Female Reproductive And Gynecologic Considerations in Chronic Kidney Disease: Adolescence And Young Adulthood Ⅱ

Kidney Disease and Sexual Activity and Function 

Adolescents with CKD tend to experience a later onset of puberty68 and initiate sexual intercourse at a later age compared with the general age-matched population.73 American adolescents with CKD are less likely to report ever having sex compared with age-, gender-, and race-matched high school students, and they became sexually active at a later age than controls (26.7% versus 41.6%; mean SD 15.1 1.6 versus 14.6 1.6 years, respectively). The percentage of participants having $2 partners and/or engaging in unprotected gender or using alcohol or illicit drugs during gender were comparable in the 2 groups.73 Nevertheless, whether these results differ by sex and gender is unknown.

HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK FOR SEXUAL ENHANCEMENT?

Sexual dysfunction in females is defined as loss of libido, reduced vaginal lubrication, and inability to orgasm, including vaginismus, dyspareunia, and infertility.74 In the United States, almost 30% of high school students reported being sexually active, 75,76 with nearly 50% of young females reporting sexual dysfunction.77 The prevalence of sexual dysfunction in the adolescent CKD population is unknown. In the adult CKD population, a systematic review found that 30% to 80% of women with CKD reported sexual dysfunction and scored lower overall and in each domain of the Female Sexual Function Index questionnaire compared with healthy women.78 In a cross-sectional study of 106 women under the age of 50 years,79 rates of female sexual dysfunction were highest in the CKD group (81%) and lowest among kidney transplant recipients (50%). In a prospective cohort study of 39 women (mean age 36 5.9 years) with kidney failure treated with hemodialysis for more than 6 months,16 41% reported an active sexual life compared with 88% after kidney transplantation, in conjunction with improved reproductive hormone profiles and Female Sexual Function Index scores. Factors that may affect sexual function in the CKD population include the adverse psychosocial effects of having a chronic illness, depression, anxiety, and negative body image.78,80,81 Physical challenges, such as decreased libido and vaginal lubrication, orgasmic impairment, and dyspareunia, are common among women with CKD, whereas comorbidities and sociodemographic factors can exacerbate the risk.78,79,81,82

Kidney Disease and Sexually Transmitted Infections

Youth aged 15 to 24 years account for approximately half of new sexually transmitted infection (STI) cases in the United States,83,84 and it is estimated that 1 of 4 sexually active adolescent females have an STI, most often Chlamydia trachomatis infection and human papillomavirus (HPV) infection. Adolescents in general are particularly at risk for STIs from both behavioral and biological standpoints. Adolescents are more likely to engage in high-risk sexual behaviors, such as having concurrent partners or sex without a condom. From a biological perspective, adolescent females are particularly susceptible to STIs, such as Chlamydia trachomatis and HPV, because of lower production of cervical mucus and increased cervical ectopy.85

For many adolescents living with kidney disease, the nephrologist functions as the primary care provider and may be the only contact to perform STI screening and reproductive health counseling.86 A high index of suspicion for STIs is particularly important in transplant recipients owing to their maintenance of immunosuppressant medications. In a single-center, American, retrospective medical record review study of all pediatric transplant recipients aged 13 years and older (n ¼ 49) spanning up to 11 years of follow-up, more than half of adolescent female kidney transplant recipients reported being sexually active, 75% of those sexually active reported using hormonal contraception, and 37.5% had had at least 1 STI.87 STIs identified in this study included gonococcal and chlamydial urethritis/ cervicitis, Trichomonas vaginitis, herpes simplex virus 2 genital sores, pelvic inflammatory disease, and human immunodeficiency virus. Owing to the retrospective nature of the study, assessment of condom use was not possible.

Though not specifically studied in the pediatric population, the prevalence of syphilis was found to be significantly higher in the kidney failure population treated with dialysis.88,89 The incidence of syphilis in the adult kidney failure population is >3 higher than in the general population, and many affected patients had late-stage syphilis.90 Potential reasons for increased STI diagnoses include immunosuppression and recognizing that patients with kidney failure have a tremendous burden of symptoms that may prevent STI detection at an early stage. The apparent elevated rate of STIs among patients with CKD may suggest increased sexual activity; however, this has not been well studied in the CKD population.

There are no guidelines for primary prevention of STIs specific to adolescents with CKD; the Centers for Disease Control and Prevention recommends that this important aspect of health be incorporated into all types of healthcare visits for adolescents and young adults.91 HPV causes most of the cervical, anal/rectal, and oropharyngeal cancers in women. A US Renal Database System study of older women (mean age 65 years) between 2005 and 2011 revealed that the incidence of HPV-associated cancers in women with kidney failure is rising annually and is overall higher than in women of the general population.92 The incidence of HPV-associated cancers in younger female populations across the stages of CKD, however, is unknown.

In the United States, HPV vaccination is recommended through the age of 26 years for those not vaccinated previously at the routine age of 11 or 12 years.93 General recommendations concerning counseling adolescents on sexual behaviors include discussions surrounding risk-reduction behaviors (e.g., consistent and correct condom use and reduction in the number of sex partners, including concurrent partners). Unfortunately, pediatric and adult nephrologists practicing in the United States and Puerto Rico never/ rarely reported documenting patient sexual activity (29.5%), number of sexual partners (74.7%), and STI history (38.1%).45 Increasing the dialogue on sexual activity and STIs among adolescents with CKD is important to providing better care, considering the immunosuppressed states of patients.

Kidney Disease and Contraception

In a retrospective cohort study of 35,732 women receiving dialysis in the United States (115,713 person-years) aged 15 to 44 years from 2005 to 2014,94 the rate of contraceptive use was low at 5.3%, with the intrauterine device and oral contraceptive pill being the most common methods of contraception. Younger age, Native American and Black race/ethnicity, kidney failure owing to glomerulonephritis, kidney failure treatment with hemodialysis, and predialysis nephrology care were associated with a higher likelihood of contraceptive use. In a national survey evaludating high-risk behaviors in American adolescents with CKD, 54.8% of sexually active adolescents reported condoms as the most common contraception method, though whether use differed by sex and gender was not reported.73 Although the oral contraceptive pill is the second most common contraceptive used by adolescents in the general population in high-income countries,75,95 oral contraceptive use by adolescents with CKD is unknown.

The hormonal composition of contraceptive options is an important consideration in adolescent females with CKD (Figure 2). Estrogen-containing oral contraceptive pills are associated with increased risk of proteinuria,96–98 increased blood pressure,99,100 venous thromboembolism, arterial thrombosis,101 and cervical cancer,59,102 in part owing to activation of the renin-angiotensin-aldosterone system,82,96,99,100,103 and should be used with caution in people with CKD. Similar concerns on the estrogen-containing transdermal patch and vaginal ring also exist, though this has not been studied specifically in the population with CKD.59,104 Of note, bone mass accrual continues up to approximately age 25 years, and although there are conflicting data on the effects of estrogen-containing hormonal contraception on bone mineral density, there is currently no evidence supporting increased risks of osteoporosis or fracture among users.105,106 How estrogen-containing hormonal contraception may affect bone health in adolescents with CKD is unknown.

Long-acting reversible contraceptives, and specifically intrauterine contraception, are recommended by multiple international societies as the first line of contraception for adolescents owing to their low typical-use failure rates and high 1-year continuation rates.107–112 The Use of long-acting reversible contraceptives in the adolescent CKD population is unknown, but compared with estrogen-containing contraceptives, these progestin-only alternatives confer lower risks of venous thromboembolism in the general population.113 Clinical practice guidelines for contraception in kidney disease recommend that the progestin-only pill, progestin subdermal implant, and progestin intrauterdevice are safe and effective for women with CKD.114,115 In addition, the progestin-only injectable may be another contraceptive option as it confers lower thrombotic risks compared to estrogen-containing choices. Of note, there are older case reports of nonhormonal intrauterine devices being associated with peritonitis in women on peritoneal dialysis,116–118 though one study highlights this association with progestin intrauterine device use.119

As with the general adolescent population, contraception counseling in the adolescent population with CKD is of critical importance. Although most contraceptives are intended for use by females, it is imperative to highlight that contraception and the consequences of unprotected sex are important priorities to discuss with patients with CKD of all gender identities. Kidney healthcare providers play an important role in ensuring that adolescents with CKD have access to high-quality and safe reproductive healthcare services and contraceptive methods. Nevertheless, in surveys of 200 German and 196 American nephrologists, fewer than half report contraception counseling to adult women on dialysis.120,121 Nephrologists who do provide contraception or preconception counseling report counseling an average of <1 woman per month, citing lack of training and personal knowledge/confidence.60 In contrast, nearly two-thirds of nephrologists caring for adolescents with CKD report being very confident or confident in providing contraceptive counseling,45 although most reported being comfortable discussing barrier methods rather than other forms of contraception, such as long-acting reversible contraceptives, which are recommended as the first line of contraception among adolescents122 and are safe in CKD.123 Although a clinical practice guideline on pregnancy and kidney disease exists,114,115 increased attention is urgently required to aid nephrologists provide patient-centered and disease-specific contraceptive care. Especially for those taking teratogenic medications, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mycophenolate mofetil for the treatment of kidney disease, these patients must use contraception to avoid adverse pregnancy outcomes. Reports of congenital malformations after taking angiotensin-converting enzyme inhibitors,124 neonatal and long-term complications for fetuses exposed to angiotensin receptor blockers,125 and an elevated incidence of structural malformations with myopia note mofetil exposure during pregnancy126 highlight the need for effective contraception when pregnancy is not desired.

Figure 2. Contraceptive options and considerations for adolescent females with kidney disease. (Adapted from Ahmed et al., 82 Attini et al., 115 Sachdeva,101Watnick,104 and Wiles and Lightstone102). CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension; N/A, not available; SLE, systemic lupus erythematosus; VTE, venous thromboembolism.

Kidney Disease and Fertility Reduced fertility has been observed in the female CKD population compared with the general population,10 postulated secondary to multiple factors, including a reduction in ovarian reserve.9,127–129 Individuals with female biology are born with a finite number of ovarian follicles,130, and anti-Müllerian hormone (AMH), produced by preantral and small antral ovarian follicles, is the gold standard measure of ovarian reserve.131,132 As a woman's ovarian reserve naturally depletes with age, AMH levels also decline.130 AMH levels can be used to evaluate female fertility and menopausal status.9,133

We are unaware of any studies evaluating ovarian reserve in the adolescent population with CKD; however, AMH levels in women of reproductive age with CKD and kidney failure, particularly in those treated with kidney transplantation, seem to be lower compared with age-matched healthy individuals, suggesting a reduced ovarian reserve in women with CKD.127–129 Furthermore, in a prospective study of 46 females with kidney failure treated with hemodialysis, those with normal uterine bleeding had higher concentrations of AMH compared with those with abnormal uterine bleeding, and an unexpected decline in AMH level was found after kidney transplantation.128

Fertility can be negatively affected by treatment for CKD, such as cyclophosphamide.11 There is limited evidence that co-treatment with a gonadotropin-releasing hormone agonist may decrease the gonadaltoxicity of this alkylating agent.134–136 Therefore, fertility preservation is an important consideration for young patients undergoing gonadotoxic treatment. For females, options include cryopreservation and banking of oocyte, embryo, and ovarian tissue; preservation of fertility in the context of kidney disease has been reviewed in detail elsewhere.9,82 Assisted reproductive technologies, such as in vitro fertilization, seem to be safe in kidney transplant recipients,137–139 although we are unaware of related studies in the non-transplant CKD population.

It is also important to note nephrologists' communication of fertility status with their patients, especially if parenthood is considered a meaningful goal. Studies evaluating Canadian, American, and Puerto Rican pediatric and adult nephrologists found that most discussed the potential teratogenicity of medication and risks of infertility with cyclophosphamide use.45,60 One study found that 95% of respondents in an international survey of pediatric and adult nephrologists agreed that kidney function affects reproductive hormone status.61 Nevertheless, only 35% reported regularly discussing fertility with their patients. Although kidney disease affects the entire spectrum of reproductive health, frequent reproductive assessment, and counseling should become a common part of Nephrologists' practices.45,60,61

Transgender Individuals and Reproductive Care 

The proportion of transgender individuals (i.e., gender identity does not align with sex assigned at birth) has increased over time, where youth account for a large proportion of this group.140 Transgender adolescents have unique reproductive health care needs. A transgender boy or nonbinary individual requires gynecologic and reproductive care, including contraception counseling, and most transgender and gender-diverse adolescents with female biology express a desire to have children in the future.141 Despite this important consideration, information regarding the reproductive care of transgender boys and nonbinary individuals within the CKD context is lacking.

Conclusion

Female reproductive and gynecologic health in CKD, and particularly in adolescents, is an important yet understudied area. Kidney disease is associated with abnormal hypothalamic-pituitary-ovarian function. Abnormal uterine bleeding and low fertility are common. Although CKD is associated with high-risk pregnancy, contraceptive use is low in the setting of CKD. Despite the high prevalence of menstrual and fertility disorders, gynecologic and reproductive health is not often addressed by nephrologists with many reporting a lack of knowledge and confidence in this area. Providers should feel comfortable obtaining detailed sexual histories to properly counsel on and test for STIs, particularly given that CKD is an immuno-compromised state. With special considerations to the transition from pediatric to adult nephrology and the growing transgender youth population, focused training in these important areas of female health in addition to multidisciplinary collaborations is urgently required. We propose a "roadmap" to female reproductive kidney research and care (Figure 3). Large, prospective studies in addition to dedicated educational resources are required to equip kidney health care providers with the knowledge needed to provide patient-centered and disease-specific care that includes gynecologic and reproductive health.

 All the authors declare no competing interests. 

The authors gratefully acknowledge Sarah Gil and Alexa Desjarlais for the graphic design. DHC is supported by graduate scholarships from the Canadian Institutes of Health Research, the University of Calgary, and the Libin Cardiovascular Institute.

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