Article
Women’s health 2015: An update for the internist
Antidepressants in pregnancy, nonhormonal therapies for menopausal symptoms, and heart failure therapy.
OVARIAN CANCER SCREENING
A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?
Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.
Little benefit and considerable harm of screening
In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial25 randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.
Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.
A new UK study also found no benefit from screening
In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.
In a 2016 UK study,26 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.
Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.
Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.
Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.
Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.
Should our patient proceed with ovarian cancer screening?
No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.28 For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.29–31
REPRODUCTIVE FACTORS AND THE RISK OF DEATH
A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.
Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.
In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.32 Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.33
However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.34
The European Prospective Investigation Into Cancer and Nutrition
To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,35 which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.
Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.35
Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.
What should we tell this patient?
After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),36 after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.
As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,37 this patient will likely benefit from promptly starting a prescription contraceptive.
HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION
This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.
Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives38 and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.39
A study of intrauterine contraception
To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.40 Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.
Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.41
Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.
The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.42 If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.43
Subdermal implants
Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.44
Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.45 As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.
What should we tell this patient?
An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.
The only option more effective than these IUCs is subdermal contraception.46 These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)47 and can be removed at any time if a patient wishes to switch to another method or to become pregnant.
Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.48 The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.