Abstract
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) can impact family planning because it can result in reduced fertility, increased risks of adverse pregnancy outcomes, and a 50% inheritance risk. This study explored considerations of people with ADPKD regarding family planning.
Methods
This prospective cohort study included patients from the “Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) observational study. We analyzed patient demographics, disease characteristics, and reproductive outcomes. Patients with children were grouped by whether ADPKD influenced their family size, with a specific focus on females. Childless patients were categorized as voluntarily or involuntarily childless, within a subgroup of nonsingle individuals over 27 years. Univariable and multivariable regression were conducted to identify characteristics of patients dissatisfied with their family size.
Results
Among 696 patients (60% female), 462 (66%) had children. Of these, 35 (12%) reported that ADPKD had influenced their desired family size. Among childless individuals, 16 (23%) were involuntarily childless. Those reporting the influence of ADPKD on family size were more often female, had hypertensive pregnancy complications, and a Mayo classification class D or E. Involuntarily childless patients were more likely to report reduced fertility, be older, and have a family member with end-stage kidney disease (ESKD).
Conclusion
Women with ADPKD were significantly more likely than men to report that ADPKD influenced their family size. Disease severity and pregnancy complications were associated with perceived influence. These results highlight the need for physicians to consider factors affecting family planning and to provide comprehensive counselling on reproductive health and genetic testing options.
Keywords: autosomal dominant polycystic kidney disease, family planning, fertility, pregnancy, reproductive health
Graphical abstract
ADPKD is the most common hereditary kidney disease, affecting men and women equally.1,2 This progressive disorder is characterized by the development of cysts in the renal parenchyma, which leads to kidney enlargement and a decline in kidney function.3 Clinical manifestations include hypertension, hematuria, abdominal pain, and increased susceptibility to urinary tract infections. At about the sixth decade, half of patients would eventually have developed ESKD,3,4 and ultimately, approximately 85% of affected individuals need kidney replacement therapy. Owing to the combination of hypertension and impaired kidney function, the incidence of cardiovascular events is also higher in these patients than in the general population. The disease course is highly variable, some patients develop ESKD before their fourth decade.5 In general, individuals with a PKD1 mutation are more likely to have a worse prognosis, especially when it is a truncating mutation.2,6 The Mayo classification system, which ranges from class A to class E, indexes height-adjusted total kidney volume for age and generally predicts kidney function endpoints, with higher classes (D and E) indicating a more severe prognosis.7
Patients with ADPKD are often diagnosed during or even before their reproductive years, which can influence family planning.7 Conceiving might be challenging because of hormonal changes associated with impaired kidney function, sperm abnormalities, or sexual dysfunction.8 When kidney function has declined, pregnancy itself comes with increased risks for both mother and child, such as hypertensive disorders of pregnancy, preterm delivery, and fetal growth restriction.7,9 Even concerns about potential pregnancy complications may affect family planning decisions.10 ADPKD is unique among most other forms of chronic kidney disease (CKD) because of its autosomal dominant inheritance pattern, meaning there is a 50% chance of passing ADPKD to their offspring.1 The possibility of parents passing on a genetic disease to their child adds another dimension to family planning, especially when they have seen their relatives needing dialysis and/or kidney transplantation with potential related problems.3,11
As per the World Health Organization's definition, family planning is the process that allows people to attain their desired number of children, if any, and to determine the spacing of their pregnancies.12 It is achieved through use of contraceptive methods and the treatment of infertility. For patients with ADPKD, advancements in the field of reproductive technology and genetic testing can play a big role in the decision-making process, if adequately discussed by physicians during counselling.13 The patient’s perspective on family planning is not well-studied but could contribute to improving personalized preconception counselling. Therefore, the aim of this study was to explore considerations of people with ADPKD regarding family planning and investigate sociodemographic and disease-related factors that influence this process.
Methods
Patient Population
Recruitment
We used data of the DIPAK observational cohort study, which is a multicenter initiative that aims to investigate the natural course of ADPKD in an unselected patient population.14,15 Individuals were recruited from the outpatient clinics of 4 participating University Medical Centers in the Netherlands (Groningen, Leiden, Nijmegen, and Rotterdam) from 2013 and is still ongoing. Participants were enrolled in the study after meeting the inclusion criteria of the DIPAK observational cohort study and completing the baseline assessments. A full list of eligibility criteria is available in the Supplementary Material: Inclusion and Exclusion Criteria.
Subgroup Formation
We conducted our analyses in 3 different subgroups, to examine factors associated with the outcomes “having children,” “experienced influence of ADPKD on family size,” and “involuntarily childlessness.”
Having Children
We first stratified the study population into those with children and those without children. Given the clear association between age, relationship status, and the likelihood of having children, as stated in previous research16 and as observed in our own exploratory analyses, we focused this analysis on nonsingle individuals aged ≥ 27 years.
Influence of ADPKD on Family Size
Among patients with children, we further divided the group into those who reported that ADPKD had influenced their family size and those who did not. This analysis was restricted to individuals with children. Considering that previous analyses identified the significant role of sex, we focused on females for the primary analysis; the results for males are provided in the Supplementary Material.
Involuntary Childlessness
We stratified the group without children based on their response to the question “Are you involuntarily childless?.” Similar to the previous analysis, we restricted this subgroup to nonsingle individuals aged ≥ 27 years. Although nowadays it is increasingly possible for individuals without a partner to pursue parenthood, this study focused exclusively on partnered individuals.
Data Collection
Patients filled out questionnaires at the baseline visit of the DIPAK study to obtain information on disease-specific factors, pregnancy outcomes, and family planning components. Data that were extracted for this study included patient characteristics, ADPKD-related history and events, and self-reported information about reproductive health and family planning. Reduced fertility and pregnancy outcomes were derived solely from self-reported data, which may not necessarily align with clinical criteria. To investigate satisfaction with family size, we asked the questions “Did ADPKD influence the size of your family” for those with children and “Are you involuntarily childless?” for those without children.
Outcomes
Primary Aim
The primary aim of this study was to explore considerations of people with ADPKD regarding family planning. To explore this aim, we examined and described factors such as anticonception use, number of children, self-reported fertility problems, and satisfaction with family size.
Secondary Outcomes
In addition, we explored patient characteristics affecting satisfaction with family size, considering sociodemographic and disease-related factors. Furthermore, we compared our findings with data from the general Dutch population.17
Statistical Analyses
We summarized the characteristics of the overall study population. Categorical variables were presented as absolute numbers with corresponding percentages, continuous variables were described using mean (SD) or median (interquartile range). The relationships between our outcomes were assessed using univariable and multivariable regression analyses. Variables significantly associated in the univariable analyses were included in the multivariable models. To address potential multicollinearity, one of each correlated pair was excluded based on clinical relevance and model diagnostics. In the final model for “influence of ADPKD on family size,” age at diagnosis and mutation type were excluded, because age and Mayo Class were already included. In the final model for involuntary childlessness, we excluded reduced fertility because of its strong but predictable association with involuntary childlessness, aiming instead to identify less obvious contributing factors.
To compare the occurrence of involuntary childlessness in our cohort with the general population, we used a 1-sample z test for proportions. To assess the distribution of children per person across different age groups in our cohort versus the general Dutch population, we employed Fisher exact test, focusing on the proportions of individuals with 0, 1, 2, 3, or 4 children. A P value ≤ 0.05 was considered statistically significant. All analyses were performed using R version 4.3.1.18
Results
Demographic data were collected of 696 individuals, of whom the majority had children (n = 462, 66%) and were female (n = 416, 60%). There was a 99% (n = 457) response rate in the group of patients with children, when asked if they experienced influence from ADPKD on the size of their family. After excluding individuals who did not answer this question and all male participants, 283 individuals remained for analysis. Of these, 35 participants (12%) reported that ADPKD had influenced the size of their family. For participants without children, 71 remained for analysis after excluding those who did not respond to the question “Are you involuntarily childless?” as well as those aged < 27 years or single. Of these, 16 individuals (23%) reported being involuntarily childless. Patient selection is displayed in Figure 1.
Figure 1.
Flow diagram displaying patient selection. ADPKD, autosomal dominant polycystic kidney disease; DIPAK, Developing Intervention Strategies to Halt Progression of Autosomal Dominant Polycystic Kidney Disease.
Baseline characteristics are summarized in Table 1 for the primary cohort. Patients without children were more often younger at the study baseline, single, attained a higher level of education, had a lower income, were younger at the time of diagnosis, had a higher estimated glomerular filtration rate, less often had hypertension, had a smaller liver volume, and more often a less favorable Mayo class compared with the group with children.
Table 1.
Demographics of the study population (n=696), stratified by having children or not having children
| Characteristics | Overall | With child (ren) | Without children | P value |
|---|---|---|---|---|
| Number of individuals | 696 | 462 | 234 | |
| Sex, n (%) | 0.171 | |||
| Male | 280 (40) | 177 (38) | 103 (44) | |
| Female | 416 (60) | 285 (62) | 131 (56) | |
| Mean age, yrs (SD) | 47 (12) | 50 (10) | 42 (13) | <0.001 |
| Age category in yrs, n (%) | <0.001 | |||
| 18–30 | 71 (10) | 10 (2) | 61 (26) | |
| 31–40 | 127 (18) | 84 (18) | 43 (18) | |
| 41–50 | 214 (31) | 157 (34) | 57 (24) | |
| 51–65 | 250 (36) | 181 (39) | 69 (30) | |
| 65+ | 34 (5) | 30 (7) | 4 (2) | |
| Number of children, n (%)a | NA | |||
| 0 | 234 (34) | 0 (0) | 234 (100) | |
| 1 | 94 (13) | 94 (20) | 0 (0) | |
| 2 | 248 (36) | 248 (54) | 0 (0) | |
| 3+ | 120 (17) | 120 (26) | 0 (0) | |
| Marital status, n (%) | <0.001 | |||
| Single | 113 (16) | 23 (5) | 90 (38) | |
| Has a partner | 491 (71) | 404 (87) | 87 (37) | |
| Had a partner | 43 (6) | 34 (7) | 9 (4) | |
| Missing | 49 (7) | 1 (0) | 48 (21) | |
| Ethnicity, n (%) | 0.272 | |||
| Caucasian | 627 (90.1) | 440 (95.2) | 187 (80) | |
| Other | 32 (4.6) | 19 (4.1) | 13 (6) | |
| Missing | 37 (5.3) | 3 (0.6) | 34 (14) | |
| Highest level of education, n (%) | 0.002 | |||
| Primary education / secondary education | 123 (18) | 88 (19) | 35 (15) | |
| Vocational education | 165 (24) | 133 (29) | 32 (14) | |
| Applied sciences/University | 312 (45) | 204 (44) | 108 (46) | |
| Missing | 96 (14) | 37 (8) | 59 (25) | |
| Working situation, n (%) | 0.144 | |||
| Working | 429 (62) | 295 (64) | 134 (57) | |
| In between jobs | 23 (3) | 16 (3) | 7 (3) | |
| Not working | 71 (10) | 56 (12) | 15 (6) | |
| Retired | 48 (7) | 40 (9) | 8 (3) | |
| Other | 73 (10) | 53 (12) | 20 (9) | |
| Missing | 52 (8) | 2 (0) | 50 (21) | |
| Monthly income per household, n (%) | <0.001 | |||
| < 2800 euro | 253 (36) | 149 (32) | 104 (44) | |
| > 2800 euro | 278 (40) | 222 (48) | 56 (24) | |
| I would rather not say/ I do not know | 91 (13) | 73 (16) | 18 (8) | |
| Missing | 74 (11) | 18 (4) | 56 (24) | |
| Mean age at the time of diagnosis, yrs (SD) | 33 (13) | 34 (13) | 30 (14) | <0.001 |
| Hypertension, n (%) | 577 (83) | 320 (77) | 257 (92) | 0.002 |
| Median eGFR, ml/min per 1.73 m2[IQR] | 58 [40, 85] | 55 [38, 80] | 71 [46, 96] | <0.001 |
| Mayo class, n (%) | <0.001 | |||
| A | 36 (5) | 29 (6) | 7 (3) | |
| B | 136 (20) | 102 (22) | 34 (15) | |
| C | 224 (32) | 150 (33) | 74 (32) | |
| D | 128 (18) | 80 (17) | 48 (21) | |
| E | 72 (10) | 32 (7) | 40 (17) | |
| Atypical | 28 (4) | 20 (4) | 8 (3) | |
| Missing | 72 (10) | 49 (11) | 23 (10) | |
| Mean height adjusted total kidney volume, L (SD) | 1.11 (0.91) | 1.13 (0.93) | 1.08 (0.87) | 0.476 |
| Mean liver volume, L (SD) | 2.54 (1.57) | 2.6 (1.60) | 2.37 (1.49) | 0.040 |
| DNA mutation category, n (%) | 0.056 | |||
| PKD2b | 166 (24) | 117 (25) | 49 (21) | |
| PKD1 nontruncatingc | 178 (26) | 128 (28) | 50 (21) | |
| PKD1 truncating | 270 (39) | 162 (35) | 108 (46) | |
| No mutation detected | 32 (5) | 21 (4) | 11 (5) | |
| No test performed | 23 (3) | 17 (4) | 6 (3) | |
| Missing | 27 (4) | 17 (4) | 10 (4) |
eGFR, estimated glomerular filtration rate; IQR, interquartile rage.
Including 4 individuals who mentioned their child(ren) were adopted.
Uncommon mutations were added to the PKD2 group.
If it was unclear whether the PKD1 mutation was truncating or nontruncating, it was classified as nontruncating.
We performed a univariable logistic regression analysis in all nonsingle individuals aged > 27 years (Supplementary Table S1). Having a PKD1 truncating mutation (odds ratio [OR]: 0.51 [0.26, 0.94], P = 0.037) and having a relative younger than 55 years old with ESKD (OR: 0.55 [0.31, 1.00], P = 0.044) were significantly associated with a lower likelihood of having children. After including these variables in the multivariable model, the PKD1 truncating mutation remained significantly associated (OR: 0.47 [0.21, 0.96], P = 0.047).
Individuals With Children
Female patients with children were divided by whether they experienced the influence of ADPKD on family size (Table 2). No differences were observed in self-reported reduced fertility between the groups (13% vs. 12% of respondents, P = 1.0). The median number of children was lower in the group that experienced the influence of ADPKD on family size than in the group that did not (1 [1,2] vs. 2 [2,3], respectively, P < 0.001). Regarding pregnancy outcomes, complications were more prevalent in the ADPKD-influenced group, although this difference was not statistically significant (54% vs. 46%, P = 0.25). The incidence of hypertensive disorders was also greater in the ADPKD-influenced group (40% vs. 24%, P = 0.06), and the rate of miscarriages was higher, although not statistically significant (26% vs. 17%, P = 0.16).
Table 2.
Items of reproductive health, among 283 females with children. Stratified by perceived influence of ADPKD on family size
| Reproductive characteristics | With children |
P value | |
|---|---|---|---|
| No influence of ADPKD | Influence of ADPKD | ||
| Number of individuals | 248 | 35 | |
| Median age of menarche, yrs [IQR] | 13 [12, 14] | 13 [12, 14] | 0.064 |
| Menopause, n (%) | 0.094 | ||
| Yes | 113 (46) | 12 (34.3) | |
| No | 97 (39) | 21 (60.0) | |
| Missing | 38 (15) | 2 (5.7) | |
| Reduced fertility, n (%) | 1.000 | ||
| Yes | 19 (8) | 3 (9) | |
| No | 133 (54) | 22 (63) | |
| Missing | 96 (39) | 10 (29) | |
| Anticonception use, n (%) | 0.064 | ||
| Yes | 41 (17) | 12 (34) | |
| No | 54 (22) | 8 (23) | |
| Not applicablea | 113 (46) | 12 (34) | |
| Missing | 40 (16) | 3 (9) | |
| Anticonception form, n (%) | 0.002 | ||
| Oral contraceptives | 16 (6) | 1 (3) | |
| Condom | 8 (3) | 0 (0) | |
| Hormonal IUD | 13 (5) | 9 (26) | |
| Copper IUD | 2 (1) | 1 (3) | |
| Other | 6 (2) | 1 (3) | |
| Not applicablea | 113 (46) | 12 (34) | |
| Missing | 90 (36) | 11 (31) | |
| Duration of anticonception use, yrs mean (SD) | 15.56 (9.03) | 20.75 (7.27) | 0.279 |
| Gravidity, n (%) | 0.095 | ||
| 1 | 30 (12) | 9 (26) | |
| 2 | 100 (40) | 11 (31) | |
| 3+ | 106 (43) | 14 (40) | |
| Missing | 12 (5) | 1 (3) | |
| Median number of children [IQR] | 2 [2, 3] | 1 [1, 2] | < 0.001 |
| Complication during pregnancy, n (%) | 0.250 | ||
| Yes | 115 (46) | 19 (54) | |
| Pregnancy induced hypertension, n (%) | 0.063 | ||
| Yes | 60 (24) | 14 (40) | |
| Miscarriage, n (%) | 0.158 | ||
| Yes | 43 (17) | 9 (26) | |
| Number of miscarriages, mean (SD) | 1.44 (0.77) | 1.12 (0.35) | 0.259 |
| Planning to have (more) children, n (%) | 1.000 | ||
| Yes | 9 (4) | 1 (3) | |
| No | 235 (95) | 32 (91) | |
| Missing | 4 (2) | 2 (6) | |
ADPKD, autosomal dominant polycystic kidney disease; IQR, interquartile range; IUD, intrauterine device.
Not applicable: females who have already reached menopause.
We performed a univariable logistic regression to analyze patient characteristics of those who experienced the influence of ADPKD on family size, the results are presented in Table 4. Females were 6 times more likely to report that they experienced the influence of ADPKD on the size of their family than men (OR: 6.00 [2.34, 20.34], P < 0.001), after which we continued with a female-only population. Age at baseline (OR: 0.95 [0.91, 0.99], P = 0.008) and age at diagnosis (OR: 0.91 [0.87, 0.95], P < 0.001) were both significantly associated with experiencing the influence of ADPKD. Patients with both the more severe disease characteristics of having a PKD1 truncating mutation and having Mayo class D or E were more likely to have experienced the influence of their disease on family size (OR: 3.39 [1.21, 12.12], P = 0.033; and OR: 2.92 [1.23, 6.74, P = 0.013, respectively). Women who experienced a hypertensive pregnancy complication were more than twice as likely to report that ADPKD influenced their family size (OR: 2.62 [1.06, 6.93], P = 0.042). The results of male participants are shown in Supplementary Table S2.
Table 4.
Overview of univariable and multivariable logistic regression results with the outcome variable being having experienced influence of ADPKD on family size
| Variables | Univariable |
Multivariable |
||
|---|---|---|---|---|
| Odds ratio [95% CI] | P value | Odds ratio [95% CI] | P value | |
| Age at baseline | 0.95 [0.91, 0.99] | 0.008 | 0.98 [0.92, 1.05] | 0.586 |
| Education (reference is primary/secondary school) | ||||
| Vocational education | 1.50 [0.54, 4.57] | 0.452 | ||
| Applied sciences/University | 1.21 [0.45, 3.59] | 0.716 | ||
| Income (reference is lower than 2800 euros monthly) | ||||
| Higher than 2800 euros monthly | 2.21 [0.96, 5.55] | 0.074 | ||
| I don’t know/I don’t want to share | 1.57 [0.49, 4.80] | 0.430 | ||
| Age at diagnosis | 0.91 [0.87, 0.95] | <0.001 | ||
| eGFR | 0.99 [0.98, 1.01] | 0.443 | ||
| Mayo class (reference is A/B/C/Atypical) | ||||
| Mayo class D/E | 2.92 [1.23, 6,74] | 0.013 | 3.27 [1.03, 10.49] | 0.043 |
| Hypertension (reference is not having hypertension) | 1.10 [0.46, 3.07] | 0.841 | ||
| Polycystic liver disease | 1.31 [0.60, 2.81] | 0.486 | ||
| Height adjusted total kidney volume | 1.20 [0.65, 2.00] | 0.491 | ||
| Mutation (reference is PKD2) | ||||
| PKD1 nontruncating | 2.40 [0.74, 9.22] | 0.163 | ||
| PKD1 truncating | 3.39 [1.21, 12.12] | 0.033 | ||
| No test performed | 2.03 [0.10, 16.05] | 0.548 | ||
| Reduced fertility (reference is not having reduced fertility) | ||||
| Reduced fertility | 0.95 [0.21, 3.11] | 0.944 | ||
| Pregnancy complication (reference is not having any pregnancy complications) | ||||
| Pregnancy complication (any complication) | 1.82 [0.78, 4.58] | 0.179 | ||
| Hypertension during pregnancy (reference is not having hypertension during pregnancy) | ||||
| Hypertension during pregnancy | 2.62 [1.06, 6.93] | 0.042 | 3.74 [1.24, 13.10] | 0.026 |
| Miscarriage (reference is not having 1 or more miscarriages) | ||||
| Miscarriage(s) | 2.35 [0.84, 6.68] | 0.100 | ||
| Relative with ESKD (reference is not having a relative with ESKD) | ||||
| Having a relative with ESKD | 0.68 [0.29, 1.50] | 0.357 | ||
| Relative with ESKD aged <55 yrs (reference is not having a relative with ESKD aged <55 yrs) | ||||
| Having a relative with ESKD aged < 55 yrs | 0.33 [0.05, 1.19] | 0.146 | ||
ADPKD, autosomal dominant polycystic kidney disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease.
The analysis population includes females with children (n = 283). The mean (SD) age of those reporting such influence (n = 35) was 44.1 (8.4), compared with those without influence (n = 248) who had a mean (SD) age of 49.0 (10.0). A total of 148 patients had complete data available for inclusion in the multivariable analysis.
In the final multivariable model, Mayo class D or E (OR: 3.27 [1.03, 10.49], P = 0.043) and having experienced hypertensive pregnancy complications (OR: 3.74 [1.24, 13.10], P = 0.026) remained significantly associated with the perceived influence of ADPKD on family size.
At the end of the questionnaire, there was an opportunity for the 35 patients in the ADPKD-influenced group to report in what ways their disease was of influence. They were provided with a list of multiple-choice options and space for open-ended responses, allowing them to select or provide multiple answers. In total, 59 responses were received. The most frequently reported reason was the fear of passing on a hereditary condition, cited by 19 respondents (32% of reported reasons, but 54% of respondents). The second most common response (n = 12, 20%), was that their physicians had advised against having additional children. Ten women (17%) expressed concerns about a potential decline in their (kidney) health, which led them to avoid further pregnancies. Fear of pregnancy complications, whether because of previous experiences, was mentioned by 7 respondents (12%). In addition, 4 patients (7%) cited concerns about cyst growth, and another 4 (7%) mentioned personal reasons. Other reasons included the need for certain teratogenic medications, lack of hope for a cure in the near future, and difficulty conceiving, each reported by 1 respondent (2%) (Figure 2).
Figure 2.
Reported reasons for experiencing influence of ADPKD on family size, among 35 females with children that reported such influence. ADPKD, autosomal dominant polycystic kidney disease.
Individuals Without Children
The childless participants in our cohort were divided between those who stated to be voluntarily childless and those who stated to be involuntarily childless. Their characteristics are displayed in Table 3. As many as 56% of respondents in the involuntarily childless group reported that they had some form of reduced fertility, which was higher than in the voluntarily childless group (12%).
Table 3.
Items of reproductive health, among 71 individuals without children over the age of 27 and nonsingle
| Reproductive characteristics | Without children |
P value | |
|---|---|---|---|
| Voluntarily childless | Involuntarily childless | ||
| Number of individuals | 55 | 16 | |
| Median age of menarche, yrs [IQR] | 13 [12, 15] | 12 [11, 13] | 0.159 |
| Menopause, n (%) | 0.063 | ||
| Yes | 14 (25) | 8 (50) | |
| No | 11 (20) | 0 (0) | |
| Not applicablea | 25 (46) | 7 (44) | |
| Missing | 5 (9) | 1 (6) | |
| Reduced fertility, n (%) | 0.011 | ||
| Yes | 5 (9) | 5 (31) | |
| No | 37 (67) | 4 (25) | |
| Missing | 13 (24) | 7 (44) | |
| Anticonception use, n (%) | 0.163 | ||
| Yes | 9 (16) | 0 (0) | |
| No | 1 (2) | 0 (0) | |
| Not applicableb | 39 (71) | 15 (94) | |
| Missing | 6 (11) | 1 (6) | |
| Anticonception form, n (%) | 0.350 | ||
| Oral contraceptives | 4 (7) | 0 (0.0) | |
| Condom | 0 (0) | 0 (0.0) | |
| Hormonal IUD | 4 (7) | 0 (0.0) | |
| Copper IUD | 0 (0) | 0 (0.0) | |
| Other | 1 (2) | 0 (0.0) | |
| Not applicableb | 39 (71) | 15 (94) | |
| Missing | 7 (13) | 1 (6) | |
| Duration of anticonception use, years mean (SD) | 14.89 (4.81) | NaN (NA) | NA |
| Gravidity, n (%) | 0.285 | ||
| 0 | 20 (36) | 5 (31) | |
| 1 | 4 (7) | 0 (0) | |
| 2 | 2 (4) | 1 (6) | |
| 3+ | 0 (0) | 1 (6) | |
| Not applicablea | 25 (45) | 7 (44) | |
| Missing | 4 (7) | 2 (13) | |
| Complication during pregnancy, n (%) | 0.136 | ||
| Yes | 1 (2) | 2 (13) | |
| Pregnancy induced hypertension, n (%) | 0.674 | ||
| Yes | 1 (2) | 0 (0) | |
| Miscarriage, n (%) | 0.136 | ||
| Yes | 1 (2) | 2 (13) | |
| Number of miscarriages, mean (SD) | NaN (NA) | 2.50 (0.71) | NA |
| Planning to have (more) children, n (%) | 1.000 | ||
| Yes | 1 (2) | 0 (0) | |
| No | 2 (4) | 1 (6) | |
| Missing | 52 (95) | 15 (94) | |
IQR, interquartile rage; IUD, intrauterine device; NA, not available.
Not applicable: males.
Not applicable: males and postmenopausal females.
In Table 5, a summary of our logistic regression analyses is presented. Individuals who self-reported reduced fertility were over 9 times more likely to be involuntarily childless (OR: 9.25 [1.89, 50.75], P = 0.007). Among disease-specific factors, estimated glomerular filtration rate (OR: 0.97 [0.95, 1.00], P = 0.046) was significantly associated with involuntary childlessness. In addition, age at baseline showed a significant association (OR: 1.11 [1.04, 1.20], P = 0.005). Patients with a family history of ESKD had more than 5 times the likelihood of being involuntarily childless (OR: 5.16 [1.48, 21.23], P = 0.014).
Table 5.
Overview of univariable and multivariable regression results with the outcome variable being involuntarily childlessness
| Variables | Univariable |
Multivariable |
||
|---|---|---|---|---|
| Odds ratio [95% CI] | P value | Odds ratio [95% CI] | P value | |
| Sex (reference is male) | ||||
| Female | 1.07 [0.35, 3.39] | 0.904 | ||
| Age | 1.11 [1.04, 1.20] | 0.005 | 1.11 [1.01, 1.22] | 0.034 |
| Marital status (reference is: has a partner) | ||||
| Had a partner | 3.33 [0.73, 14.56] | 0.106 | ||
| Education (reference is primary/secondary school) | ||||
| Vocational education | 1.67 [0.24, 11.85] | 0.597 | ||
| Applied sciences/University | 0.63 [0.14, 3.33] | 0.553 | ||
| Weekly working hours | 0.96 [0.92, 1.02] | 0.169 | ||
| Income (reference is < 2800 euros monthly) | ||||
| More than 2800 euros monthly | 0.38 [0.10, 1.36] | 0.141 | ||
| Income–I don’t know/I don’t want to share | 2.43 [0.37, 16.23] | 0.341 | ||
| Age at diagnosis | 1.03 [0.99, 1.08] | 0.167 | ||
| eGFR | 0.97 [0.95, 1.00] | 0.046 | 1.00 [0.96, 1.03] | 0.821 |
| Mayo class (reference is A/B/C/Atypical) | ||||
| D/E | 0.72 [0.18, 2.47] | 0.611 | ||
| Hypertension (reference is not having hypertension) | ||||
| Having hypertension | 3.75 [0.64, 71.44] | 0.224 | ||
| Height adjusted total kidney volume | 1.06 [0.54, 1.88] | 0.860 | ||
| Polycystic liver disease | 1.52 [0.45, 4,87] | 0.485 | ||
| Mutation (reference is PKD2) | ||||
| PKD1 nontruncating | 0.78 [0.35, 4.78] | 0.713 | ||
| PKD1 truncating | 0.82 [0.15, 4.87] | 0.774 | ||
| Reduced fertility (reference is not having reduced fertility) | ||||
| Reduced fertility | 9.25 [1.89, 50.75] | 0.007 | ||
| Relative with ESKD (reference is not having a relative with ESKD) | ||||
| Having a relative with ESKD | 5.16 [1.48, 21.23] | 0.014 | 6.29 [1.60, 30.72] | 0.013 |
| Relative with ESKD aged < 55 yrs (reference is not having a relative with ESKD aged < 55 yrs) | ||||
| Having a relative with ESKD aged < 55 yrs | 3.23 [0.84, 13.05] | 0.088 | ||
CI, confidence interval; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease.
The analysis population includes individuals without children, over the age of 27 who are not single (n = 71).
The mean (SD) age of those voluntarily childless (n = 55) was 45.8 (10.7), compared with those involuntarily childless (n = 16), who had a mean (SD) age of 55.4 (9.6). A total of 63 patients had complete data available for inclusion in the multivariable analysis.
After performing a preliminary analysis, which showed that reduced fertility was strongly associated with involuntary childlessness, we excluded reduced fertility from the final multivariable logistic regression model to better identify other contributing factors. In this final model, age (OR: 1.11 [1.01, 1.22], P = 0.034) and having a relative with ESKD (OR: 6.29 [1.60, 30.72], P = 0.013) were significantly associated with involuntary childlessness.
Comparison With the General Population
We obtained data from the general Dutch population,19 regarding the percentage of postmenopausal women who are involuntarily childless and have attempted to conceive. To facilitate a direct comparison with our cohort, we performed a subgroup analysis concentrating on postmenopausal women who either had children or reported being involuntarily childless. This analysis included 161 women from our cohort, with 10 (6%) identifying as involuntarily childless. Comparing this proportion with the 4% reported by Statistics Netherlands for the general population, a 1-sample z test for proportions indicated no significant difference (P = 0.152).
We compared the number of children conceived per person per age group with data of the general Dutch population and found no significant differences between the 2 populations. Specifically, there were no differences observed in the proportions of individuals with 0, 1, 2, 3, or 4 children, with 1 marginally significant difference in the proportion with 1 child in individuals aged 55 to 65 years. These results are summarized in Figure 3 and Supplementary Table S3.
Figure 3.
The number of children per age group in our ADPKD (DIPAK) cohort versus the general Dutch population. ADPKD, autosomal dominant polycystic kidney disease; DIPAK, Developing Intervention Strategies to Halt Progression of Autosomal Dominant Polycystic Kidney Disease.
Discussion
To our knowledge, this is the largest study to explore family planning in patients with ADPKD from the patient's perspective. We included almost 700 patients of which the majority had children. A substantial number of patients reported not to have reached their ideal family size because of their disease. Those who reported to have experienced negative influence of ADPKD on family size were more likely to be female, to have a Mayo class D or E, and to have experienced hypertensive pregnancy complications. In addition, those who reported to be involuntarily childless were more likely to have self-reported reduced fertility, to be older, and to have a relative with ESKD (Figure 4).
Figure 4.
Patient characteristics of individuals who are more at risk of not reaching their desired number of children. Characteristics included in the figure are the factors that remained significantly associated with the outcome in the multivariable regression analyses. ADPKD, autosomal dominant polycystic kidney disease; ESKD, end-stage kidney disease.
Our study shows that 12% of female patients with children were unable to achieve their desired family size because of ADPKD. In this group, we observed a higher rate of self-reported adverse pregnancy outcomes, which may explain why further attempts at family expansion were either unsuccessful or not undertaken. These findings are in agreement with several other studies that describe an increase in pregnancy complications in patients with ADPKD or CKD in general,20, 21, 22, 23 which tends to worsen as kidney function declines. Notably, hypertensive complications are more common in all women with ADPKD21 than in the general population, regardless of kidney function. The health risks associated with pregnancy for female patients with ADPKD likely explain why the impact of ADPKD on family size is more frequently reported by women in our cohort, as reflected in Figure 2. Conversely, only 4 men (2%) reported that ADPKD affected their family size. This discrepancy may be attributed to the absence of direct health risks related to having children for men with ADPKD, or it could reflect a lower concern about family size or adverse effects among men than among women in general. In addition, although medication use, particularly tolvaptan, was hypothesized to influence family planning because of teratogenic risks, it was not mentioned in open-ended questions or frequently cited in Figure 2. Similarly, no significant associations were found with liver volume or cyst bleeds, suggesting that liver involvement may be less relevant than other factors in reproductive decision-making.
In our cohort, 23% of childless individuals reported that their childlessness was involuntary. Those that were involuntarily childless were older, which may reflect advances in reproductive health over time. With innovations in fertility treatments, more options are now available to address subfertility in both men and women, further enhancing the prospects for those seeking to conceive. Although much of the focus has been on women's reproductive health, it is important to recognize that men also face involuntarily childlessness (n=10 in our cohort), because of factors such as reduced sperm quality and hormonal changes because of low kidney function.8 In addition, individuals past their reproductive years may feel more comfortable identifying their childlessness as involuntary than younger individuals who are still trying. The association between involuntary childlessness and having a family member with ESKD, rather than factors such as Mayo class or mutation type, could be due to the more tangible and impactful nature of witnessing the disease's progression in a relative.11,24 However, further qualitative research is needed to explore this and other potential contributing factors in depth.
This is not the first study to explore family planning among patients with ADPKD. A recent qualitative study25 investigated reproductive health in the ADPKD population through focus groups. They found that disease severity and family history significantly influence family planning decisions, aligning with our findings. Similarly, a Chinese study examined fertility intentions among 260 patients with ADPKD who are of childbearing age. Consistent with our results, genetic concerns emerged as the primary reason for not wanting children.
Our study builds on these findings by incorporating a larger cohort and including individuals beyond childbearing age. This broader inclusion offers unique insights from patients who have concluded their reproductive decision process. Unlike studies that focus exclusively on intentions, our research captures the outcomes of patient choices, providing a more comprehensive perspective on family planning in the context of ADPKD.
We searched for data from the general Dutch population to identify the number of women who did not get the desired number of children. We obtained information from a national survey conducted by Statistics Netherlands,19 which revealed that 7% of women who had their first child between 1995 and 1999 were unable to have additional children despite wanting them. However, this survey was conducted in 2000, which complicates direct comparisons with our cohort. In recent years, women tend to have their first child later in life,26 which can further reduce their chances of conceiving and could partially explain why we observed a much larger proportion of women dissatisfied with family size. Statistics Netherlands also reports that 4% of women born between 1945 and 1965 who actively tried to conceive were unsuccessful and became involuntarily childless, compared with the 6% observed in females with the same age-demographics in our cohort.
When we compared our findings to data from the general Dutch population, we found no differences in the number of children per person per age group. This observation differs from previous research that has compared birth rates between the general population and individuals with all-cause CKD,27 where they found lower birth rates in women with CKD than in the general population. One possible explanation for this discrepancy is the difference in the patient populations included in these studies. Our cohort consists exclusively of a group of relatively unselected patients with ADPKD, male and female; whereas the Swedish cohort included female-only patients with all-cause CKD with an estimated glomerular filtration rate < 60 ml/min per 1.73 m2, potentially selecting a more severely affected population; and therefore resulting in lower birth rates, whereas several studies show that patients with ADPKD who are at reproductive age tend to have a relatively preserved kidney function, and are expected to have comparable fertility rates and live births as the general population.21,28,29 A comparison with a CKD population would have provided additional insights; however, we were unable to identify a CKD cohort with directly comparable outcomes.
One strength of this study is that we had access to a large and well-phenotyped cohort, consisting of nearly 700 patients with ADPKD in whom prospectively comprehensive information on family planning was collected. In addition, we utilized data from national registries to compare and validate our findings. Our study has some limitations. Our cohort consists of patients who were recruited from university medical centers; this may not fully represent the broader ADPKD population, potentially limiting the generalizability of our findings. Because most questionnaires were completed on paper, some patients accidentally skipped questions. In addition, we relied on patient characteristics recorded at the baseline of the DIPAK observational study; it is possible that these characteristics may differ at the time of family planning. Nevertheless, certain factors, such as Mayo class30 and mutation type, would remain consistent. Lastly, the survey design itself using questionnaires rather than interviews is another limitation. Although this enables a large sample size, it restricted the depth of questioning and left room for potential misinterpretation. Future research could consider gaining a more comprehensive understanding of these processes using a qualitative approach.
Conclusion
Women with ADPKD were significantly more likely than men to report that ADPKD impacted their family size. Our findings indicate that this perceived influence is correlated with disease severity and pregnancy complications. In addition, involuntary childlessness was predominantly observed among older individuals and those who reported reduced fertility. The presence of a relative with ESKD was associated with childlessness, suggesting that witnessing the disease's progression in a relative may influence decisions about whether or when to pursue family planning.
When we compared our findings with those of the general population, we observed similar birthrates but slightly higher levels of dissatisfaction with family size, primarily driven by concerns about the potential transmission of the disease to offspring and fears regarding the patient’s own declining health. Especially considering advancements in reproductive health and genetic testing, we encourage physicians to provide comprehensive counselling for patients with ADPKD. It is essential to support patients in the family planning process by informing them about all available options, allowing them to make informed choices about their reproductive health.
Appendix
List of the DIPAK Consortium
J.P.H. Drenth, J.W. de Fijter, D.J.M. Peters, M. Salih, E.J. Hoorn, and T. Nijenhuis
Disclosure
All the authors declared no competing interests.
Acknowledgments
We thank all participating patients for their willingness to participate in the DIPAK Observational Cohort and their openness to discuss sensitive topics such as family planning. We would like to extend our special thanks to Ms. Brenda de Coninck, one of the participants, for reading this manuscript and giving more valuable insights from the patient’s perspective.
Footnotes
Inclusion and Exclusion Criteria.
Table S1. Overview of univariable and multivariable logistic regression results with the outcome variable being the presence of 1 or more children.
Table S2. Overview of univariable logistic regression results with the outcome variable being having experienced influence of ADPKD on family size.
Table S3. Overview of the mean and median number of children in both the DIPAK population and the general Dutch population, by age category.
Contributor Information
Willemijn A.L. Vrijlandt, Email: w.a.l.vrijlandt@umcg.nl.
DIPAK Consortium:
J.P.H. Drenth, J.W. de Fijter, D.J.M. Peters, M. Salih, E.J. Hoorn, and T. Nijenhuis
Supplementary Material
Inclusion and Exclusion Criteria. Table S1. Overview of univariable and multivariable logistic regression results with the outcome variable being the presence of 1 or more children. Table S2. Overview of univariable logistic regression results with the outcome variable being having experienced influence of ADPKD on family size. Table S3. Overview of the mean and median number of children in both the DIPAK population and the general Dutch population, by age category.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Inclusion and Exclusion Criteria. Table S1. Overview of univariable and multivariable logistic regression results with the outcome variable being the presence of 1 or more children. Table S2. Overview of univariable logistic regression results with the outcome variable being having experienced influence of ADPKD on family size. Table S3. Overview of the mean and median number of children in both the DIPAK population and the general Dutch population, by age category.