Female Reproductive And Gynecologic Considerations in Chronic Kidney Disease: Adolescence And Young Adulthood Ⅰ
May 11, 2024
Chronic kidney disease (CKD) increasingly affects younger people, including adolescents and young adults. CKD among females is accompanied by unique reproductive and gynecologic health concerns; though to date, this area has not been well studied. Hormonal disruptions attributed to CKD may underlie the high prevalence of abnormal uterine bleeding and influence the age of menarche in adolescents. Period poverty as a socioeconomic barrier further exacerbates the female-specific burdens of CKD.
Reduced fertility in CKD is likely multifactorial and may be related to a reduction in ovarian reserve, reproductive hormone disturbances, and gonadotoxic medication use in addition to low sexual function and activity. Fertility, sexual function and activity, and risk of sexually transmitted infections increase with transplantation. Pregnancy is possible at any stage of CKD, although often accompanied by high risks of maternal and fetal complications. Contraception is thus an important consideration in CKD, but use is low and the risks and benefits of different forms in the setting of CKD are not well characterized. Though patients with CKD report reproductive health as an important element of care, many nephrologists report a lack of confidence and training in this area, highlighting the need for targeted research and education. The unique reproductive health care needs of the growing transgender youth population warrant attention in nephrology training with multidisciplinary input. This review will discuss female reproductive health and gynecologic considerations in adolescents and young adults with CKD while proposing clinical and research strategies to improve this understudied yet important aspect of kidney care.
HOW LONG DOES IT TAKE FOR CISTANCHE TO WORK?
The prevalence of CKD in children is steadily increasing, with a higher incidence of kidney replacement therapy in adolescents compared with other age groups worldwide.1 Although the most common causes of kidney disease at a global level are hypertension and diabetes,2,3 childhood onset of kidney disease is most frequently due to congenital abnormalities and hereditary disorders.4–7 The reduced rate of congenital abnormalities of the kidney and urinary tract among females may help to explain the lower incidence of CKD compared with males in the adolescent population.8 Furthermore, compared with the adult population, glomerulonephritides are a more common cause of CKD in children, particularly in the adolescent population after puberty.4,8
CKD in the female population is often accompanied by abnormal uterine bleeding, sexual dysfunction, reduced fertility, and higher-risk pregnancies.9,10 Commonly used immunosuppressive medications (e.g., cyclophosphamide, mycophenolate mofetil) for autoimmune glomerular disorders, which disproportionately affect females, have important implications for uterine bleeding, fertility, and the potential for fetal malformations.11 According to the North American Pediatric Renal Trials and Collaborative Studies database, adolescents represent the largest pediatric kidney transplant recipients.12 Although CKD is associated with increased abnormal uterine bleeding,13– 15 kidney transplantation, at least in the adult population, may restore uterine bleeding.15,16 Kidney transplantation guidelines17,18 discourage pregnancy in females for the first year post-transplant owing to the risk of allograft rejection and pregnancy complications. Finally, pregnancy itself can have a detrimental and permanent impact on kidney function.19,20 Taken together, these multiple factors underscore the critical value of providing reproductive care to all females living with CKD, including adolescents who require individualized care during this phase of physiological
and social transition. This narrative review will broadly summarize female reproductive and gynecologic considerations in the care of the adolescent and young adult populations with CKD.
Methods
To provide a summary of female reproductive and gynecologic health among adolescents with CKD, the first author (DHC) searched 2 electronic sources, MEDLINE and Google Scholar. The terms "reproductive health" or "gynecology" in combination with "chronic kidney disease," "chronic renal insuffi- ciency," "end-stage kidney disease," "chronic renal failure," "dialysis," "transplant," and "nephrology" and other related terms helped identify relevant literature. The terms "contraception," "menstruation," "sexual dysfunction," and "adolescent" in combination with the same Medical Subject Headings were also searched in MEDLINE. These searches were completed by May 2021. Reference lists from relevant articles were hand-searched, and the search was further supplemented by key articles from nephrologists with expertise in women's health (SBA and SMD). Priority for inclusion in this review was given to original articles reporting original data (i.e., observational studies as randomized control trials were lacking), clinical practice guidelines, and systematic reviews.
Kidney Disease and the Menstrual Cycle
The menstrual cycle encompasses the time between the first day of uterine bleeding to the next first day of uterine bleeding,21 and a healthy menstrual cycle lasts 24 to 38 days with bleeding occurring for #8 days (on average, 5 days).22 Details regarding the healthy menstrual cycle are outlined elsewhere.21,23
In CKD, disruption of the hypothalamic-pituitary-ovarian axis results in an abnormal reproductive hormone profile, where the degree of disruption increases with CKD progression (Figure 1).13,14,24 As such, those with kidney failure are believed to have the most severe hormonal disruptions, and most studies have been conducted in this population.13,24 In kidney failure, the pulsatile release of gonadotropin-releasing hormone is impaired, resulting in a lack of follicle-stimulating hormone and luteinizing hormone cyclicity.13 Consequently, estradiol levels stay relatively low, inhibiting the surge and ovulation of the luteinizing hormone. Elevated prolactin levels owing to reduced clearance and increased production also contribute to annulation.13,24,25 A possible mechanism of hormonal abnormalities in kidney failure is that high prolactin levels negatively feed back into the hypothalamic-pituitary-ovarian axis and inhibit gonadotropin-releasing hormone secretion, thus preventing gonadotropin release resulting in abnormal uterine bleeding.26–28 In a prospective study of 57 female adolescents with stage 4 CKD and kidney failure treated with hemodialysis and peritoneal dialysis, 49% had hyperprolactinemia.29 When comparing participants with and without menstrual disturbances, prolactin levels were higher in those with menstrual disturbances.29
Kidney Disease and Age of Menarche
Menarche is the first occurrence of uterine bleeding and the beginning of the female reproductive lifespan. Among healthy adolescents, the median age of menarche is approximately 12 to 13 years.30,31 Multiple factors are associated with the onset of menarche in the general population. An inverse association between body mass index,32–34 height, and weight35 with age of menarche has been found. Earlier menarche is reported among those living with anyone other than a family consisting of 2 biological parents,33,36–38 though study results vary regarding the impact of low socioeconomic status on early36,38,39 and late33 onset of menarche. Urban residence and Black race/ethnicity have been associated with earlier menarche, although these differences may or may not be in part attributed to socioeconomic status.33,34,38,40 Increasing reports reveal associations between both early and late menarche and adverse health outcomes, including the risk of cardiovascular disease, CKD, and overall mortality.41–43
Figure 1. Hypothalamic-pituitary-ovarian axis in females with kidney disease. From Ahmed SB, Ramesh S. Sex hormones in women with kidney disease. Nephrology Dialysis Transplantation, 2016, volume 31, issue 11, pages 1787–1795 ª The Author(s). Published by Oxford University Press on behalf of the ERA-EDTA. All rights reserved.26 CKD, chronic kidney disease; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.
Given the multiple factors associated with the onset of menarche, it is challenging to elucidate the association, if any, between CKD and the onset of uterine bleeding. In a prospective cohort study of 57 female adolescents with stage 4 CKD and kidney failure treated with hemodialysis and peritoneal dialysis, Serret-Montaya et al.29 reported a median age of menarche of 12 years after the exclusion of participants with primary amenorrhea. The primary causes of CKD were glomerulonephritis (22.8%) and congenital abnormalities of the kidney and urinary tract (22.8%), and most participants had a healthy nutritional status. Although the median age of menarche was similar in those with and without abnormal uterine bleeding, information including estimated glomerular filtration rate, ethnicity, and socioeconomic status was not reported. In a cross-sectional study of 287 girls with CKD onset before menarche, the median age of menarche was 12 years, though 10% had delayed menarche (defined as menarche at $15 years), which was associated with African-American race, lower estimated glomerular filtration rate, corticosteroid use, and longer CKD duration, concluding delayed menarche may suggest a risk of short stature.44
From the perspective of nephrologists, being aware of the age of menarche is an important consideration as the American Academy of Pediatrics has suggested that the menstrual cycle is a vital sign in female patients.31 Nevertheless, in a study of 75 nephrologists (95% pediatric, 5% adult) practicing in the United States and Puerto Rico, Vasylyeva et al.45 reported that 17% never/ rarely documented the age of menarche of adolescent patients and more than a third never/rarely documented the date of the patient's last menstrual period. This discrepancy highlights the need for nephrologists to take comprehensive menstrual histories, including the age of menarche, to consider this sex-specific factor in the care of adolescents living with kidney disease.
Kidney Disease and Abnormal Uterine Bleeding
Abnormal uterine bleeding is defined as any disruption of a healthy menstrual cycle in terms of the volume of blood loss, duration, frequency, and regularity of menses.22 Abnormal uterine bleeding, particularly irregular or long ($40 days) menstrual cycles, has been associated with premature mortality in comparison to regular or short cycles in the general population.46 Abnormal uterine bleeding is also associated with absenteeism in school and work.47–49 In the general population of reproductive-aged women, the estimated prevalence of abnormal uterine bleeding is at least 10% to 30%,50 whereas heavy menstrual bleeding affects 30% of women throughout their reproductive lifespan.51 Heavy menstrual bleeding is defined as the loss of $80 ml of blood on each menstrual cycle, which is clinically indicated by 1 or more of the following factors: bleeding that lasts >7 days, bleeding that soaks through $1 menstrual product every hour for several hours, bleeding that requires simultaneous use of multiple menstrual products to manage flow, bleeding that requires a change of menstrual product during the night, or the presence of blood clots at least the size of a quarter.52,53 Abnormal duration of menses includes prolonged (>8 days) and shortened (<3 days) uterine bleeding, whereas the abnormal frequency of menses includes infrequent (>38 days apart) and frequent (<24 days apart) uterine bleeding.22 Absent uterine bleeding is defined by an absence of menses for 90 days, and irregular uterine bleeding is defined by variation in cycle length by $10 days.
Among adolescents in the general population, the prevalence of heavy, infrequent, and absent menstrual bleeding is reported as 34%, 20%, and 8%, respectively.54 Nevertheless, information on abnormal uterine bleeding is sparse in the adolescent CKD population. A prospective cohort study found that >50% of adolescent girls with stage 4 CKD and kidney failure treated with dialysis reported abnormal uterine bleeding.29 Moreover, although 54% reported regular menstrual cycles at baseline, only 47% reported regular menses a year after. Nevertheless, in premenopausal adult female populations with CKD, the prevalence of abnormal uterine bleeding is high and becomes increasingly common with disease progression.13,14,24 In a small study of 17 women aged 18 to 42 years with kidney failure treated with hemodialysis, only 1 woman reported regular uterine bleeding, whereas 6 reported irregular uterine bleeding, and 10 had absent uterine bleeding.13 In a cross-sectional study of women <55 years of age with kidney failure treated with hemodialysis and peritoneal dialysis,14 58% reported the absence of uterine bleeding. Furthermore, most of the menstruating women experienced irregular uterine bleeding, which was most often heavy menstrual bleeding. Abnormal uterine bleeding, especially heavy menstrual bleeding, is an important consideration in the CKD population, as potential implications include worsening anemia, increasing the need for erythropoietin-stimulating agents, and blood transfusions.24,55 This may be especially relevant for those in need of a kidney transplant, given the risk of sensitization. 24 A retrospective cohort study of 129 women with kidney failure (aged 41.6 14.2 years with follow-up for 9.5 10.2 years) treated with dialysis or kidney transplantation and followed by a gynecologist,15 78.7% had regular uterine bleeding before dialysis, though this decreased to 30.6% after dialysis initiation. The remaining participants reported infrequent (26%) or absent (43%) uterine bleeding after dialysis initiation.
We are unaware of any specific treatment regimens for abnormal uterine bleeding that differentiate between stages of CKD. Nevertheless, possible treatment for abnormal uterine bleeding must be balanced with the risks of worsening patients' kidney health and evaluation of their comorbidities, contraindications, preferences, and suitability for adolescents and young adults. Hormone therapy using progestin-only or combined estrogen-progestin hormonal contraception can temporarily improve uterine bleeding.56 For instance, with the progestin-only intrauterine device, injectable, and subdermal implant, some individuals experience a cessation of bleeding after months to a year of use despite initially having irregular and/or heavy bleeding.53,56–58 The combined oral contraceptive pill, transdermal patch, and vaginal ring can also regulate bleeding, and if used continuously without hormone-free weeks (i.e., long/extended-cycle use), they can prevent uterine bleeding and related symptoms.57,59 It is important to note, however, that estrogen-containing options increase thrombotic risk.59 Tranexamic acid, danazol therapy, gonadotropin-releasing hormone agonists, and nonsteroidal anti-inflammatory medications are additional treatment options, though risks and timelines of use must be assessed carefully in the context of CKD, especially with the latter.56
Though abnormal uterine bleeding is prevalent in the context of kidney disease, a study consisting of largely pediatric nephrologists from the United States and Puerto Rico reported that almost 90% were not at all confident/somewhat confident in managing abnormal uterine bleeding.45 In addition, in a study of adult nephrologists from the United States and Canada, more than 65% of the respondents reported a lack of confidence in women's health issues, including menstrual disorders,60 whereas only 15% reported discussing menstrual irregularities with their patients.61 These findings highlight a gap in knowledge about the gynecologic care of female patients with CKD and underscore the need for accessible educational resources and training for nephrologists in this important area of patient care.
Kidney Disease and Period Poverty
Period poverty is defined as a lack of knowledge about uterine bleeding and an inability to access menstrual products,62 serving as a socioeconomic, cultural, and political barrier. CKD is associated with significant socioeconomic disparities,63,64, and period poverty only exacerbates the economic toll of CKD. Menarche and menstrual management are fundamental aspects of adolescent female health,65 but a lack of education and resources leads to challenges with menstrual management, leaving female adolescents to deal with stigma, shame, fear, and anxiety; for some, there are direct effects on education, health, and wellbeing.66 Period poverty results in some young people missing up to a fifth of their school year.67 Coupled with missing school for medical appointments, adolescents with CKD may be at greater risk of absenteeism, leading to grade retention, academic underachievement, and interruption of studies, all compromising their psychosocial well-being and quality of life.68,69 Finally, although no studies are focusing on period poverty among menstruating individuals with CKD, socioeconomic position and country income level may also influence one's access to safe menstrual products and hygiene management facilities.63,64,70–72
