among the gastrointestinal side effects found, the most prevalent included increased appetite (52.5%) and nausea (47.5%).  Various studies have also shown the occurrence of these adverse reactions.(6)(12)  Increased appetite has been associated with the anabolic effect of estrogens; (11)(15) and nausea, with the rapid gastrointestinal absorption of the ethinyl estradiol contained in the pills.(2)(13)

Table 9 shows the results of a comparative analysis of the gynecological adverse reactions found in the cohorts studied.  There was a higher incidence of this type of adverse reactions in Cohort 2.  A statistically significant distribution was obtained (p<0.05).

Table 9. — Gynecological adverse reactions in both cohorts   

The adverse reaction that prevailed in Cohort 1 was painful mammary distention (70.0%).  The International Federation of Family Planning has conducted studies that show similar results.(2)(16)  Painful mammary distension has been associated with the concurrent action of progesterone and estrogen on the proliferation of mammary gland acini.  Estrogens are responsible for the proliferation of mammary ducts and glandular tips; while progesterone acts on the growth of the stroma, causing interstitial edema.  These effects cause a sensation of mammary distension.(1)(2)(17) Amenorrhea was another prevailing adverse reaction in this cohort.  It appeared in 7 women (17.5%).  Many authors say that this effect results from the endometrial atrophy or destruction caused by the action of the progesterone contained in the pills.(5)(18)(19)(20)

In Cohort 2, the most common adverse reactions included uterine colic (62.2%) and pelvic inflammatory disease (40.5%).  Various studies have reported that women using intrauterine contraceptive devices usually complain of uterine colic.  Some of them have even revealed that 80% of women using this type of contraception suffer from this adverse reaction, which sometimes results from local swelling.(2)(21)(22) In our study we found a strong correlation between uterine colic and pelvic inflammatory disease.  However, in the majority of women who reported pelvic inflammatory disease, this was not diagnosed by a specialist, which means these patients may have mistaken a local inflammatory process or a banal uterine colic for pelvic inflammatory disease.

The study of central nervous system adverse reactions (Table 10) revealed a high incidence of dizziness (63.3%) and cephalalgia (46.7%), with a statistical significance of p=0.05.

Table 10. — Central nervous system adverse reactions in Cohort 1

An association between CNS adverse reactions and progesterone is still under discussion.  Many experts, like Judith Norsigian, from the Boston Women’s Health Book Collective, affirm that such side effects have not yet been clarified.  However, Dr. Judith Weiz, professor of Obstetrics and Gynecology at the Milton S. Hershey Medical Center at the University of Pennsylvania, asserts that progesterone causes blood vessel constriction, which can cause headache.(11)

Table 11 shows cardiovascular adverse reactions associated with the use of oral hormonal contraceptives.  We found this type of reaction in less than 3.5% of cases.  No statistical significance was obtained (p>0.05); therefore, no correlation existed between the use of oral hormonal contraceptives and the development of cardiovascular adverse reactions in our study subjects during the period studied.  However, this type of reaction has been reported to occur in long-term treatment. (2)(23)(24)

Table 11. — Cardiovascular adverse reactions found in Cohort 1

Women’s Satisfaction with Contraception and Beneficial Effects of Contraceptives

Table 12 shows the level of satisfaction with contraception of women in both cohorts.  We obtained a statistically significant result (p<0.05).  The number of women satisfied with the contraceptive they were using was higher in Cohort 1 (55.9%) than in Cohort 2 (44.1%).

This result can be explained by the fact that adverse reactions with the use of oral contraceptives appear during the first months of treatment, are usually mild, and generally disappear spontaneously in most women, leaving a feeling well-being.  Disorders such as premenstrual tension, dysmenorrhea or other irregularities usually disappear in most women who suffered from them before taking oral contraceptives.(2) For these patients, the risk of developing adverse reactions is lower than the prejudicial effects of unwanted pregnancy, both for their health and their quality of life.

Table 12. — Distribution of women in the cohorts studied by level of satisfaction with contraceptive method         

Table 13. — Distribution of patients in Cohort 1 by the effects of contraceptive treatment

Table 13 shows the distribution of women reporting additional beneficial effects of oral hormonal contraceptives.  In Cohort 1, 27 women reported additional beneficial effects (27.8%); 93.0% of them referring to a more menstrual regularity (both in duration and quantity of discharge) (Figure 1).  This effect results from a reduction in the thickness of the endometrial wall due to the action of progesterone(25)

Figure 1.—Beneficial effects obtained during our study with the use of oral contraceptives

In a study carried out by Schering, similar results are reported.(25)  In women using intrauterine contraceptive devices, besides pregnancy prevention, no other beneficial effect was reported in our study.

Analysis of Incidence Rate of the Adverse Reactions Found in Our Study

Figure 2.—Incidence rate of adverse reactions

Figure 2 shows that the most prevalent adverse reaction in patients taking oral hormonal contraceptives for six months were endocrine and metabolic disorders (0.57), followed by gastrointestinal and gynecological disorders, respectively (0.41).  There was a very low risk of onset of cardiovascular adverse reactions in the 97 women studied (0.03).  In the cohort of women using intrauterine contraceptive devices, the risk of developing gynecological disorders in a period of six months was 0.76. 

Analysis of Relative Risk and Attributable Risk with the Use of Oral Contraceptives in the Period Studied

Table 14 shows the behavior of gynecological adverse reactions according to the cohort study methodology.

Table 14.—Distribution of patients in the cohorts studied by adverse reactions found

                        RR=0.54         AR= -0.35

The relative risk (RR) related to use of oral hormonal contraceptives over six months was 0.54, which means that the probability of developing adverse reactions was 0.54 times higher than with the use of intrauterine devices.

The absolute risk (AR) was –0.35.  This negative figure indicates that the development of gynecological adverse reactions in 97 of the women studied during six months would not have been eliminated avoiding the use of oral hormonal contraceptives.  This is due to the fact that gynecological adverse reactions do not significantly occur in women using this type of contraceptive.

Given the results obtained in our six-month study, as well as the fact that this is a preliminary research paper, we believe that if this study is conducted for a longer period of time and the size of the sample is increased, other adverse reactions may be found as well as long-term disorders that can affect patients’ health.  We also recommend   carrying out randomized blind studies to determine which of the oral hormonal contraceptives used causes the least side effects.

Conclusions

• Drug interactions were found in Cohort 1.  Only two cases had clinical manifestations indicative of a decrease in the effectiveness of treatment.
• The adverse reactions more commonly found in Cohort 1 were endocrine and metabolic ones and, in a lower degree, cardiovascular.  In Cohort 2, only gynecological adverse reactions were found.
• The adverse reactions found in Cohort 1 included: weight gain, increased appetite, nausea, painful mammary distension, amenorrhea, dizziness, and cephalalgia.  In Cohort 2, these included: uterine colic and pelvic inflammatory disease.
• Cohort 1 had the largest number of women satisfied with the contraceptive used.  Some reported other beneficial effects besides contraception, the most frequent being regulation of their menstrual cycle.
• The incidence rate of the adverse reactions found was: endocrine and metabolic (0.57), gastrointestinal and gynecological (0.41), central nervous system (0.31), and cardiovascular (0.03).
• The relative risk with the use of oral hormonal contraceptives in the population studied, for six months, was 0.54; and the attributable risk, -0.35.

References

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