Antibiotic Interference with Oral Contraceptives: Can a Dental Visit Make You Pregnant? a Peer-Reviewed Publication Written by Michael Wahl, DDS

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Antibiotic Interference with Oral Contraceptives: Can a Dental Visit Make you Pregnant? A Peer-Reviewed Publication Written by Michael Wahl, DDS

Abstract Educational Objectives: Author Profile Oral contraceptives are a safe and effective form of birth control used At the conclusion of this educational activity Michael Wahl, DDS practices general dentistry in Wilmington, by millions of women in the United States and around the world. participants will be able to: Delaware and received his undergraduate and dental degrees There have been anecdotal reports of unintended pregnancies 1. Describe the difference between anecdotal from Case Western Reserve University. He has published over after antibiotics were prescribed to women on oral contraceptives. reports and scientific studies on the interaction 50 articles in many dental and medical journals and lectured Dentists and physicians have therefore been advised to warn female of antibiotics and oral contraceptives at many major national and international meetings on dental patients on oral contraceptives of a potential interaction and to advise 2. Discuss the legal implications of the interaction treatment of medically compromised patients, amalgam and additional forms of contraception when prescribing antibiotics. between antibiotics and oral contraceptives composite, and practice management, among other topics. This issue has caused consternation among dentists, physicians, He is a part-time assistant attending dentist at Christiana Care 3. Describe the difference in how rifampin and Health System. He can be reached at [email protected] . and patients, coming to a climax in the lay media with the headline non-rifampin antibiotics affect contraceptive “A Dentist Visit Can Make You Pregnant” in a supermarket tabloid. efficacy Fortunately, scientific studies have failed to show any decrease in oral 4. Discuss international and national medical Author Disclosure contraceptive efficacy with any antibiotics except for one: rifampin, and dental group statements on the issue of Michael Wahl, DDS has no commercial ties with the sponsors which is not typically used in dentistry. It is therefore not necessary antibiotic interference with oral contraceptives or providers of the unrestricted educational grant for this to warn patients of a potential interaction between antibiotics used course. in dentistry and oral contraceptives when scientific evidence has consistently and repeatedly failed to support such an interaction.

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Publication date: Apr. 2014 This educational activity was developed by PennWell’s Dental Group with no commercial support. Supplement to PennWell Publications This course was written for dentists, dental hygienists and assistants, from novice to skilled. Expiration date: Mar. 2017 Educational Methods: This course is a self-instructional journal and web activity. Provider Disclosure: PennWell does not have a leadership position or a commercial interest in any products or services discussed or shared in this educational activity nor with the commercial supporter. No manufacturer or third party has had any input into the development of course content. Requirements for Successful Completion: To obtain 2 CE credits for this educational activity you must pay the required fee, review the material, complete the course evaluation and obtain a score of at least 70%. CE Planner Disclosure: Heather Hodges, CE Coordinator does not have a leadership or commercial interest with products or services discussed in this educational activity. Heather can be reached at [email protected] Educational Disclaimer: Completing a single continuing education course does not provide enough information PennWell designates this activity for 2 Continuing Educational Credits to result in the participant being an expert in the field related to the course topic. It is a combination of many educational courses and clinical experience that allows the participant to develop skills and expertise. Dental Board of California: Provider 4527, course registration number CA#02-4527-14010 Image Authenticity Statement: The images in this educational activity have not been altered. “This course meets the Dental Board of California’s requirements for 2 units of continuing education.” Scientific Integrity Statement: Information shared in this CE course is developed from clinical research and represents the most current information available from evidence based dentistry. The PennWell Corporation is designated as an Approved PACE Program Provider by the Known Benefits and Limitations of the Data: The information presented in this educational activity is derived Academy of General Dentistry. The formal continuing dental education programs of this from the data and information contained in reference section. The research data is extensive and provides direct benefit program provider are accepted by the AGD for Fellowship, Mastership and membership to the patient and improvements in oral health. maintenance credit. Approval does not imply acceptance by a state or provincial board of Registration: The cost of this CE course is $49.00 for 2 CE credits. dentistry or AGD endorsement. The current term of approval extends from (11/1/2011) to Cancellation/Refund Policy: Any participant who is not 100% satisfied with this course can request a full (10/31/2015) Provider ID# 320452. refund by contacting PennWell in writing. Educational Objectives It is possible for various medications to impact oral con- At the conclusion of this educational activity participants traceptive efficacy, causing unintended pregnancies. There will be able to: have been many classes of drugs implicated in oral contra- 1. Describe the difference between anecdotal reports and ceptive failure, including antibiotics, anticonvulsants, anti- scientific studies on the interaction of antibiotics and depressants, antihistamines, thyroid hormones, diuretics, oral contraceptives vitamins, and antiulcer medications [Table 1].3 In the 1970s, 2. Discuss the legal implications of the interaction the potent enzyme-inducer rifampin, an antibiotic used for between antibiotics and oral contraceptives tuberculosis treatment, was first implicated in oral contra- 3. Describe the difference in how rifampin and non- ceptive failure due to its interaction with the oral contracep- rifampin antibiotics affect contraceptive efficacy tive, rendering them less effective. Since then, many other 4. Discuss international and national medical and dental antibiotics have also been blamed for unwanted pregnancies group statements on the issue of antibiotic interfer- and their interaction. As a result, dentists and physicians ence with oral contraceptives have been indoctrinated with the fear of “wrongful birth”: an unwanted pregnancy due to a possible interaction of which Abstract the woman was not informed. A manufacturer’s warning of Oral contraceptives are a safe and effective form of birth a possible interaction is included in many package inserts of control used by millions of women in the United States and antibiotics and oral contraceptive formulations. It is alleged around the world. There have been anecdotal reports of that if the dentist or physician does not warn of a possible in- unintended pregnancies after antibiotics were prescribed teraction and advise additional birth control methods when to women on oral contraceptives. Dentists and physicians on the antibiotic, then he or she can be legally liable for this have therefore been advised to warn female patients on oral “wrongful birth,” including child support payments until contraceptives of a potential interaction and to advise addi- the child is 18 years of age. tional forms of contraception when prescribing antibiotics. This issue has caused consternation among dentists, physi- Table 1. Drugs implicated in oral contraceptive failure. cians, and patients, coming to a climax in the lay media with Antibiotics the headline “A Dentist Visit Can Make You Pregnant” in Anticonvulsants a supermarket tabloid. Fortunately, scientific studies have Antidepressants failed to show any decrease in oral contraceptive efficacy with any antibiotics except for one: rifampin, which is not Antihistamines typically used in dentistry. It is therefore not necessary to Thyroid hormone warn patients of a potential interaction between antibiotics Diuretics used in dentistry and oral contraceptives when scientific Vitamins evidence has consistently and repeatedly failed to support such an interaction. Antiulcer medications

The history of modern birth control can be traced Fortunately for dentists and their patients, scientific stud- back to 3000 BC, when condoms were made out of fish ies of the antibiotics used in dentistry have failed to show an bladders, linen sheaths, or animal intestines. By 1838, interaction with oral contraceptives. Moreover, legal cases do condoms and diaphragms were made out of vulcanized not support the idea that a dentist who prescribes antibiot- rubber. Margaret Sanger was a birth control activist who ics has a legal duty to warn patients of a potential interaction helped reproductive physiologist Gregory Pincus obtain with oral contraceptives. Finally, current statements by a small grant to begin contraceptive research in 1951. the World Health Organization, the Centers for Disease In 1957, the United States Food and Drug Administra- Control and Prevention (CDC) and the American College tion (FDA) approved an oral contraceptive (Envoid) for of Obstetricians and Gynecologists concur that there is no menstrual disorders. In 1960, the FDA approved the scientific evidence for an interaction between non-rifampin first hormonal oral contraceptive for birth control. The antibiotics and oral contraceptives; however, the American pill was not available to married women in all states until Dental Association and the American Medical Association a Supreme Court ruling in 1965. It became available to advise a cautious approach, recommending that physicians unmarried women in all states after another Supreme and dentists advise women of a possible interaction. Court ruling in 1972. Today there are more than 100 Like any medication, birth control pills are not 100% ef- million women using birth control pills globally, with fective, even if taken perfectly. The failure rate is less than 1% more than 11 million in the United States.1 Modern oral (less than 1 pregnancy per 100 women per year of use) when contraceptives typically contain two hormones, estrogen used perfectly, without missing any pills,3 but the typical use and progestin. failure rate is about 9%. [Table 2.] The most common cause

2 www.ineedce.com of contraceptive failure is non-use, and the average teenager In 1975, Dossetor reported seeing three cases of preg- misses 3 pills a cycle.4 If a patient on oral contraceptives ex- nancy in her patients who were prescribed ampicillin while periences diarrhea or vomiting, regardless of whether it is on oral contraceptives. No details were provided, including caused by an additional medication, it is possible that the whether any doses of contraceptive were missed or if the contraceptive will be less effective, and these women should patients were also on other medications that may have inter- use additional contraceptive measures. Antibiotics used in acted with the oral contraceptive.7 dentistry have been alleged to interact with oral contracep- In an anecdotal report from 1980, Bacon and Shenfield tives, causing decreased efficacy. The oral contraceptive reported a case of pregnancy in a woman who had been tak- efficacy is reduced theoretically by a decrease in normal gut ing Microgynon 30® (ethinyloestradiol 30 μg, D-norgestrol flora that would otherwise increase bioavailability.5 150 μg) for two years and had recently taken a course of tetracycline 500 mg every six hours for three days and 250 mg 57 Table 2. Oral contraceptive typical use failure rate: every six hours for another two days. She claimed not to have Method Typical use failure rate missed any doses of oral contraceptive and had no diarrhea, IUD 0.2 – 0.8% vomiting, or breakthrough bleeding. The authors concluded Implant 0.05% that women taking oral contraceptives should use additional birth control methods when tetracycline is also administered.8 Injection 6% In 1987, Sàndor and Uffen cited many case reports impli- Combined (estrogen and 9% progestin) oral contraceptive cating penicillin, ampicillin, metronidazole, and tetracycline in oral contraceptive failure and recommended warning Progestin only contraceptive 9% dental patients of a potential interaction when prescrib- Patch 9% ing such antibiotics.9 In 1993, Harvey recommended that Vaginal ring 9% dentists should be aware of a potential interaction between Diaphragm 12% oral contraceptives and antibiotics and “advise their patients Condom 18% accordingly.” 10 Female condom 21% In 1993, Pyle et al. asserted, “Commonly used anti- Spermicides 28% biotics [including penicillins, cephalosporins, and fluoro- Rhythm method 24% quinolones] interact with oral contraceptives reducing the contraceptive’s effectiveness. [Warn patients.]”11 After citing scientific studies that seem to rule out the Anecdotal reports and interaction warnings potential interaction of antibiotics with oral contraceptives There have been many anecdotal reports of pregnancies after in 1993, Shenfield nevertheless recommended counseling interactions between antibiotics and oral contraceptives. The patients to use additional contraceptive measures when an- following antibiotics have been alleged to contribute to oral tibiotics are prescribed for medicolegal reasons.12 contraceptive failure: penicillin, tetracyclines, sulfonamides, In 1994, Porterfield described a hypothetical case of erythromycins, metronidazole, griseofulvin, cephalosporin, an unwanted pregnancy after root canal therapy in which cotrimoxazole, fluoroquinolones, and rifampin [Table 3].6 ampicillin was prescribed. Without citing any sources, she Many authors have issued warnings as a result of such re- asserted, “Like several other penicillins and tetracyclines, ports, but many of the anecdotal reports included women ampicillin can decrease the effectiveness of oral contracep- taking antibiotics, with additional medications. Some of the tives when the drugs are taken concurrently. The patient pregnancies might have been within the normal failure rate should have been advised to use additional contraception of the oral contraceptive. during the time she was also taking ampicillin.”13 Also in 1994, Gibson and McGowan recommended Table 3. Antibiotics and oral contraceptive failure. giving an informational leaflet to all female dental patients Antibiotics alleged Antibiotics shown for whom antibiotics are prescribed, warning of a potential to contribute to oral to cause oral interaction with oral contraceptives and that additional birth contraceptive failure contraceptive failure control measures should be used.14 Penicillin Rifampin Tetracyclines In 1999, Weisberg asserted rifampin and possibly Sulfonamides griseofulvin reduce the efficacy of oral contraceptives, but Erythromycins there was a possibility other antibiotics may also reduce oral Metronidazole contraceptive efficacy in a few women. She stated, “There Griseofulvin Cephalosporin are no scientific data to support the anecdotal evidence that Cotrimoxazole the concomitant use of combined oral contraceptives and Fluoroquinolones antimicrobials reduces contraceptive efficacy in the majority Rifampin of women.” She concluded that since some small subset of www.ineedce.com 3 women may be affected, all women should be advised of the (follicle stimulating hormone) or LH (luteinizing hormone) potential interaction and advised to use additional contracep- concentrations. The authors concluded that there was no tive methods.15 evidence of any interaction between temafloxacin and oral Wynn stated in 2001 that antibiotics used in dentistry contraceptive steroids.24 could interfere with oral contraceptives, including penicil- Penicillins and metronidazole. In a study of 11 lin V, amoxicillin, cephalexin, tetracyclines, and erythro- women in 1980 during two consecutive menstrual cycles, mycins, but no scientific studies were cited to support this the women were given oral contraceptives along with a pla- claim.16 When prescribing such antibiotics, he asserted that cebo or ampicillin, and levels of serum estradiol, progester- dentists should recommend additional contraceptive meth- one, luteinizing hormone, and follicle stimulating hormone ods. This author wrote a letter challenging these assertions, were evaluated. Testosterone binding globulin capacity was citing many scientific studies failing to show any interaction shown to be unaffected by ampicillin administration. The between such antibiotics and oral contraceptives.17 Wynn’s authors concluded, “Ampicillin appears unlikely to dimin- response was to quote warnings about a potential interaction ish the effectiveness of the oral contraceptive studied.”25 from the United States Pharmacopeia Drug Information In 1980, Joshi et al. studied 16 women who were taking (USPDI) data base and manufacturers’ statements from the low-dose oral contraceptive combination pills (norethister- Physician’s Desk Reference.18 Again, however, no scientific one acetate 1 mg and ethinyl estradiol 30 μg). These women studies were referenced. were given either ampicillin or metronidazole, neither of In 2009, Lomaestro recommended advising all female which affected the peak levels of norethisterone or ethynyl- patients of the potential interaction, even if the incidence estradiol. The authors concluded that neither ampicillin nor is rare.19 metronidazole decreased oral contraceptive efficacy.26 In a 1982 study of 13 women taking long-term oral Scientific studies of interactions with contraceptive steroids, there were no significant changes in various antibiotics and contraceptives plasma concentrations of ethinyl estradiol, levonorgestrel, Rifampin. Although traditionally used as an antitubercu- follicle stimulating hormone, or progesterone after adminis- losis treatment, rifampin is sometimes used to treat other tering ampicillin. The authors concluded that “women tak- infections, including AIDS, bacterial meningitis, and meth- ing oral contraceptive steroids do not need to take alternative icillin-resistant staphylococcal infections.20 In a 1979 study contraceptive precautions when prescribed ampicillin.”27 of 8 women on norethisterone, the norethisterone plasma Sulfa drugs. In 9 women taking long-term oral contra- levels and half-life were significantly reduced after rifampi- ceptive steroids, concomitant cotrimoxazole was actually cin treatment.21 In 1980, while taking rifampicin 450-600 mg shown to increase plasma levels of ethinyl estradiol, but did per day, seven women were given a single dose of Minovlar® not affect plasma levels of levonorgestrel or progesterone. (50 μg ethinyl estradiol and 1μg norethindrone acetate) and The authors concluded, “Short courses of cotrimoxazole another single dose one month after stopping rifampicin. are unlikely to cause any adverse effects on contraceptive The ethinyl estradiol plasma levels and the terminal plasma control when given to women taking long-term oral contra- half-life were significantly increased after stopping rifam- ceptive steroids.”28 picin. The authors concluded, “The data show that women Antifungals. In 1990, ten healthy women on oral con- taking oral contraceptive steroids and rifampicin at the same traceptives (150 μg ethinyl estradiol and 300 μg norgestrel) time are likely to suffer a decrease in the effectiveness of the were also given fluconazole. There were no clinically or contraceptive steroid. We suggest that in most women tak- statistically significant effects on the plasma levels of ethinyl ing rifampicin it is unwise to use oral contraceptive steroids estradiol or norgestrel before or after fluconazole adminis- as the sole method of contraception.”22 tration. The authors concluded that there is no increased One study has shown that 600 mg daily rifampin signifi- risk of pregnancy in oral contraceptive users who are also cantly decreased the plasma levels of ethinyl estradiol and prescribed fluconazole.29 norethindrone and increased levels of follicle-stimulating In 1994, London and Lookingbill conducted a mail hormone in women taking oral contraceptive (35 μg ethinyl questionnaire and survey in patients on oral contraceptives estradiol/1mg norethindrone), but not enough to reverse and antibiotics of a dermatology clinic and showed no signif- ovulation suppression.23 Unlike other antibiotics, rifampin icant difference between the calculated contraceptive failure is an enzyme-inducer, and that may explain how it decreases rate and the normal contraceptive failure rate, but did not contraceptive efficacy. rule out the possibility of an interaction in some patients.30 Fluoroquinolones. A 1991 study of temafloxacin ad- Macrolide antibiotics (erythromycin). Meyer et al. ministered to 12 women on oral contraceptive steroids with studied twenty-two healthy women over four menstrual ethinyl estradiol and levonorgestrel for at least 6 months cycles. In the first cycle, there were no medications and nor- failed to show a decrease in plasma progesterone concentra- mal ovulation. In the second cycle, triphasic oral contraception. There was also no significant increase in plasma FSH tives were taken and ovulation was suppressed. In the third

4 www.ineedce.com cycle, oral contraceptives and roxithromycin, 300 mg daily Archer and Archer conducted a comprehensive review was given, and in the fourth cycle oral contraceptives and of the available studies on antibiotic interference with oral rifampin, 300 mg a day was given. All women ovulated in contraceptives in 2002 and concluded, “Clinical reports of the first cycle, and ovulation was suppressed in the second contraceptive failure with antibiotic use are retrospective, and third cycles in all women, demonstrating that roxithro- have multiple potential biases, and are not supported by mycin did not interfere with the oral contraceptive. In the pharmacokinetic data. Available scientific and pharmaco- fourth cycle, 11 women ovulated when rifampin and the oral kinetic data do not support the hypothesis that antibiotics contraceptive were given, demonstrating that rifampin does (with the exception of rifampin) lower the contraceptive interfere with oral contraceptives.31 efficacy of oral contraceptives.” They went on to state that Griseofulvin. In a 1984 letter, Dijke and Weber backup contraception in women on antibiotics and oral con- reported on 20 women on oral contraceptives who expe- traceptives is unnecessary.38 rienced bleeding or amenorrhea. Two became pregnant From 1973 through 1984, there were over 300,000,000 after taking concomitant griseofulvin.32 The two pregnant prescriptions for antibiotics not including rifampin in Eng- women were also taking other medications. The authors land, but there were only 63 pregnancies during a similar cited studies in mice, showing a modification of hepatic period (1968 through 1984) in England among women on enzyme activity in mice on griseofulvin and warned of an oral contraceptives and antibiotics not including rifampin.39 interaction between oral contraceptives and griseofulvin, The fact that there were so few pregnancies in these women possibly decreasing the effectiveness of oral contraception shows that many or all of these pregnancies may not be from in women. Back disagreed, however, stating, “Although any interaction at all between the two medications, but rather griseofulvin has been shown to modify hepatic enzyme ac- that they may have been part of the normal expected failure tivity in mice, there is no good evidence of a major enzyme- rate of the oral contraceptives. Similarly large numbers of inducing effect in humans.”33 non-rifampin antibiotic prescriptions and few unintended Tetracyclines. Murphy et al. studied the effect of tetra- pregnancies in women on contraceptives receiving these cycline on oral contraceptive levels in 1991 in seven women antibiotics have been reported in the United States.40 on oral contraceptive containing ethinyl estradiol 35 μg and Legal liability and malpractice exposure. Most norethindrone 1mg. Tetracycline 500 mg every six hours dentists are aware of the possibility of “wrongful death” was given for up to ten days while continuing the oral con- lawsuits, in which the practitioner could be legally liable for traceptive. There was no significant decrease in the plasma negligence in dental treatment, after which a dental patient ethinyl estradiol or norethindrone levels at 1 day or 5 to 10 dies. For example, an overdose of a local anesthetic could days. The authors concluded that tetracycline does not affect possibly result in the death of a patient, and the patient’s low-dose oral contraceptive levels.34 survivors could sue the dentist for negligence and “wrong- In a 1991 study of 24 women on low-dose oral contra- ful death”. Lawyers are very creative, and there are now ceptive, 100 mg doxycycline was administered twice daily. “wrongful birth” lawsuits in which a practitioner could There were no statistically significant differences in plasma be accused of negligence in failing to warn of a potential levels of ethinyl estradiol, norethindrone, or endogenous interaction between a prescribed medication that interacts progesterone before and after doxycycline was adminis- with oral contraceptives, rendering the contraceptive inef- tered. The authors concluded that pregnancies blamed on fective in preventing pregnancy. As previously mentioned, an interaction between tetracycline and oral contraceptives the interaction, it is alleged, contributes to an unwanted may occur for other reasons or could be due to an interaction pregnancy after which a child is born, and the dentist is in a small proportion of women who are at risk.35 sued for liability for child support until the child is 18 years In two randomized studies of women on NuvaRing® of age. This issue has caused consternation among dentists, contraceptive in 2005, serum etonogestrel and ethinyl es- physicians, and patients, culminating in the lay media with tradiol levels were measured before and after amoxicillin or the headline “A Dentist Visit Can Make You Pregnant” in a doxycycline ingestion and were found to be unchanged. The supermarket tabloid.6 authors concluded that there was no interaction between the Many physicians and dentists have changed their pre- antibiotics amoxicillin or doxycycline and the contraceptive scribing protocol based on this alleged interaction. A derma- and that contraceptive efficacy would not be affected by tologist stated in 1981, “I for one have discontinued giving concomitant antibiotic usage.36 oral antibiotics to patients taking oral contraceptives.”41 In a 2011 case-crossover study of 1,330 oral contracep- When one considers how commonly antibiotics are used in tive failure cases in 17,721 women, there was no relationship dermatology and that women on oral contraceptives prob- between antibiotic usage and the risk of breakthrough preg- ably make up a significant segment of most dermatologists’ nancies although because of the study’s limited power, the practices, then this statement was very bold indeed. authors cautioned that they could not rule out a greater risk Writing in The Dental Law Digest in 1992, Frank of oral contraceptive failure in those who ingest antibiotics.37 Recker, DDS, JD, stated, “[T]here is no legal evidence that www.ineedce.com 5 a dentist can be held liable for the failure to warn a patient apprehensive and does not want an unintended pregnancy. of the effect of antibiotic on oral contraceptives. In fact, the Rather than use additional contraception or even abstaining, only two known claims were settled out of court….”42 she chooses not to take the prescribed antibiotic at all. The swelling gets worse, turning into osteomyelitis and eventu- A “wrongful life” legal case ally fatally obstructs the airway. The woman’s surviving The case of Karen T. Jones and Chris Jones v. United States of family members sue the dentist for negligently advising the America was tried in the United States District Court in the woman of an interaction without scientific evidence for such Northern District of California in 1996.43 A woman and her an interaction. In court, the dentist claims in his defense, “I husband sued her gynecologist and oral surgeon for wrongful was just playing it safe” or “better safe than sorry,” but the birth and lost. The woman alleged that she became pregnant judge could reject these as invalid defenses. The dentist, in after the gynecologist prescribed oral contraceptives and the this case, was doing what was best for the dentist. Although oral surgeon prescribed penicillin for oral surgery but neither this case is hypothetical, it is also plausible, and it shows that doctor had warned of a potential interaction between the when it comes to legal liability, the safest course of action is drugs, rendering the contraception less effective. The court to try to do what is best for the patient, not necessarily what ruled in the doctors’ favor for several reasons. There was no is best for the doctor. scientific evidence of an interaction between the antibiotic and the contraceptive. Although the plaintiffs’ experts cited National dental and medical group articles blaming pregnancies on the decreased efficacy of oral statements contraception after antibiotics were prescribed, the articles In 2000, the American College of Obstetricians and Gy- were simply anecdotal reports and not scientific studies. The necologists stated that in addition to rifampin, griseofulvin court held that anecdotal reports are not evidence, and these also decreased oral contraceptive steroid levels in women experts were unable to show scientific studies that docu- but tetracycline, doxycycline, ampicillin, metronidazole mented a significant interaction or that she became pregnant and quinolone antibiotics did not decrease such levels.46 while taking penicillin. Under California law, practitioners In 2006 and 2008, the American College of Obstetricians are not required to discuss risks of very low incidences. The and Gynecologists stated that tetracycline, doxycycline, failure rate would have to exceed double the expected failure ampicillin, metronidazole, miconazole, fluconazole, and rate for a practitioner to be required to discuss the potential fluoroquinolones do not decrease oral contraceptive steroid risk. The plaintiffs also argued that the package label for the levels in women taking combination oral contraceptives. oral contraceptive proved that an interaction occurs between Additional forms of contraception are not necessary unless antibiotics and oral contraceptives. The court held, however, rifampin is co-administered with oral contraceptives.47 that the label simply warns that such an interaction is pos- In 2002, the American Dental Association Council on sible. “Furthermore, the inclusion of a boilerplate warning Scientific Affairs concluded that even though the interac- on a drug package insert may reflect no more than an overly tion between non-rifampin antibiotics and oral contracep- cautious response to possible liability, not scientific proof tives could not be classified as “established, probable, or of causation.”44 This case was later affirmed by the Ninth even suspected,” it still seemed prudent for practitioners to Circuit Court of Appeals.45 warn women of a potential interaction and to use additional Some argue that it is “better safe than sorry”; that is, why methods of birth control while taking antibiotics.48 In 2006, not advise female patients of a potential interaction between the American Dental Association Council on Access, Pre- the antibiotic and the oral contraceptive so that alternate vention and Interprofessional Relations addressed the issue methods of contraception can be used? At a minimum, so of antibiotic interference with oral and other (implant or this line of thinking goes, the dentist would be protected transdermal patch) contraceptives and concluded that when from legal liability by dispensing this advice. But in the antibiotics are prescribed, women on oral contraceptives United States, lawsuits can be initiated for virtually any should be warned of a potential interaction, rendering the reason. It is fairly easy to imagine the following hypotheti- contraceptive less effective.49 cal case possibly happening: A 24-year-old woman on oral The Council of Scientific Affairs of the American contraceptives comes to the dentist with pain and swelling Medical Association conducted a comprehensive review in tooth 31. The dentist diagnoses a carious molar requir- of 199 studies relating to antibiotic interference with oral ing root canal therapy or an extraction. The patient chooses contraceptives in 2001. The oral contraceptive failure rate in root canal therapy to save the tooth so the dentist prescribes women taking non-rifampin antibiotics corresponded to the amoxicillin and schedules the root canal treatment in one usual failure rate of oral contraceptives without concomi- week. Since the patient is on oral contraceptives, the dentist tant antibiotic usage. The authors concluded that rifampin warns of a potential interaction that could render the oral can impair oral contraceptive efficacy, but studies of other contraceptive ineffective and strongly urges additional con- antibiotics have not shown any interaction between the traception while on amoxicillin. The woman is extremely antibiotics and oral contraceptives. They added, “However,

6 www.ineedce.com individual patients do show large decreases in the plasma advise warning patients of a potential interaction, but actual concentrations of ethinyl estradiol when they take certain legal proceedings do not necessarily support this. DeRossi other antibiotics, notably tetracycline and penicillin deriva- and Hersh concluded, “With the exception of rifampin-like tives. Because it is not possible to identify these women in drugs, there is a lack of scientific evidence supporting the advance, a cautious approach is advised.”50 ability of commonly prescribed antibiotics, including all The World Health Organization concluded in 2010 that those routinely employed in outpatient dentistry, to either there is no evidence that antibiotics other than rifampin in- reduce blood levels and/or the effectiveness of oral contra- teract with oral contraceptive efficacy.51 These findings were ceptives.”40 endorsed by the CDC in 2010.52 When prescribing antibiotics to women on oral contra- The package insert of an oral contraceptive states, ceptives, it is neither necessary nor prudent to warn patients “drugs such as rifampin and some antibiotics may decrease about an interaction that has failed to be confirmed scientifi- oral contraceptive effectiveness.”53 The popular website cally. Instead, women should stay on their oral contraceptive WebMD® states that there may be an interaction between medications and be aware that diarrhea or vomiting can the penicillins and oral contraceptives but also states that decrease oral contraceptive efficacy. there is consensus that additional backup contraception need not be used when penicillins are taken.54 References In 2012, Taylor and Pemberton reviewed the evidence 1. Combined oral contraceptive pill. Wikipedia. Available: http:// en.wikipedia.org/wiki/Combined_oral_contraceptive_pill#History and concluded that unlike previous recommendations, Accessed October 11, 2013. “When prescribing non-enzyme-inducing antibiotics [i.e., 2. Szoka PR, Edgren RA. Drug interactions with oral contraceptives: compilation and analysis of an adverse experience report database. non-rifampin antibiotics] to patients using combined hor- Fertility and Sterility 1988;49(Suppl):31S-38S. monal contraception, the current guidance is that there is 3. Trussell J. Contraceptive Efficacy. In Hatcher RA, Trussell J, Nelson AL, Cates W, Kowal D, Policar M. Contraceptive Techology: Twentieth now no need to tell patients that they should use additional Revised Edition. New York NY: Ardent Media, 2011. Available: http:// contraceptive methods while they take the antibiotics [un- www.contraceptivetechnology.org/CTFailureTable.pdf Accessed 55 September 28, 2013. less they are suffering from diarrhea or vomiting].” 4. Sondheimer SJ. Update on oral contraceptive pills and postcoital Helms et al. examined the effect of antibiotics that were contraception. Current Opin Obstet Gynecol 1992;4:502-4. 5. Becker DE. Adverse drug interactions. Anesth Prog 2011;58(1):31- commonly prescribed in dermatologic practice (tetracy- 41. Available: http://www.ncbi.nlm.nih.gov/pmc/articles/ clines, penicillins, cephalosporins) on the oral contraceptive PMC3265267/ Accessed October 13, 2013. 6. Demystifying medical complexities. J Calif Dent Assoc 2000;28(7):510- (OC) failure rate by retrospectively studying the records of 8. Available: http://www.cda.org/Portals/0/journal/journal_072000. 356 patients who were on combined antibiotic and oral con- pdf Accessed October 29, 2013. 7. Dossetor J. Drug interactions with oral contraceptives. [Letter.] Br traceptives. Of these patients, 263 served as controls along Med J 1975;4(5994):467-8. Available: http://www.ncbi.nlm.nih.gov/ with an additional 162 patients. There was no significant dif- pmc/articles/PMC1675414/pdf/brmedj01475-0059f.pdf Accessed September 15, 2013. ference between the failure rate of oral contraceptives when 8. Bacon JF, Shenfield GM. Pregnancy attributable to interaction taken concurrently with antibiotics (1.6% per year failure between tetracycline and oral contraceptives. [Letter.] Br Med J 1980;280(6210):293. Available: http://www.ncbi.nlm.nih.gov/ rate) and the failure rate of the oral contraceptives alone pmc/articles/PMC1600125/pdf/brmedj00005-0027a.pdf Accessed (0.96% per year failure rate). The authors concluded, “The September 15, 2013. difference in failure rates of OCs when taken concurrently 9. Sàndor GKB, Uffen KF. Antibiotic administration and oral contraceptive failure: a drug interaction to note. J Canad Dent Assoc with antibiotics commonly used in dermatology versus OC 1987;53(10):775-7. use alone suggests that these antibiotics do not increase the 10. Harvey BD. The pill and antibiotics. [Letter.] Br Dent J 1993;175(1):12. 11. Pyle MA, Faddoul FF, Terezhalmy GT. Clinical implications of drugs risk of pregnancy. Physicians and patients need to recognize taken by our patients. Dent Clin N Amer 1993;37(1):73-90. that the expected OC failure rate, regardless of antibiotic 12. Shenfield GM. Oral contraceptives: are drug interactions of clinical significance? Drug Safety 1993;9(1)21-37. use, is at least 1% per year and it is not yet possible to predict 13. Porterfield LM. Don’t assume the patient was noncompliant. RN in whom OCs may fail.”56 1994;57(5):83. 14. Gibson J, McGowan DA. Oral contraceptives and antibiotics: In a 2011 review article, Becker concluded, “There is no important considerations for dental practice. Br Dent J 1994;177:419- sound evidence to support the contention that antibiotics, 22. 15. Weisberg E. Interactions between oral contraceptives and antifungals/ other than rifampin, reduce the effectiveness of oral contra- antibacterials. Is contraceptive failure the result? Clin Pharmacokinet ceptives.”5 1999;36(5):309-13. 16. Wynn RL. The top 50 prescription medications dispensed in In 2002, DeRossi and Hersh reviewed studies on the pharmacies in 2000. Gen Dent 2001;49(5):445-50. interaction between antibiotics and oral contraceptives and 17. Wahl MJ. Do antibiotics cause unwanted pregnancies? [Letter.] Gen Dent 2002;50(1):12-3. made the following observations: 1) Other than rifampin and 18. Wynn RL. Response from Dr. Wynn. [Reply to letter.] Gen Dent rifabutin, no clinical study has shown any antibiotic reduc- 2002;50(1):13. 19. Lomaestro BM. Do antibiotics reduce the efficacy of combination ing the efficacy of oral contraceptives, 2) as with all drugs, oral contraceptives? Available: http://www.medscape.com/ oral contraceptives are not 100% effective and their failure viewarticle/707926 Accessed September 29, 2013. rate may be why pregnancies sometimes occur in women on 20. Micromedix Consumer Medication Information. Rifampin (by mouth). Pubmed Health. Available: http://www.ncbi.nlm.nih.gov/ antibiotics other than rifampin, and 3) medicolegal experts pubmedhealth/PMHT0011985/?report=details Accessed September www.ineedce.com 7 28, 2013. practice bulletin: The use of hormonal contraception in women with 21. Back DJ, Breckenridge AM, Crawford F et al. The effect of rifampicin coexisting medical conditions. Int J Gynecol Obstet;2001:75:93-106. on norethisterone pharmacokinetics. Europ J Clin Pharmacol Available: http://obgynresidents.stanford.edu/documents/ 1979;15:193-7. hormonalcontraceptioninmedicalconditions.pdf Accessed September 22. Back DJ, Breckenridge AM, Crawford FE et al. The effect of rifampicin 22, 2013. on the pharmacokinetics of ethynylestradiol in women. Contraception 47. American College of Obstetricians and Gynecologists. Use of 1980;21(2):135-43. hormonal contraception in women with coexisting medical conditions. 23. Barditch-Crovo P, Trapnell CB, Ette E et al. The effects of rifampin and ACOG Practice Bulletin. 2006;107:1453-1472. Available: http:// rifabutin on the pharmacokinetics of a combination oral contraceptive. csmcobgynresidents.files.wordpress.com/2010/02/contraception- Clin Pharmacol Ther 1999;65(4):428-38. in-women-with-coexisting-medical-conditions-pb-731.pdf Accessed 24. Back DJ, Tjia J, Martin C et al. The lack of interaction between September 22, 2013. temafloxacin and combined oral contraceptive steroids. Contraception 48. American Dental Association Council on Scientific Affairs. Antibiotic 1991;43(4):317-23. interference with oral contraceptives. JADA 2002;133(7):880. 25. Friedman CI, Huneke AL, Kim MH, Powell J. The effect of ampicillin Available: http://jada.ada.org/content/133/7/880.extract# Accessed on oral contraceptive effectiveness. Obstet Gynecol 1980;55(1):33-7. September 27, 2013. 26. Joshi JV, Joshi UM, Sankholi GM et al. A study of interaction 49. Carpenter W, Glick M, Nelson SR, Roser SM, Patton LL. American of low-dose combination oral contraceptive with ampicillin and Dental Association Council on Access, Prevention and Interprofessional metronidazole. Contraception 1980;22(6):643-52. Relations. Women’s Oral Health Issues. November 2006:1-39. 27. Back DJ, Breckenridge AM, MacIver M et al. The effects of ampicillin Available: http://www.ada.org/sections/professionalResources/ on oral contraceptive steroids in women. Br J Clin Pharmacol pdfs/healthcare_womens.pdf Accessed September 28, 2013. 1982;14:43-8. 50. Dickinson BD, Altman RD, Nielsen NH, Sterling ML. Council on 28. Grimmer SFM, Allen WL, Back DJ et al. The effect of cotrimoxazole Scientific Affairs, American Medical Association. Drug interactions on oral contraceptive steroids in women. Contraception 1983;28(1):53- between oral contraceptives and antibiotics. Obstet Gynecol 9. 2001;98(5):853-60. 29. Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect 51. World Health Organization. Medical Eligibility Criteria for Dis 1990;12:Suppl 1:S327-S333. Contraceptive Use, 4th edition. 2010:1-125. Available: http:// 30. London BM, Lookingbill DP. Frequency of pregnancy in acne patients whqlibdoc.who.int/publications/2010/9789241563888_eng.pdf taking oral antibiotics and oral contraceptives. [Letter.] Arch Dermatol Accessed: September 22, 2013. 1994;130:392-3. 52. U.S. Medical Eligibility Criteria for Contraceptive Use, 2010: adapted 31. Meyer B, Müller F, Wessels P, Maree J. A model to detect interactions from the World Health Organization Medical Eligibility Criteria for between roxithromycin and oral contraceptives. Clin Pharmacol Ther Contraceptive Use, 4th edition. Morbidity and Mortality Weekly 1990;47:671-4. Report (MMWR). 2010;59(May 28):1-86. Available: http://www.cdc. 32. Dijke CPH, Weber JCP. Interaction between oral contraceptives and gov/mmwr/pdf/rr/rr59e0528.pdf Accessed September 22, 2013. griseofulvin. [Letter.] Br Med J 1984;288:1125-6. Available: http:// 53. Ortho tri-cyclen® tablets, Ortho-cyclen® tablets (norgestimate/ www.bmj.com/highwire/filestream/262848/field_highwire_article_ ethinyl estradiol). Physicians’ package insert. Available: http://www. pdf/0/1125.2.full.pdf Accessed September 25, 2013. accessdata.fda.gov/drugsatfda_docs/label/2005/021690lbl.pdf 33. Back DJ, Orme ML’E. Pharmacokinetic drug interactions with oral Accessed September 27, 2013. contraceptives. Clin Pharmacokinet 1990;18(6):472-84. 54. Contraceptives/Penicillins. Available: http://www.webmd.com/ 34. Murphy AA, Zacur HA, Charache P, Burkman RT. The effect of drugs/drug-154480-Heather+Oral.aspx?drugid=154480&drugname= tetracycline on levels of oral contraceptives. Am J Obstet Gynecol Heather+Oral&dmid=177&dmtitle=CONTRACEPTIVES/PENIC 1991;164:28-33. ILLINS&intrtype=DRUG&pagenumber=9 Accessed September 28, 35. Neely JL, Swinker, D’Angio R. The effect of doxycycline on 2013. serum levels of ethinyl estradiol, norethindrone, and endogenous 55. Taylor J, Pemberton MN. Antibiotics and oral contraceptives: new con- progesterone. Obstet Gynecol 1991;77:416-20. siderations for dental practice. Br Dent J 2012;212(10):481-3. Available: 36. Dogterom P, van den Heuvel MW, Thomsen T. Absence of http://www.exodontia.info/files/BDJ_2012._Antibiotics_Oral_ pharmacokinetic interactions of the combined contraceptive vaginal Contraceptives_-_New_Considerations_for_Dental_Practice.pdf ring NuvaRing with oral amoxicillin or doxycycline in two randomised Accessed September 22, 2013. trials. Clin Pharmacokinet 2005;44(4):429-38. 56. Helms SE, Bredle DL, Zajic J et al. Oral contraceptive failure rates and 37. Toh S, Mitchell AA, Anderka M et al. Antibiotics and oral contraceptive oral antibiotics. J Am Acad Dermatol 1997;36(5):705-10. failure – a case-crossover study. Contraception 2011;83(5):418- 57. Centers for Disease Control and Prevention. Contraception: how 25. Available: http://www.ncbi.nlm.nih.gov/pmc/articles/ effective are birth control methods? Available: http://www.cdc. PMC3326585/pdf/nihms-367784.pdf Accessed September 21, 2013. gov/reproductivehealth/unintendedpregnancy/contraception.htm 38. Archer JSM, Archer DF. Oral contraceptive efficacy and antibiotic Accessed September 28, 2013. interaction: a myth debunked. J Am Acad Dermatol 2002;46:917- 23. Available: http://depts.washington.edu/hmcderma/OCPs.pdf Accessed September 28, 2013. 39. Back DJ. Evaluation of Committee on Safety of Medicines yellow card Author Profile reports on oral contraceptive-drug interactions with anticonvulsants and antibiotics. Br J Clin Pharmac 1988;25:527-32. Michael Wahl, DDS practices general dentistry in Wilm- 40. DeRossi SS, Hersh EV. Antibiotics and oral contraceptives. Dent ington, Delaware and received his undergraduate and dental Clin North Am. 2002 Oct;46(4):653-64. Available: http://student. ahc.umn.edu/dental/coursearchives/3yr_Summer/DENT5701/ degrees from Case Western Reserve University. He has Antibiotics%20and%20Oral%20Contraception.pdf Accessed published over 50 articles in many dental and medical jour- September 28, 2013. nals and lectured at many major national and international 41. Coskey RJ. Tetracycline and oral contraceptives [Letter]. J Am Acad Dermatol 1981;5:222. meetings on dental treatment of medically compromised pa- 42. Becker DE. Drug interactions in dental practice: a summary of facts tients, amalgam and composite, and practice management, and controversies. Compend Contin Educ Dent 1994;15:1228-43. 43. Jones v. United States, 933 F.Supp. 894, 902 n. 15 (N.D.Cal.1996). among other topics. He is a part-time assistant attending Available: http://scholar.google.com/scholar_case?case=1729963248 dentist at Christiana Care Health System. He can be reached 8188472512&q=antibiotic+interaction+contraceptive+%22wrongful+ life%22&hl=en&as_sdt=2,8 Accessed September 27, 2013. at [email protected] . 44. LaCasa C. California court denies wrongful birth claim. J Law Med Ethics 1996;24(3):273-4. 45. Jones v. United States, 127 F. 3d 1154 - Court of Appeals, 9th Circuit Author Disclosure 1997. Available: http://scholar.google.com/scholar_case?case=65 Michael Wahl, DDS has no commercial ties with the spon- 74005872458831894&q=related:wOxHMxekFPAJ:scholar.google. com/&hl=en&as_sdt=2,8 Accessed September 22, 2013. sors or providers of the unrestricted educational grant for 46. American College of Obstetricians and Gynecologists. ACOG this course.

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Questions

1. The history of modern birth control 9. Which of the following classes of drugs a. Rifampin can be traced back to 3000 BC, when have been implicated in oral contraceptive b. Penicillin condoms were made out of which of the failure due to drug interactions? c. Tetracycline following materials? a. Anticonvulsants d. All of the above a. Fish bladders b. Antidepressants 18. Scientific studies have failed to show b. Linen sheaths c. Vitamins lowered contraceptive efficacy when c. Animal intestines d. All of the above which of the following antibiotics are also d. All of the above 10. Unlike other antibiotics, rifampin is a given? 2. Who was a birth control activist who potent a. Fluoroquinolones helped reproductive physiologist Gregory a. Enzyme-inducer b. Penicillins Pincus obtain a grant to begin contracep- b. Macrolide c. Sulfa drugs tive research in 1951? c. Fluoroquinolone d. All of the above a. Eleanor Roosevelt d. All of the above 19. Scientific studies have failed to show b. Gloria Steinem 11. When a lawsuit occurs because of failure lowered contraceptive efficacy when which c. Margaret Sanger to warn of a possible interaction between of the following antibiotics are also given? d. None of the above an antibiotic and oral contraceptive, a. Antifungals b. Macrolide antibiotics 3. In 1951, the Food and Drug Administra- rendering the contraceptive less effica- cious, what is a common legal theory for c. Griseofulvin tion approved an oral contraceptive for d. All of the above which of the following? such a case? a. Morning after pill a. Wrongful death 20. Scientific studies have failed to show b. Wrongful birth b. Menstrual disorders lowered contraceptive efficacy when c. Res ipsa loquitor c. Birth control which of the following antibiotics are also d. None of the above d. None of the above given? 12. Which of the following international or a. Rifampin 4. In 1960, the Food and Drug Administra- national health organizations assert that b. Tetracycline tion approved an oral contraceptive for there is no scientific evidence supporting c. Both a & b which of the following? an interaction between non-rifampin d. None of the above a. Morning after pill antibiotics and oral contraceptives? 21. A problem with anecdotal reports of b. Menstrual disorders a. World Health Organization unintended pregnancies due antibiotic c. Birth control b. Centers for Disease Control interaction with oral contraceptives can d. None of the above c. American College of Obstetricians and Gynecolo- be which of the following? 5. When first approved by the Food and gists a. Some patients were taking other medications Drug Administration, the pill was d. All of the above concomitantly available to 13. The typical use failure rate of oral b. No information on whether any doses of contracep- a. Unmarried women in all states contraceptives is about tive were missed b. Married women in all states a. Less than 1 % c. The pregnancies may have been within the normal c. All women in all states b. 1% failure rate of the contraceptive d. All of the above d. None of the above c. 4% 6. The theoretical mechanism for decreased d. 9% 22. To support his assertion that dentists contraceptive efficacy with antibiotic 14. The average teenager who uses oral should recommend additional contracep- interaction is which of the following? contraceptives misses how many pills a tive methods when prescribing antibiotics a. Decrease in normal gut flora that normally increase cycle? for women on oral contraeptives, how many scientific studies did Dr. Wynn cite bioavailability a. 1 in his 2001 article and response to a letter b. Increase in normal gut flora that normally decrease b. 2 challenging the assertion? bioavailability c. 3 a. None c. Decrease in normal gut flora that normally decrease d. 4 b. One bioavailability 15. Regardless of drug interactions, which of c. Two d. Increase in normal gut flora that normaly increase the following causes decreased efficacy of d. Three bioavailability oral contraceptives? 23. Which of the following is a valid legal 7. How many women worldwide use birth a. Vomiting defense for a dentist sued in a malpractice control pills? b. Diarrhea suit? c. Both a & b a. Between 1 million and 2 million a. Playing it safe b. Between 10 million and 20 million d. None of the above b. Doing what’s best for the dentist c. Between 50 million and 100 million 16. For which of the following conditions is c. Doing what’s best for the patient d. More than 100 million rifampin prescribed? d. All of the above 8. Which of the following ingredients are a. Tuberculosis 24. From 1973 to 1984, how many usually found in modern oral contracep- b. AIDS prescriptions for antibiotics not including tives? c. Methicillin-resistant staphylococcal infections rifampin were there in England? a. Estrogen d. All of the above a. 3 million b. Progestin 17. Which of the following antibiotics has b. 30 million c. Both of the above been scientifically shown to lower oral c. 300 million d. None of the above contraceptive efficacy? d. Over 300 million

www.ineedce.com 9 Questions

25. From 1968 to 1984, how many preg- a. The plaintiff’s experts cited anecdotal reports and 29. What was the subsequent disposition of nancies in women on oral contraceptives not scientific studies to support the theory that Karen T. Jones and Chris Jones v. United and antibiotics not including rifampin penicillin interfere with antibiotics States of America? were there in England? b. Under California law, practitioners are not a. Affirmed by the US Supreme Court a. 63 required to discuss risks of very low incidences b. Affirmed by the Ninth Circuit Court of b. 163 c. Anecdotal reports are not evidence Appeals c. 630 d. All of the above d. 1630 c. Overturned by the US Supreme Court 28. In Karen T. Jones and Chris Jones v. d. Overturned by the Ninth Circuit Court of 26. In both England and the United States, United States of America, the plaintiff Appeals comparing the numbers of non-rifampin asserted that the oral contraceptive antibiotic prescriptions versus the package insert proved that an interaction 30. What is the possible legal liability for numbers of pregnancies on women on a dentist who warns a patient being oral contraceptives and non-rifampin would occur if pencillin were prescribed. antibiotics leads to what conclusion? What was the judge’s response to this of a potential interaction with oral a. The pregnancy rate suggests it was the result of the assertion? contraceptives when an antibiotic is normal expected failure rate of oral contraceptives a. “The inclusion of a boilerplate warning on a drug prescribed? b. The pregnancy rate suggests unintended package insert is scientific proof of causation.” a. The dentist is immunized from a malpractice pregnancies are a frequent result of non-rifampin b. “The inclusion of a boilerplate warning on a lawsuit drug package insert may reflect no more than an antibiotic interaction with oral contraceptives b. It is possible that the patient could sue the c. The pregnancy rate suggests that rifampin does overly cautious response to possible liability, not dentist if the patient relies on the warning to not interact with oral contraceptive efficacy scientific proof of causation.” d. None of the above c. “The inclusion of a boilerplate warning on a stop taking the antibiotic and an infection 27. In Karen T. Jones and Chris Jones v. drug package insert carries the same weight as gets worse United States of America, the judge a scientific study published in a peer-reviewed c. The patient could sue the dentist for an ruled in favor of the oral surgeon and journal.” unwanted pregnancy gynecologist because d. All of the above d. None of the above

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