Answering questions on when to use pills.

PIP: This article answers vital questions regarding the administration of oral contraceptives (OCs) to women with high blood pressure conditions and migraine headaches. It was stated that the choice of OC formulation in women with a strong history of hypercholesterolemia, whether it uses norgestrel or levonorgestrel, is not of primary importance from a lipid perspective. However, clinicians should practice extreme cautiousness in prescribing any combination OC to hypertensive women. Another physician stated that in such cases a low-dose OC (preferably 20 mcg) should be instituted in conjunction with careful monitoring of their blood pressure. Concerning women with a history of migraine headaches, the use of progestin-only or intrauterine contraception are suggested. Lastly, the two primary considerations in the choice of an OC for any woman, with or without a health condition, are that it should be a low-dose formulation (less than 50 mcg) and that it should be covered by her insurance formulary.^ieng

Combined oral contraceptives versus levonorgestrel for emergency contraception.

PIP: A study supported by the World Health Organization's Task Force on Postovulatory Methods of Fertility Control compared the efficacy of the Yuzpe and levonorgestrel-only methods of emergency contraception (EC). Enrolled in this double-blind, randomized trial were 1998 women from 21 centers around the world who requested EC within 72 hours of unprotected intercourse. The pregnancy rate was 1.1% for levonorgestrel alone and 3.2% for the combined ethinyl estradiol-levonorgestrel regimen. The crude relative risk of pregnancy was 0.36 (95% confidence interval, 0.18-0.70) for levonorgestrel compared with the Yuzpe regimen. The former method prevented 85% of expected pregnancies, while the latter prevented only 57%. Finally, side effects such as nausea, vomiting, dizziness, and fatigue were significantly less common in the levonorgestrel group. Although these findings document the superiority of the levonorgestrel regimen for EC, the 0.75 mg tablets are not currently manufactured in the US.^ieng

Cardiovascular safety of oral contraceptives. What has changed in the last decade?

PIP: As a result of careful patient selection, the cardiovascular safety of oral contraceptives (OCs) has improved dramatically in the past decade. The incidence of stroke and myocardial infarction is exceedingly low among women who use OCs containing 35 mcg or less of ethinyl estradiol, and formulations containing under 50 mcg of estrogen account for almost all current use in the US. This article reviews the epidemiologic data on use of OCs of varying steroid dosages on the risks of myocardial infarction, hemorrhagic and ischemic stroke, and venous thromboembolism. Although four studies published since 1995 have suggested that OCs containing desogestrel or gestodene increase the risk of venous thromboembolism above that associated with levonorgestrel, these findings are likely due to prescribing bias and differences in the duration of use. The greatest risk of an arterial cardiovascular event comes from smoking while taking OCs.^ieng

Omitting the first oral contraceptive pills of the cycle does not automatically lead to ovulation.

OBJECTIVE: Our purpose was to test the hypothesis that omitting the first three pills of the contraceptive cycle leads to ovulation. STUDY DESIGN: Ninety-nine women, randomly assigned to 1 of 3 treatments of combined oral contraceptives, completed the study. Treatments contained ethinyl estradiol and either monophasic gestodene, triphasic gestodene, or monophasic desogestrel. Pituitary-ovarian activity was monitored by ultrasonography of the ovaries and assay of serum concentrations of estradiol, progesterone, and follicle-stimulating hormone over 1 normal cycle (study period 1) and 1 cycle after an extended pill-free interval of 10 days (study period 2). RESULTS: None of the women experienced normal ovulation as evaluated by ultrasonography and serum progesterone concentrations. However, follicle-stimulating hormone reached a maximal serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery, and increases in serum estradiol concentrations were seen in each woman although with marked interindividual variation. During study period 2 we found follicles of >18 mm in 24%, 24%, and 40% of the monophasic gestodene, triphasic gestodene, and monophasic desogestrel groups, respectively. CONCLUSIONS: Follicular growth up to preovulatory size is common in women missing the first one to three pills of their contraceptive cycle. Although this creates the prerequisite for ovulation, normal ovulation did not occur when pill omissions were limited to only 3 days.

PIP: The hypothesis that omission of the first three pills of the oral contraceptive (OC) cycle leads to ovulation by extending further the pill-free period was investigated in 107 healthy women 18-35 years of age recruited from family planning programs in Finland, the Netherlands, and Belgium. Study participants were randomly allocated to one of the following treatment groups: 1) monophasic gestodene--75 mcg of gestodene and 30 mcg of ethinyl estradiol; 2) triphasic gestodene--6 days of 50 mcg gestodene and 30 mcg ethinyl estradiol, 5 days of 70 mcg gestodene and 40 mcg ethinyl estradiol, and 10 days of 100 mcg gestodene and 30 mcg ethinyl estradiol; or 3) monophasic desogestrel--150 mcg desogestrel and 20 mcg ethinyl estradiol. Noncompliance with OC taking was simulated by extending the pill-free period from 7 to 10 days. During or after the extended pill-free interval, follicular growth exceeding 18 mm occurred in 24% of women in the monophasic gestodene group, 24% in the triphasic gestodene group, and 40% in the monophasic desogestrel group. Follicle-stimulating hormone reached a maximum serum concentration in most women during the first 7 pill-free days, indicating complete pituitary recovery. No normal ovulation was observed after either a 7- or 10-day pill-free period as evaluated by ultrasonography of follicles and serum progesterone assays. Since normal ovulation did not occur when pill omissions were limited to 3 days, OC users who forget to take these three tablets can be safely advised to start the pill cycle on day 11.

A regimen of oral contraceptives restricted to the periovulatory period may permit folliculogenesis but inhibit ovulation.

Increased safety of oral contraceptives (OC) has resulted from a reduction in the estrogen and progestin content per tablet. A reduction in the number of hormonally active pills and their placement at critical points within the cycle may provide a novel regimen for further reducing the hormonal content of OC per cycle and their attendant side effects without compromising efficacy. The objective of this study was to determine the effectiveness of two OC regimens that incorporate a delayed start and limited midcycle use of the combination of ethinyl estradiol and norethindrone, and limited use of norethindrone only during the second half of the cycle. Main outcome measures were defined as ovulation, serum concentrations of estradiol (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), progesterone (P), follicular diameters, and endometrial thickness. Volunteers were issued blister packs containing 28 pills and randomized to one of two groups. Group 1 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet day 6-10, and 0.70 mg norethindrone only day 11-19. Placebo tablets were used on days 1-5 and day 20-28. Group 2 used a combination of 50 micrograms ethinyl estradiol and 1 mg norethindrone per tablet on day 8-12, and 0.70 mg norethindrone only on day 13-21. Placebo tablets were used on day 1-7 and day 22-28. A total of 20 cycles were studied using 10 volunteers. To assess any possible carryover effect, two successive cycles were studied for each subject. Serum sampling for E2, FSH, LH, and P, and transvaginal ultrasound imaging to assess endometrial thickness and follicle diameter were carried out at 4 day intervals throughout the cycle. One ovulation occurred in 10 cycles in group 1. Five ovulations occurred in 10 cycles in group 2. All ovulations, regardless of group, occurred in the second cycle. Peak E2 concentrations were not significantly different between groups (152.04 +/- 107.1 pg/mL vs 162.1 +/- 56.1 pg/mL [mean +/- SD] for groups 1 and 2, respectively] but occurred earlier in the cycle in group 1. No differences were noted between the groups in serum concentrations of FSH or LH for any given cycle day. Maximum follicle diameters were not different between groups 1 and 2, regardless of ovulatory status (20.5 +/- 8.1 mm2 vs 20.6 +/- 14.2 mm2, respectively). Ultrasound imaging assessment of midcycle follicle growth revealed diameters ranging from 18.5 mm2 to 34.0 mm2 with gradual resolution through the second half of the cycle in anovulatory cycles, and 16.0 mm2 to 23.5 mm2 with abrupt disappearance in ovulatory cycles. Endometrial thickness did not exceed 10 mm for any anovulatory cycle regardless of group, but ranged from 6 to 9 and 6 to 11 during the luteal phase of ovulatory cycles of groups 1 and 2, respectively. Peak serum P concentrations at midluteal phase in ovulatory cycles ranged from 9.2 ng/ml to 18.2 ng/ml. Data from this preliminary study suggest that ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration using norethindrone only for 9 days during the second half of the cycle. Such a restricted regimen may offer both an effective method of contraception and a means of further reducing both estrogen and progestin content per cycle and the possible short and long term adverse side effects of these hormones.

PIP: A reduction in the number of hormonally active oral contraceptive (OC) pills and their placement at critical points within the cycle represents a novel potential regimen for further reducing the hormonal load of OCs per cycle and the attendant side effects without compromising efficacy. The present study evaluated the effectiveness of two such OC regimens: group 1--placebo tablet on days 1-5, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 6-10, 0.70 mg of norethindrone only on days 11-19, and placebo tablets on days 20-28; and group 2--placebo tablet on days 1-7, 50 mcg of ethinyl estradiol and 1 mg of norethindrone per tablet on days 8-12, 0.70 mg of norethindrone only on days 13-21, and placebo on days 22-28. 10 volunteers were randomized to one of the two groups for two cycles. There was 1 ovulation in the 10 cycles completed in group 1 and 5 ovulations in the 10 cycles in group 2. All ovulations occurred in the second cycle. Peak estradiol concentrations occurred earlier in the cycle in group 1, but were not significantly different between groups. Serum concentrations of follicle-stimulating hormone or luteinizing hormone and mean follicle diameters were not different between groups. Folliculogenesis occurred in all 20 cycles. Mid-cycle follicular growth resolved gradually during the second half of the cycle in anovulatory cycles and abruptly in ovulatory cycles. The length of the luteal phase for ovulatory cycles was 7 days in group 1 and 8-12 days in group 2. These findings suggest ovulation may be prevented with a combination of ethinyl estradiol and norethindrone started as late as cycle day 6 and limited to 5 days' duration, using norethindrone only for 9 days during the second half of the cycle.

Shortened pill-free interval delivered by new 20 mcg pill. Organon's Mircette scheduled for U.S. debut this summer.

PIP: The new low-dose oral contraceptive (OC), Mircette, is the first pill to shorten the hormone-free interval. The dosing regimen begins with 21 days of 20 mcg of ethinyl estradiol and 150 mcg of desogestrel; the last 7 days start with 2 days of placebo, followed by 5 days of 10 mcg of ethinyl estradiol. These 5 days of ethinyl estradiol are expected to oppose the effect of any follicle-stimulating hormone in promoting growth of a follicle in the estimated 20% of pill takers who are close to ovulation at the end of each pill-free interval. The efficacy trial, which included more than 1000 women followed for 18 menstrual cycles, reported a Pearl index of 1.02. Breakthrough bleeding occurred in 3.5% of the 18 cycles. Less than 3% of women discontinued Mircette use because of menstruation-related side effects. The small amount of estrogen provided by Mircette during the last 5 days of the cycle helps prevent the withdrawal headaches many users of OCs with a longer hormone-free interval experience. Mircette will become available in the US in July 1998.^ieng

Understand the needs of women with epilepsy, or risk OC failure.

PIP: An estimated 700,000 to 1.2 million US women of childbearing age have epilepsy. A survey of US physicians revealed widespread lack of awareness of potential interactions between common anti-epileptic drugs and oral contraceptives (OCs) that can lead to OC failure. Increasing the OC's estrogen dose to 50 mcg can compensate for the clearance caused by anti-epileptics that affect the hepatic cytochrome P450 enzyme system. Although 91% of providers surveyed treated women of childbearing age with epilepsy, less than half made such adjustments in estrogen dose. 27% of neurologists and 21% of obstetricians surveyed reported OC failures in their patients taking anti-epileptic drugs. The Epilepsy Foundation of America has launched an initiative to educate health care providers about the disease. Family planning staff should assure women with epilepsy that this condition is not a contraindication for either OC use or pregnancy and correct beliefs that OCs exacerbate seizures. The first North American registry for pregnant women on anti-epileptic drugs has been established at Massachusetts General Hospital and will assess the effects of these drugs on fetal outcomes.^ieng

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

Emergency contraception as a backup method.

PIP: Studies are underway to determine if women who rely on condoms or other barrier methods for contraception should be given emergency, postcoital contraception (PC) to use as a back-up in the event unprotected intercourse or method failure occurs. Such a use constitutes a new "dual method" approach. One study will compare the probability of pregnancy in a group of women who rely on condoms and receive counseling only and a group of women who rely on condoms and receive counseling as well as the Yuzpe regimen of PC. There is some concern that the availability of PC will lead some women to use their barrier method less consistently. Studies in China and Scotland are comparing the experience of couples who use condoms only with couples who use condoms with progestin-only pills as a backup method. Other studies are investigating service delivery (South Africa) and the mechanisms of action of PC. Women who are given PC agents prior to unprotected intercourse should be counseled about use, potential side effects, problems requiring further treatment, and what to do in case of PC failure. Appropriate doses of the oral contraceptives (OCs) Ovral, Lo/Ovral, Nordette, Levlen, Tri-Levlen, or Tiphasil can be used for PC, as can certain progestin-only OCs. PC can be achieved with insertion of copper-releasing IUDs within five days of unprotected intercourse. PC can prevent 75% of the pregnancies that might otherwise have occurred, but other action must be taken to protect against sexually transmitted diseases in cases of rape.^ieng

Estrogen component of OCs.

PIP: Dramatic reductions in both the estrogen and progestin doses of combined oral contraceptives (OCs) have created a need for regular reassessment of safety and side effect issues. The development of OCs with estrogen doses of less than 50 mcg has resulted in fewer adverse hematologic and cardiovascular effects while retaining the contraceptive and noncontraceptive benefits of these agents. This article, intended to help US clinicians make sound OC prescribing recommendations, reviews the effect of the estrogen component of available OCs on adverse cardiovascular effects (venous thrombosis and embolism, myocardial infarction, and thrombotic and hemorrhagic stroke), breast cancer risk, and menstrual cycle control. Although a review of the available research evidence suggests that OC use is associated with a three-fold increase in the risk of venous thromboembolism, this is half of the risk associated with pregnancy. OCs with more than 35 mcg of estrogen should be reserved for women with specific conditions (e.g., concomitant use of hepatic enzyme-inducing drugs). From the perspective of safety, compliance, and noncontraceptive health benefits, OCs containing 30-35 mcg of estrogen represent a more prudent choice for the majority of women than do 20-mcg-dose OCs due, in large part, to the poor cycle control associated with the lowest-dose OCs.^ieng

Practice guidelines for OC selection: update.

PIP: This report updates practice guidelines for oral contraceptive (OC) selection developed by US clinicians and researchers in 1996 on the basis of clinical experience, expert opinion, and a review of the research literature. The update was necessitated by the availability of new OC formulations, increased awareness of the range of noncontraceptive benefits of OCs, and emerging evidence linking OCs to cardiovascular and breast cancer risks. To facilitate the review, available OCs are categorized on the basis of low, medium, or high androgenic activity of the progestin component. Overall, the report recommends OC use as a first-choice method unless a woman has a clear contraindication, suffers intolerable side effects despite changes in the type of progestin or dose, or has difficulty taking the tablets consistently. Tables included in this report present the estrogen and progestin doses in all OCs currently available in the US; set forth guidelines for OC selection for different categories of women (e.g., adolescent, postpartum, perimenopausal) and to minimize OC-related side effects and adverse health effects; and offer recommendations to guide the formulation selection in women with pre-existing medical conditions, menstrual disorders, and other reproductive health problems.^ieng

The 1995 pill scare revisited: anatomy of a non-epidemic.

Two years after the October 1995 pill scare that received worldwide attention, this synthesis of evidence goes back to the earliest research on risks of first generation oral contraceptives (OCs). It also covers epidemiological data published since, emphasising the 1995-1996 findings. Late breaking data are also examined. The key issue: are there differences in the risk profiles of second and third generation OCs. The ultimate question is: did any epidemics of venous thromboembolism (VTE) occur? This synthesis of evidence leads to the following conclusions and observations: (i) all OCs on the market are becoming progressively safer; (ii) relative risks of about 2 for VTE, even if real, are clinically unimportant and of no public health significance; (iii) the weak odds ratios contrasting third and second generation OCs, ranging from 1.5 to 2.3 in the 1995-1996 studies are more likely explained by bias than by a causal relationship; (iv) incidences of VTE among users of any OC have been declining over the past three decades; (v) absolute rates of VTE for third generation OC users reported in 1995-1996 are lower than those for users of second generation OCs in 1988 and 1991; (vi) there is no difference in risk of VTE between first starters on second generation OCs versus first starters on third generation OCs; (vii) users of third generation OCs are at much lower risk of acute myocardial infarction than users of second generation OCs; (viii) among users of any OC, the occurrence rates of stroke are low, they are declining, and no differences between second and third generation OCs are apparent; (ix) 2 years after the pill scare there are no epidemics of VTE; (x) there have been excessive rates of therapeutic abortions in some countries; and (xi) the benefit-risk ratio is favourable for users of any OC.

PIP: Presented is a synthesis of the research data on the association between oral contraceptive (OC) use and the risk of venous thromboembolism (VTE), including epidemiologic studies published after the 1995 "pill scare" in the UK. The review suggests 11 general conclusions and observations: 1) all OCs on the market are becoming progressively safer with time as a result of dosage changes; 2) even if OCs are associated with a VTE risk as high as 2.0, this risk is of no clinical or public health significance due to the rarity of VTE; 3) the low odds ratios (1.5-2.3) for third compared with second-generation OCs found in the most recent studies are likely a result of selective referral bias; 4) the incidence of VTE among OC users has been steadily declining over the past three decades; 5) absolute rates of VTE for third-generation OC users in 1995-96 are lower than those for second-generation OCs; 6) there is no difference in VTE risk between first starters on second-generation OCs compared with first starters on third-generation formulations; 7) users of third-generation OCs are at a substantially reduced risk of acute myocardial infarction compared with those of second-generation OCs; 8) occurrence rates of stroke are low among users of both second and third-generation OCs and continue to decline; 9) 2 years after the "pill scare," no epidemics of VTE have occurred; 10) excessive rates of therapeutic abortion have been recorded in some countries as a result of anxieties induced by mass media coverage; and 11) the risk-benefit ratio is favorable for users of any OC.

Haemostatic changes and the oral contraceptive pill.

Oral contraceptives have been linked to an increased incidence of thrombovascular disease. This may be mediated by their effects on the haemostatic system. An increase in the activity of coagulation Factors VII, X and fibrinogen occur with pill usage. Increased Factor VII levels are dependent on both the oestrogen and progestogen component of the oral contraceptive. A reduction in antithrombin III levels has also been observed in some but not all studies. Increased fibrinolysis has also been shown in oral contraceptive users which should balance the changes in the coagulation pathway. The increase in fibrinolytic potential is thought to be due to a decrease in the levels of plasminogen activator inhibitor I combined with an increase in the levels of plasminogen; tissue plasminogen activator antigen is decreased in most studies. The increased levels of endpoints of coagulation and fibrinolysis in pill users indicate that enhanced activity of both systems is occurring in vivo. The increased coagulation activity appears to be balanced by the rise in fibrinolytic activity, so preserving haemostatic balance. Enhanced platelet activity has also been shown in women taking oral contraceptives. Thrombus formation can result, however, when local vascular wall damage exists, or when other risk factors for thrombo-embolism, such as older age and smoking, coexist and create a local activation resulting in a thrombus. In these situations, the small differences in levels of coagulation factors in women taking different oral contraceptive formulations may be important. Pills containing the lowest doses of oestrogen (20 micrograms ethinyloestradiol) have shown the least changes in haemostatic factors. The progestogen component of the pill modifies the effect of oestrogen on the haemostatic system.

PIP: Numerous studies have investigated the mechanisms whereby, in some healthy women, oral contraceptives (OCs) can cause thrombosis. In healthy OC users, the coagulation and fibrinolytic systems are in dynamic balance and control fibrin deposition within the vascular compartment. The production of fibrin can be initiated by either the intrinsic or extrinsic coagulation pathway. Factors such as light smoking in older women or an asymptomatic borderline deficiency in a coagulation inhibitor may cause thrombogenic changes in the hemostatic system in women with a normal blood flow and a healthy vascular endothelium. OC usage is associated with an increase in the activity of coagulation factors VII, X, and fibrinogen; a reduction in antithrombin III levels has been shown in some studies. The Factor V Leiden mutation explains 20-50% of cases of venous thromboembolism. Low doses of ethinyl estradiol combined with less androgenic third-generation progestogens were thought to represent little or no risk of thromboembolic or cardiovascular disease, which may have led to overprescribing of these formulations to women with possible risk factors for thromboembolic disease. Pills containing 20 mcg of ethinyl estradiol have shown the least changes in hemostatic factors. The progestogen component of the OC modifies the effect of estrogen on the hemostatic system. The recent epidemiologic reports suggest that all pills carry an increased thrombotic risk, and each woman requesting OCs should undergo careful clinical screening.

The pill and thrombosis: epidemiological considerations.

The oral contraceptive is one of the most widely taken medications in the healthy population. The clinically important side-effects are venous and arterial thrombosis. Accurate estimates of incidence of these side-effects have proven to be difficult. Diagnostic modalities for thrombosis are sub-optimal and the problems of study methodology, primarily a reliance on non-experimental studies, have limited the ability to define the attributable risk of thrombosis from oral contraception. Pharmacological attempts to further decrease venous thrombotic side-effects by the use of third-generation oral contraceptives have failed. This places a greater emphasis on the selection of patients to help avoid giving medication to those patients with underlying thrombotic risk factors. An example of this approach has been the clear confirmation of the adverse effects of cigarette smoking and arterial thrombosis in oral contraceptive users. At the biochemical level, hypercoagulability testing may be useful. Screening for high-frequency prothrombotic abnormalities, such as the Factor V Leiden genotype, represents an important addition to the process by which patients are selected, and may be prototypic of further advances.

PIP: Precise definition of the attributable risk of thrombosis from oral contraceptive (OC) use has been limited by a reliance on nonexperimental studies and suboptimal diagnostic modalities. The consensus of studies conducted up to 1995 was that there is a small but real increase in the incidence of deep venous thrombosis in OC users that can be overcome by careful patient selection and use of formulations containing low doses of estrogen. The subsequent finding of an increased thrombotic risk associated with third-generation OCs containing the progestins desogestrel and gestodene placed an even greater emphasis on the need to select patients without underlying thrombotic risk factors. At the biochemical level, hypercoagulability may be useful. Screening for high-frequency thrombotic abnormalities such as Factor V Leiden genotype may be the prototype of further advances. In general, however, nonexperimental studies will continue to dominate, with the concomitant risk of referral bias.

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.

Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC) sex hormone levels approximately 40% and increase the risk of unplanned pregnancies in women with epilepsy. AEDs also increase the risk of birth defects in offspring of women with epilepsy. We performed a national survey to determine obstetricians' and neurologists' knowledge of OC and AED interactions and the risk of birth defects for women with epilepsy taking AEDs. We received responses to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000 obstetricians (15%) from 47 states. Practice demographics and ages of responders were typical for U.S. neurologists and obstetricians. Ninety-one percent of neurologists and 75% of obstetricians said they treat women with epilepsy of child-bearing age. Only 4% of the neurologists and none of the obstetricians, however, knew the effects of the six most common AEDs on OCs, even though 27% of neurologists and 21% of obstetricians reported OC failures in their patients taking AEDs. Although increasing OC doses can compensate for insufficient OC sex hormone levels due to AEDs, most physicians do not increase the doses. Even though the risk of birth defects for the offspring of women with epilepsy is 4 to 6%, up from the background level of 2%, 44% of neurologists thought the risk was lower (0 to 3%), and some of the respondents guessed that it was as high as 50%. Many neurologists and obstetricians do not have accurate information to counsel women with epilepsy properly about their contraceptive and pregnancy choices.

PIP: Responses from 160 of 1000 neurologists (16%) and 147 of 1000 obstetricians (15%), selected from an American Medical Association listing to receive a mailed questionnaire, revealed a disturbing lack of knowledge about the interactions between antiepileptic medications and oral contraceptives (OCs). Hepatic enzyme-inducing antiepileptic drugs lower OC estradiol levels by about 40% and may reduce free progestin levels, thereby increasing the risk of unplanned pregnancy; moreover, antiepileptics increase the risk of birth defects in their epileptic users, who already have a 4-6% increased risk of such defects. Physicians can reduce, but not prevent, the risk of unwanted pregnancy by increasing the OC estradiol dose to at least 50 mcg and prescribing valproic acid and gabapentin (non-enzyme-inducing antiepileptics). 91% of neurologists and 75% of obstetricians reported that they treated epileptic women of childbearing age, and 27% of the former and 21% of the latter physicians acknowledged cases of OC failure in these patients. Only 4% of the neurologists and none of the obstetricians knew the effects of the 6 most common antiepileptic drugs on OCs. Just 41% of neurologists and 43% of obstetricians routinely had patients adjust their OC doses if they were taking antiepileptics. Such adjustment was more likely among physicians who had an epileptic patient with an unintended pregnancy and those who had accurate knowledge of OC-antiepileptic drug interactions. 44% of neurologists and 23% of obstetricians underestimated the birth defects risk as 0-3%. Since the physicians who chose to respond to this survey were presumably more concerned and knowledgeable about the reproductive effects of antiepileptic drugs than those who chose not to respond, continuing education efforts are urged to enable health care providers to counsel epileptic women about contraception.

Practice guidelines for OC selection.

PIP: Clinical practice guidelines are important to clarify the potential risks, benefits, and costs of available interventions. Although oral contraceptives (OCs) are the most popular reversible method of fertility control in the US, there are at present no evidence-based guidelines for OC selection. Toward this end, members of the Editorial Board of "Dialogues in Contraception" met to develop initial guidelines for OC selection that reflected both a reasonable interpretation of the available literature and the authors' clinical experiences. Today's OCs contain differing types and doses of estrogen. The central principle in OC prescribing should be that the formulation selected contains the least amount of estrogen and progestin that is possible given the patient's needs. These guidelines divide available OCs into categories of low, medium, and high androgenic activity of the progestin component. The low androgenic progestin-containing OCs are associated with reduced side effects, improved cycle control, improved lipoprotein profile, and enhanced tolerability. Included with the guidelines are tables that classify OCs by their composition, identify OCs with the potential to minimize or manage unwanted side effects, recommend formulations for women with medical conditions, and outline use of OCs for the treatment of gynecologic symptoms.^ieng

Bone mass and long-term monophasic oral contraceptive treatment in young women.

A prospective study has been designed to investigate bone metabolism in young women taking an oral monophasic contraceptive formulation (ethinylestradiol 20 micrograms + desogestrel 0.150 mg) over 5 years. Healthy women (n = 200) between 19 and 22 years of age were divided into two groups. Group A received oral contraception, Group B did not receive any treatment. All the subjects underwent a bone mass density (BMD) evaluation at spinal level L2-L4 with Dexa (Norland XR-26) and a measurement of the serum alkaline phosphatase levels and urinary excretion of OH-proline at baseline and every 12 months over 5 years. Our results demonstrated that Group A did not show any significant BMD change after 5 years of oral contraceptive treatment, while Group B demonstrated a significant increase (p < 0.01) in the bone mass content at the end of the time of observation (+7.8% after 5 years). No significant changes were found in serum alkaline phosphatase levels and in urinary excretion of OH-proline at the end of the study in comparison with basal levels in both groups. Our data suggested that long-term treatment with an oral monophasic contraceptive formulation (ethinylestradiol 20 micrograms + desogestrel 0.150 mg) did not modify the BMD but prevented the occurrence of the physiologic peak of bone mass in young women.

PIP: Between June 1988 and March 1989 in Italy, health workers enrolled 200 women aged 19-23 attending obstetric-gynecology clinics in and around Pavia into a five-year study of the effects of an oral contraceptive (OC) with 20 mcg ethinyl estradiol and 0.15 mg desogestrel on bone mass. They were able to follow 76 of the 100 women using the OC and 71 of the 100 women using no OC for five years. Health workers conducted a bone mass density (BMD) evaluation at spinal level L2-L4 with Dexa (Norland XR-26). They measured serum alkaline phosphatase levels and urinary excretion of hydroxyproline (OH-proline) at baseline and every 12 months for five years. Neither urinary excretion of OH-proline levels nor alkaline phosphatase levels differed significantly in the two groups during the five years from baseline levels. Over the five years, the BMD of OC users did not change significantly while the BMD of the controls increased 7.8% from baseline (p 0.01). These findings suggest that this monophasic OC prevented or delayed the physiologic peak bone mass. Even though the low dosage of ethinyl estradiol (20 mcg) may have contributed to the prevention of bone mass loss, it could not achieve the peak bone mass. More studies are needed to understand the effect of long-term OC treatment on bone mineral content.

A two-year clinical study of the effects of two triphasic oral contraceptives on plasma lipids.

OBJECTIVE: Oral contraceptive formulations can alter plasma lipid and lipoprotein levels; however, lower-dose triphasic tablets show only minimal metabolic effects during 6 or 12 cycles of use. Involvement of lipids in chronic cardiovascular conditions, plus long-term use of oral contraceptive tablets, prompted this first 24-cycle study of the effect of triphasic formulations on young women. METHODS: 69 women assigned randomly to an ethinyl estradiol/levonorgestrel formulation (Triphasil) or an ethinyl estradiol/norethindrone formulation (Ortho 7/7/7) and 25 control women (no hormonal contraception) had blood sampled for lipids and lipoproteins pre-trial, and at 3- or 6-cycle intervals for 24 cycles. RESULTS: At cycle 24, control women experienced no significant change from baseline in any variable except apolipoprotein B (apo B). Plasma apo B increased 42% (P < .01), reflecting the LDL apo B increase (42%, P < .01). Both combination formulations significantly increased apo B (plasma, VLDL, IDL and LDL); the increases ranged between 47% and 84%. Plasma apo A1 rose (15%, P < .001) in the Ortho 7/7/7 group only. Plasma and LDL triglycerides were increased significantly (P < .001) by the norethindrone product, 43% and 81%, respectively, and plasma and LDL cholesterol, 14% and 28%, respectively. Cholesterol decreased in all other subfractions, including HDL (11%, P < .01). HDL cholesterol decreased significantly in the Triphasil group (8%, P < .05); no other cholesterol subfractions changed significantly. All cycle-24 lipid and lipoprotein values remained well within respective normal ranges. CONCLUSION: Although 2-year exposure to the triphasic oral contraceptive formulations changed the lipid risk factors for cardiovascular disease only within normal ranges, there remains potential for long-term health effects when compounded with other risk factors.

PIP: The first 24-cycle study of the metabolic effects of triphasic oral contraceptives (OCs) recorded significant changes in lipid values, yet none of these values moved outside the normal range. Included in the study were 69 non-smoking Canadian women 19-29 years of age with no history of obesity, diabetes, or alcohol misuse. Subjects were randomly assigned to receive either an ethinyl estradiol-norethindrone formulation (Ortho 7/7/7) or an ethinyl estradiol-levonorgestrel preparation (Triphasic). 25 controls underwent periodic blood samplings for lipid and lipoprotein levels. The only significant change recorded among controls was a 42% increase in the plasma apo B level resulting from changes in the low density lipoprotein (LDL) apo B subfraction. In the Ortho 7/7/7 and Triphasic groups, both plasma and LDL triglycerides were increased above baseline and above values for controls at the 24-month point. In Ortho 7/7/7 acceptors, LDL cholesterol increased by 28%, high density lipoprotein (HDL) decreased by 11%, and plasma cholesterol increased by 14%; other cholesterol levels decreased significantly. In the Triphasic group, HDL decreased by 8%, but no other significant changes occurred. Apo A1 increased by 15% in the Ortho 7/7/7 group, but not among Triphasic users; all apo B values increased significantly in both treatment groups. Although these changes in lipid profiles among triphasic OC users do not seem to increase the risk of cardiovascular disease, there is potential for adverse health effects when other cardiovascular risk factors, especially smoking, are present.

Are low-dose oral contraceptives safer and better?

It is widely believed that the use of low-dose oral contraceptives decreases thrombotic risks, compared with higher-dose oral contraceptives. Two recent epidemiologic studies infer a lower risk with 30 to 35 mcg than with 50 mcg estrogen oral contraceptives. However, as with prior studies from which similar conclusions were drawn, these studies have major flaws, the worst being that all 50 mcg oral contraceptives are lumped together, whereas 50 mcg mestranol oral contraceptives are actually bioequivalent to 35 mcg ethinyl estradiol oral contraceptives, thus confounding all such studies. Moreover, while rare thrombotic events have received inordinate attention, the major protective effect against endometrial and ovarian cancer that has been shown in older studies among users of oral contraceptives containing > or = 50 mcg ethinyl estradiol or > or = 80 mcg mestranol are almost totally ignored. The theoretical benefits of using lower-dose oral contraceptives have not been demonstrated, whereas the protection against these types of reproductive cancer have been shown repeatedly with high-dose oral contraceptives but not, to date, with lower-dose oral contraceptives. Such protection may be diminished by lowering the oral contraceptive dosage. Should every woman of reproductive age use high-dose oral contraceptives for 2 years? Are we throwing out the baby with the bath water?

A prospective study of a monophasic oral contraceptive containing 30 mcg ethinyl oestradiol and 150 mcg desogestrel (Marvelon).

PIP: Marvelon, a monophasic oral contraceptive (OC) containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, has been available to Malaysian women through the national family planning program since 1982. To assess the safety, effectiveness, and side effects associated with this OC, 247 women who requested the pill were enrolled in a multicenter prospective study that included follow-up after the first, third, and sixth cycles of use. 81% of participants had never used any form of contraception before Marvelon. 194 women (79%) completed the 6-month study. There were no pregnancies recorded. Although women reported a slightly increased incidence of nausea, breast tenderness, and headache in the first treatment cycle, these side effects had abated by the end of the third cycle. After six cycles, mean body weight had decreased by an average of 0.4 kg. Both systolic and diastolic blood pressure were unaffected. An unexpected finding was a decrease in the severity of acne with continuous use of Marvelon. Although both spotting and breakthrough bleeding increased slightly in the first two cycles, irregular bleeding returned to pretreatment levels by the third cycle. The length of the withdrawal bleed in the pill-free week was reduced. The incidence of irregular bleeding and other side effects was substantially lower in this sample of Malaysian women than in Asian and Caucasian Marvelon users surveyed in other studies.^ieng