With a focus on mild to moderate CKD in a Hispanic/Latino population, our study builds upon prior literature evaluating the impact of CKD on women’s fertility and reproductive health. An altered hypothalamic-pituitary-gonadal axis and uremic toxins are thought to produce a state of functional menopause in women with advanced CKD or requiring dialysis.[20–22] As such, impaired fertility with anovulatory cycles are common, and it is generally accepted that fertility declines in parallel with kidney disease progression. However, it is unclear what threshold of kidney impairment can be attributed to infertility. Taking into account comorbidities such as obesity and diabetes that are also known to be associated with menstrual irregularities and infertility,[23, 24] our study provides support that mild to moderate CKD may not be associated with increased risk.
Previous research has demonstrated that dysfunctional uterine bleeding, menorrhagia, and amenorrhea are common in women with advanced CKD.[3, 25, 26] Given this, we hypothesized that women with CKD may be at higher risk for undergoing hysterectomy compared to those without CKD. Unfortunately, the small number of events here limited statistical power. In a larger population, data from the Women’s Health Initiative found no difference in prevalence of hysterectomy in women with CKD vs women without CKD (1.2% vs 2.0%, p = 0.16) though women with CKD more likely to have had menopause before age 45 years (26% vs 23%, p = 0.02).
Spontaneous abortion, or miscarriage, is the most common complication in early pregnancy, and the incidence in clinically recognized pregnancies is between 8–20%.[28, 29] Well-known risk factors include maternal age over 35 years old, previous spontaneous abortion and maternal smoking, though minority women, including Hispanic/Latino women, may also be at higher risk for miscarriage. Our study seemed to suggest this as well, with 45.9% of parous women reporting at least one nonviable loss (pregnancy loss before 24 weeks). The rates of nonviable pregnancy loss in women with CKD are not well described. In those with advanced CKD or requiring dialysis, the blood urea nitrogen level is inversely related to the length of gestation and offspring’s birth weight. For those with milder CKD, it is unclear if mechanisms aside from uremic toxins increase risk of early loss. Although women who receive a kidney transplant can often see a rapid return of fertility, reported miscarriage rates range between 15.4–45% in this population.[31–33] In the general population, elevated preconception maternal blood pressure has been found to increase the risk of miscarriage. Though 30.7% of our CKD cohort were considered to have hypertension, it did not emerge as a strong confounder in our final model when assessing risk for nonviable pregnancy loss.
There are several limitations to our study. In our young, reproductive age women from the HCHS/SOL, CKD was mostly defined by an elevated UACR and was present in a small number (4.6% of women included), which ultimately limited the power of our analyses. While the percent of Hispanic/Latino women of reproductive age with CKD is largely unknown, prior literature has estimated CKD to affect 6% of all reproductive age women. To confirm true chronic kidney disease, we were able to utilize measurements from two study visits, approximately 6.2 years apart. However, borderline values in CKD measurements existed when using a strict cutoff estimated GFR of < 60 ml/min per 1.73 m2 and UACR ratio > 30 mg/g. To include mild CKD, we broadened our definition to include those with an estimated GFR < 60 ml/min per 1.73 m2 at one visit and < 70 ml/min per 1.73 m2 at another as we felt this was still a significantly low GFR to constitute CKD in this young population. We also included those with a UACR > 300 mg/g at either visit as this is considered a clinical cutoff for severely increased albuminuria which has been shown to be a risk marker for CKD progression.[35–37] Finally, we included women with a UACR > 30 mg/g at baseline visit while taking an ACE-I or ARB but UACR < 30 mg/g at the second visit, as we felt this discrepancy could be explained by the anti-proteinuric effects of the medications. Sensitivity analyses performed with a stricter definition of CKD as either an estimated GFR < 60 ml/min per 1.73 m2 or UACR > 30 mg/g at both visits (n = 96) showed similar odds ratios among women with CKD.
Importantly, the timing of CKD onset was unknown as we only had measurements from the baseline and second study visit. This may help account for why we did not see an increased risk for nonviable pregnancy loss occurring at any time but did see higher odds ratios in women with CKD when examining pregnancies that occurred specifically after baseline visit. Likewise, the specific dates of pregnancy losses were not provided and only reported as either before or after baseline visit. Thus, while pregnancy could have occurred very close to the baseline visit, for some individuals a nonviable pregnancy loss could have occurred many years prior to the baseline visit. We therefore cannot be fully certain that CKD specifically preceded the loss and as such, only prevalence odds ratios could be performed. Data from the Nurses’ Health Study II suggests that early pregnancy loss (especially those between 12–19 weeks) may be associated with increased risk for future type 2 diabetes, hypercholesterolemia, and hypertension. As such, it could be hypothesized that pregnancy loss may also contribute to future CKD by way of an increased burden of CKD risk factors.
Finally, the women’s health and reproductive outcomes gathered were self-reported and thus subject to recall bias and/or inaccurate reporting. While infertility was assessed in all women by asking whether they had “ever tried to become pregnant for greater than one year without success”, it is currently recognized that for women older 35 years old, this interval should be shortened to six months. Cessation of menses was assessed by asking whether natural periods had ended but this was not confirmed with biochemical evidence and does not include women who may be menstruating but having anovulatory cycles, a condition that is common in CKD.