Abstract
Rationale & Objective:
While there are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, evidence that they increase the risk of kidney stones during pregnancy is lacking. This study aimed to determine whether there was an increased risk of a first-time symptomatic kidney stone during and after pregnancy.
Study Design:
A population-based matched case-control study.
Setting & Participants:
945 female first-time symptomatic kidney stone formers aged 15–45 years and 1,890 age-matched female controls in Olmsted County, Minnesota from 1984–2012. Index date was the date of onset of a symptomatic kidney stone for both the case and their matched controls.
Exposure:
The primary exposure was pregnancy with assessment for variation in risk across different time intervals before, during, and after pregnancy. Medical records were manually reviewed to determine the conception and delivery dates for pregnancies.
Outcome:
Medical record-validated first-time symptomatic kidney stone.
Analytic approach:
Conditional and unconditional multivariable logistic regression analysis.
Results:
Compared to non-pregnant women, the odds of a symptomatic kidney stone in women was similar in the first trimester (OR, 0.92; p=0.8), began to increase during the second trimester (OR, 2.00; p=0.007), further increased during the third trimester (OR, 2.69; p=0.001), peaked at 0–3 months after delivery (OR, 3.53; p<0.001), and returned to baseline by 1-year after delivery. These associations persisted after adjustment for age and race or for diabetes mellitus, hypertension, and obesity. These results did not significantly differ by age, race, time period, or number of prior pregnancies. Having a prior pregnancy (delivery date >1 year ago) was also associated with a first-time symptomatic kidney stone (OR, 1.27; p=0.01).
Limitations:
Observational study design in predominantly white population. The exact timing of stone formation cannot be determined.
Conclusions:
Pregnancy increases the risk of a first-time symptomatic kidney stone. This risk peaks close to delivery and then improves by 1 year after delivery, though a modest risk of a kidney stone still exists beyond 1 year after delivery.
Keywords: Kidney stones, nephrolithiasis, recurrence, symptoms, computed tomography (CT), pregnancy, obstetric complications, stone composition, imaging, ultrasound, hydronephrosis, population-based
Plain-language summary
While there are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, evidence that they increase the risk of kidney stones during pregnancy is lacking. In a population-based case-control study using 945 female first time symptomatic formers and 1890 aged-matched female controls in Olmsted County, Minnesota, pregnancy was associated with an increased risk of a symptomatic kidney stone, starting during the second trimester, peaking around the time of delivery, and persisting until 1 year after delivery. Awareness of higher risk of symptomatic kidney stones during pregnancy and the postpartum period informs diagnostic and preventative strategies in women, particularly for women who are already at high risk for kidney stones.
INTRODUCTION
A symptomatic kidney stone is the most common non-obstetric hospital admission diagnosis for pregnant women.1 A symptomatic kidney stone event has been reported to occur in 1 out of every 200–1500 pregnancies, most often during the second and third trimesters.2–8 Potential complications of a kidney stone during pregnancy include preterm labor/delivery, premature rupture of membranes, gestational hypertension, pre-eclampsia, urinary tract infection, and pregnancy loss.3–5, 8, 9 Diagnosis and treatment of a kidney stone during pregnancy is challenging given limited diagnostic imaging and treatment options due to concern for radiation exposure and obstetric complications. Kidney stones are relatively common and have increased over time, particularly in young women.10–14 However, it is unknown whether or not pregnancy increases the risk of a symptomatic kidney stone.
There are several physiological reasons why pregnancy could contribute to kidney stone formation. During pregnancy, ureteral compression, together with ureteral relaxation secondary to elevated progesterone hormone, results in collecting system dilatation and urinary stasis. In addition, increased urine calcium excretion and elevated urine pH with pregnancy may lead to calcium phosphate stone formation.15–18 While these physiological changes with pregnancy are well known, evidence that they increase the risk of kidney stones during pregnancy is lacking. Prior studies have lacked control groups, validation of a kidney stone episode, and analysis of the temporal relationship between the pregnancy and the kidney stone episode.
To address these limitations, we performed a population-based case-control study using women from the Rochester Epidemiology Project.19, 20 The objective was to determine whether the risk of a first-time symptomatic kidney stone was increased with pregnancy and if this risk varied across different time periods before, during, and after pregnancy.
METHODS
Study Design
The Rochester Epidemiology Project (REP) is a medical record linkage system for nearly all medical care in Olmsted County, Minnesota, with a capture rate of 99.9% as compared with US census estimates.19, 20 US census estimates of female aged 15–45 years in Olmsted County ranged from 25,811 in 1984 to 30,425 in 2012. As previously reported, manual chart review was performed on all kidney stone formers in the county from 1984 to 2012 as identified from ICD9 codes (592, 594, and 274.11) for validation of first time symptomatic kidney stone episodes and to determine the date of symptomatic onset.10, 21 Symptomatic stone formers were required to have flank/abdominal pain or gross hematuria and either a stone obstructing the ureter on imaging or a voided or surgically removed stone. A detailed review of stone composition analysis, imaging, medical, and surgical treatment was performed in stone formers. Patients with prior kidney stone episodes, only asymptomatic kidney stone incidentally found on imaging, or only a suspected symptomatic kidney stone not confirmed with an obstructing stone on imaging or by a voided or surgically removed stone were excluded. Hydronephrosis alone on imaging was not considered adequate evidence for an obstructing stone.
Since kidney stones are relatively uncommon during pregnancy,2–7 a case-control study was performed. Cases were limited to confirmed first-time symptomatic kidney stone formers that were female and ages 15 to 45 years at the time of symptom onset (index date). Each case was randomly matched on age (±1 year) to two female controls who resided in Olmsted County and who had no history of kidney stones prior to the index date. The index date of stone formers’ matched controls was the date of the first symptomatic stone event in the stone formers. To provide accurate estimates of risk in the population, a woman was allowed to serve as both a control (if they had not had their first stone episode prior to the index date of their matched case) and as case (when they had their first stone episode). Comorbidities prior to the index date were determined from ICD-9/10 codes for diabetes, hypertension, chronic kidney disease, obesity, gout, and smoking. The study was approved by both the Mayo Clinic and Olmsted Medical Center institutional review boards with a waiver of informed consent for medical record review.
Characterization of pregnancies
All pregnancies resulting in a livebirth or stillbirth among the cases and controls were identified electronically using the REP birth database. Medical records were then manually reviewed in a random order to identify pregnancies with delivery dates within ±2 years of the index date for abstraction. Conception date was determined from the documented gestational age at the time of delivery. Most gestational ages were estimated based on the earliest obstetric ultrasound exam performed during pregnancy. If obstetric ultrasound exam during pregnancy was not obtained, gestational age was estimated based on the date of last menstrual period or uterine exam. The first trimester was defined from the date of conception date through week 14, second trimester from week 15 through week 28, and third trimester from week 29 through delivery. Peri-pregnancy time periods were also defined: the 6 months prior to conception, the quarterly 3 month periods during the first year after delivery, and the entire second year after delivery (Figure 1). If a woman had more than 1 pregnancy during these time windows, she was categorized according to the pregnancy that was closest to the index date after conception. All maternal and fetal pregnancy complications were also recorded.
Figure 1.
Timing of index date (date of symptom onset for stone formers) in relation to pregnancy
Statistical Analysis
Variables were summarized as mean (SD) for continuous variables and as n (%) for categorical variables. Logistic regression models were fit to determine the association of each pregnancy or peri-pregnancy time period with a first-time symptomatic kidney stone (case) versus not (control) at the index date. For the primary analysis, the reference group was defined as the time period outside of any peri-pregnancy interval (6 months prior to conception to up to 2 years after delivery). The odds ratio for a first-time symptomatic kidney stone at each trimester of pregnancy and at each peri-pregnancy time period was calculated. Odds ratios were calculated unadjusted, adjusted for age (for residual confounding) and race, and adjusted for diabetes mellitus, hypertension, and obesity. Additional logistic regression models were fit to evaluate the association between a symptomatic kidney stone and pregnancy, defined as an index date within the period of second trimester through 1 year after delivery, both overall and within each of the following subgroups: age (<35 vs 35+ years), race (white vs other), time period (1984–1999 vs 2000–2012), diabetes (yes vs. no), hypertension (yes vs. no), obesity (yes vs. no) and the number of prior pregnancies (0 vs 1+), where prior pregnancies were defined as deliveries that were more than 1 year prior to the index date. Further analyses were performed to investigate the association between a symptomatic kidney stone and a woman’s number of prior pregnancies (parity), modeled as categories of 0 (reference), 1, 2, or 3+. Analyses using the full cohort were conducted using conditional logistic regression to account for our matched pairs design; subgroup analyses and analyses restricted to women with a pregnancy during the aforementioned time window were conducted using unconditional logistic regression, since matching was broken.
The relationships between urologic interventions, different stone compositions, and radiographic stone burden for kidney stone episodes that occurred 0–6 months prior to conception, during pregnancy, 0–6 months after delivery, 6–12 months after delivery and 12–24 months after delivery were evaluated using the Chi-square test. Stone composition was categorized into mutually exclusive groups as previously described.22
Since the duration of pregnancy is variable, additional analyses assessed the odds of a first-time symptomatic kidney stone versus not by time after conception, regardless of when delivery occurred. A restricted cubic spline with six knots was constructed to estimate the functional form of the odds ratios for symptomatic kidney stone formers versus controls over time relative to the date of conception (reference point). All statistical analyses were performed using the SAS version 9.4 software package (SAS Institute, Cary, NC) and with R version 3.6.2 (R Foundation for Statistical Computing, www.Rproject.org, Vienna, Austria) using the rms package22a.
RESULTS
Study sample
There were 945 women aged 15 to 45 years with a confirmed first-time symptomatic kidney stone (cases) that were age-matched to 1890 women controls. Figure 2 shows the number of stone formers and controls with and without index dates occurring between 6 months prior to conception to 2 years after delivery. Table 1 and Table 2 compare clinical and pregnancy-related characteristics of stone formers and controls at their index date. As a result of matching, the mean age at index date for both cases and controls was 31 years. Stone formers were more likely to be white, diabetic, hypertensive, obese, and have had a past pregnancy, compared to controls.
Figure 2.
Case-control study design. Index date is the date of onset of a symptomatic kidney stone for both the case and their matched controls. There were 175 (18.5%) stone formers and 174 (9.2%) controls whose index dates occurred between 2nd trimester and 1 year after delivery.
Table 1.
Clinical characteristics of first-time symptomatic kidney stone formers (cases) and matched controls
| Patient characteristic at index date | Stone formers (n=945) | Matched controls (n=1890) | P † |
|---|---|---|---|
| Age, y | 31.0 +/− 7.8 | 30.9 +/− 7.8 | --* |
| Race | <0.001 | ||
| White | 814 (86.1%) | 1513 (80.1%) | |
| Non-white | 84 (8.9%) | 236 (12.5%) | |
| Unknown | 47 (5.0%) | 141 (7.5%) | |
| Diabetes mellitus, % | 90 (9.5%) | 92 (4.9%) | <0.001 |
| Hypertension, % | 98 (10.4%) | 113 (6.0%) | <0.001 |
| Chronic kidney disease, % | 17 (1.8%) | 20 (1.1%) | 0.1 |
| Obesity, % | 201 (21.3%) | 258 (13.7%) | <0.001 |
| Gout, % | 4 (0.4%) | 5 (0.3%) | 0.5 |
| Smoking, % | 136 (14.4%) | 274 (14.5%) | 0.9 |
| Past pregnancy: delivery >1 year ago, % | 448 (47.4%) | 815 (43.1%) | 0.01 |
| Current or recent pregnancy: 2nd trimester to 1 year after delivery, % | 175 (18.5%) | 174 (9.2%) | <0.001 |
Variable used for matching, so no p reported.
P-values adjusted for matched pairs, derived from conditional logistic regression.
P-values in bold denote significance at the 0.05 alpha level. Age given as mean +/− SD.
Table 2.
Pregnancy characteristics of first-time symptomatic kidney stone formers (cases) and matched controls, among those with pregnancy exposure*
| Pregnancy characteristic* | Stone formers (n=175) | Matched controls (n=174) | P ‡ |
|---|---|---|---|
| Gestational diabetes, % | 4 (2.3%) | 5 (2.9%) | 0.7 |
| Gestational hypertension or preeclampsia, % | 9 (5.1%) | 4 (2.3%) | 0.2 |
| Mode of delivery, % | 0.9 | ||
| Vaginal | 148 (84.6%) | 147 (84.5%) | |
| Cesarean Section | 27 (15.4%) | 27 (15.5%) | |
| Preterm: gestational age <37 wk, % | 19 (10.9%) | 11 (6.3%) | 0.1 |
| Number of fetuses, % | 0.7 | ||
| 1 | 171 (97.7%) | 169 (97.1%) | |
| 2+ | 4 (2.3%) | 5 (2.9%) | |
| APGAR score at 1 minute < 7, % | 21 (12.0%) | 23 (13.3%) | 0.7 |
for those with an index date (symptomatic stone episode onset for the stone former and their matched control) between the 2nd trimester and 1 year after delivery
P-values derived from unconditional logistic regression, since matching is broken after sub setting to women with an index date between the 2nd trimester and 1 year after delivery
Odds of a first-time symptomatic kidney stone before, during, and after pregnancy
The odds of a first-time symptomatic kidney stone were significantly increased during the second and third trimesters, peaking within 3 months after delivery (OR, 3.53; p<0.001) (Table 3). The odds of a first-time symptomatic kidney stone then decreased over time and were fully attenuated and no longer statistically significant by 12 months after delivery. These results were not substantively different with adjustment for age and race, or with adjustment for obesity, diabetes, and hypertension. Figure 3 shows a cubic spline fit modeling the change in the odds of a first-time kidney stone formation compared to controls by months after conception compared to at conception. The odds ratio was found to be highest at 9.2 months after conception (OR, 3.66; p<0.001), and as 95% of pregnancies in our cohort had a gestational age at delivery within 8.3 to 9.5 months, it can be inferred that the odds of a symptomatic kidney stone peak around the time of delivery. The odds of a symptomatic kidney stone in women with a pregnancy exposure (defined as occurring from the time of the second trimester to 1 year after delivery) compared to women without a pregnancy in this timeframe was significantly increased as well (OR, 2.24; p<0.001), and did not differ by age, race, time period, prior pregnancy, or history of diabetes or hypertension (P for interaction >0.05 for all) (Table 4).However, the odds of a symptomatic kidney stone in women with a pregnancy exposure were found to be higher in obese, compared to non-obese women (P for interaction=0.01).
Table 3.
Association of a first-time symptomatic kidney stone with different time periods before, during, and after pregnancy
| Exposure | Stone formers (n=945) | Matched controls (n=1890) | Unadjusted | Adjusted for age and race* | Adjusted for DM, HTN, obesity | |||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | P† | OR (95% CI) | P† | OR (95% CI) | P† | |||
| Index date 0–6 mo prior to conception | 13 (1.4%) | 49 (2.6%) | 0.611 (0.325, 1.148) | 0.1 | 0.609 (0.323, 1.149) | 0.1 | 0.634 (0.335, 1.198) | 0.2 |
| Index date during 1st trimester | 11 (1.2%) | 28 (1.5%) | 0.917 (0.453, 1.857) | 0.8 | 0.903 (0.444, 1.835) | 0.8 | 0.934 (0.461, 1.893) | 0.9 |
| Index date during 2nd trimester | 30 (3.2%) | 38 (2.0%) | 2.003 (1.207, 3.322) | 0.007 | 1.967 (1.179, 3.282) | 0.01 | 2.15 (1.289, 3.587) | 0.003 |
| Index date during 3rd trimester | 25 (2.6%) | 21 (1.1%) | 2.685 (1.489, 4.84) | 0.001 | 2.633 (1.455, 4.764) | 0.001 | 2.996 (1.649, 5.444) | <0.001 |
| Index date within 3 mo after delivery | 49 (5.2%) | 32 (1.7%) | 3.525 (2.205, 5.634) | <0.001 | 3.587 (2.23, 5.77) | <0.001 | 3.452 (2.142, 5.562) | <0.001 |
| Index date within 3–6 mo after delivery | 31 (3.3%) | 30 (1.6%) | 2.268 (1.346, 3.822) | 0.002 | 2.196 (1.297, 3.719) | 0.003 | 2.262 (1.332, 3.842) | 0.003 |
| Index date within 6–9 mo after delivery | 18 (1.9%) | 30 (1.6%) | 1.313 (0.72, 2.392) | 0.4 | 1.267 (0.693, 2.317) | 0.4 | 1.304 (0.71, 2.392) | 0.4 |
| Index date within 9–12 mo after delivery | 22 (2.3%) | 23 (1.2%) | 2.093 (1.157, 3.785) | 0.02 | 2.086 (1.149, 3.787) | 0.02 | 2.077 (1.14, 3.782) | 0.02 |
| Index date within 12–24 mo after delivery | 39 (4.1%) | 92 (4.9%) | 1.036 (0.701, 1.53) | 0.9 | 1.022 (0.69, 1.511) | 0.9 | 1.051 (0.708, 1.56) | 0.8 |
| Index date not in the above time frames | 707 (74.8%) | 1547 (81.9%) | 1.00 (reference) | -- | 1.00 (reference) | -- | 1.00 (reference) | -- |
Index date = date of symptomatic stone episode onset for the stone former and their matched controls. DM, diabetes mellitus; HTN, hypertension.
Age was continuous and race was categorized as white, non-white, or unknown for adjustment.
P-values adjusted for matched pairs, derived from conditional logistic regression.
P-values in bold denote significance at the 0.05 alpha level.
Trimesters are defined as follows: 1st trimester = through end of week 14; 2nd Trimester = week 15 through end of week 28; 3rd Trimester = week 29 through delivery
Figure 3.
Odds ratios for first-time symptomatic kidney stone formers versus control relative to date of conception (time 0=reference value). Black line (odds ratio) is estimated using a restricted cubic spline with six knots and shown from 5 months prior to conception to 23 months after conception. Grey areas represent 95% confidence limits. Dashed line is set at odds ratio=1.
Table 4.
Association of a first-time symptomatic kidney stone with pregnancy across different subgroups
| Subgroup | Stone formers (n=945) | Controls (n=1890) | OR (95% CI) | P† | P for interaction | ||
|---|---|---|---|---|---|---|---|
| Pregnancy exposure* | No pregnancy exposure* | Pregnancy exposure* | No pregnancy exposure* | ||||
| Overall | 175 (18.5%) | 770 (81.5%) | 174 (9.2%) | 1716 (90.8%) | 2.241 (1.787–2.811) | <0.001 | - |
| Age | 0.9 | ||||||
| <35 y | 156 (24.6%) | 477 (75.4%) | 158 (12.4%) | 1116 (87.6%) | 2.310 (1.807–2.954) | <0.001 | |
| 35+ y | 19 (6.1%) | 293 (93.9%) | 16 (2.6%) | 600 (97.4%) | 2.431 (1.232–4.796) | <0.001 | |
| Race | 0.9 | ||||||
| Caucasian | 147 (18.1%) | 667 (81.9%) | 135 (8.9%) | 1378 (91.1%) | 2.249 (1.750–2.892) | <0.001 | |
| Non-Caucasian/Unknown | 28 (21.4%) | 103 (78.6%) | 39 (10.3%) | 338 (89.7%) | 2.356 (1.382–4.016) | 0.002 | |
| Year | 0.9 | ||||||
| 1984–1999 | 75 (20.9%) | 284 (79.1%) | 75 (10.4%) | 643 (89.6%) | 2.264 (1.597–3.210) | <0.001 | |
| 2000–2012 | 100 (17.1%) | 486 (82.9%) | 99 (8.4%) | 1073 (91.6%) | 2.230 (1.656–3.004) | <0.001 | |
| Any prior pregnancy # | 0.3 | ||||||
| 0 | 73 (14.7%) | 424 (85.3%) | 69 (6.4%) | 1006 (93.6%) | 2.278 (1.286–4.033) | 0.005 | |
| 1+ | 102 (22.8%) | 346 (77.2%) | 105 (12.9%) | 710 (87.1%) | 2.080 (1.603–2.698) | <0.001 | |
| Diabetes mellitus | 0.9 | ||||||
| No | 161 (18.8%) | 694 (81.2%) | 167 (9.4%) | 1610 (90.6%) | 2.266 (1.793–2.863) | <0.001 | |
| Yes | 14 (15.6%) | 76 (84.4%) | 7 (6.2%) | 106 (93.8%) | 2.237 (0.858–5.833) | 0.10 | |
| Hypertension | 0.4 | ||||||
| No | 157 (18.5%) | 690 (81.5%) | 167 (9.3%) | 1631 (90.7%) | 2.194 (1.734–2.776) | <0.001 | |
| Yes | 18 (18.4%) | 80 (81.6%) | 7 (7.6%) | 85 (92.4%) | 3.407 (1.358–8.550) | 0.009 | |
| Obesity | 0.01 | ||||||
| No | 148 (19.9%) | 596 (80.1%) | 169 (10.4%) | 1463 (89.6%) | 2.150 (1.691–2.734) | <0.001 | |
| Yes | 27 (13.4%) | 174 (86.6%) | 5 (1.9%) | 253 (98.1%) | 7.850 (2.965–20.781) | <0.001 | |
Pregnancy exposure defined as having an index date from the 2nd trimester to 1 year after delivery;
Prior pregnancy defined as having a delivery date more than 1 year before index date
P-values derived from unconditional logistic regression, since matching is broken with subset cohorts
P-values in bold denote significance at the 0.05 alpha level.
First-time symptomatic kidney stones and number of prior pregnancies
The association between a first-time symptomatic kidney stone and a woman’s number of prior pregnancies (with delivery dates a year or more prior to index date) was also assessed (Table S1). Compared to no prior pregnancies, 1 prior pregnancy was associated with an increased odds of a symptomatic kidney stone episode (unadjusted OR 1.29; p=0.03); results were quantitatively similar for 2 and 3+ prior pregnancies, but did not reach statistical significance. As such, having 1+ prior pregnancy was associated with an increased odds of a symptomatic stone episode (unadjusted OR, 1.27; p=0.01). This finding was not substantively different with adjustment for age and sex or with adjustment for diabetes, hypertension, and obesity (Table S1). We also investigated the relationship between a first-time symptomatic kidney stone and a woman having two pregnancies with overlapping risk periods. During the first year after delivery of a prior pregnancy, another pregnancy conception only occurred in 3/120 (2.5%) of stone formers and 2/115 (1.7%) of controls (OR, 1.45; p=0.7)
Kidney stone characteristics of first-time stone formers before, during and after pregnancy
Kidney stone compositions, radiographic findings, and urology interventions of first-time stone formers before, during, and after pregnancy are shown in Table S2. Stone compositions were more likely to be calcium phosphate (hydroxyapatite) during pregnancy. Kidney stone imaging studies were less frequently obtained during pregnancy and when obtained were more likely to be ultrasound. The stone was less often seen on imaging during pregnancy. Kidney stones during pregnancy were less frequently bilateral and fewer in number, though these differences may reflect the preferential use of ultrasound for imaging during pregnancy.
DISCUSSION
This study identified pregnancy as an important risk factor for a first-time symptomatic kidney stone. An elevated risk of a symptomatic stone is noted beginning in the second trimester, peaking right after delivery, and returning to baseline by a year after delivery. This finding does not support the previously reported hypothesis that risk of a kidney stone is not increased during pregnancy.23–25 Moreover, as young woman have been shown to have a 2- to 3-fold increase in the incidence of symptomatic kidney stones over recent decades,10–14 the increased risk of kidney stones with pregnancy is important for prenatal counseling, particularly for women who have other risk factors for kidney stones such as obesity.
Consistent with these findings, the prevalence of kidney stones in women has been previously reported to increase with the number of prior pregnancies (from 5% with 0, 7% with 1, 9% with 2, and 12% with 3 or more), even after age and comorbidity adjustment.26 Since each pregnancy is associated with a time period of increased risk for a kidney stone episode, more pregnancies will lead to an accrual of a larger time period of increased risk. Besides the rise and fall in stone risk with a recent pregnancy, a prior pregnancy (delivery more than 1 year ago) also modestly increased the risk of a first-time symptomatic kidney stone episode, but this risk did not further increase with multiple prior pregnancies. This might be explained by two competing factors. We hypothesize that a prior pregnancy may lead to an asymptomatic stone formation, but this stone may not grow and pass until a subsequent pregnancy. At the same time, each pregnancy is possibly a “stress test” for kidney stones; a woman who repeatedly does not have kidney stone episodes with multiple pregnancies may be inherently more resistant to stone formation.
Several physiological changes with pregnancy could explain an increased risk of kidney stone formation. The ureter is compressed by the enlarging uterus against the fixed iliac vessels. Furthermore, ureteral peristalsis is impaired by elevated progesterone levels. These two factors contribute to the hydronephrosis seen in up to 90% of pregnancies.1 Urinary stasis from hydronephrosis prolongs contact time between lithogenic metabolites (e.g. calcium) in the urine, enhancing crystallization and stone formation. In addition, physiological hypercalciuria occurs during pregnancy15–18 and hypercalciuria can cause calcium stone formation.27 The increase in glomerular filtration rate with pregnancy contributes to an increase in the filtered load of calcium.16 Pregnant women have an increased gastrointestinal absorption and bone mobilization of calcium due to elevated 1,25-dihydroxyvitamin D produced by the placenta to support fetal bone formation.17, 28–30 The kidney reabsorbs less filtered calcium due to a suppression of parathyroid hormone caused by an elevated 1,25 dihydroxyvitamin D.17, 29 Calcium and vitamin D supplements are also routinely recommended for pregnant women and can further contribute to hypercalciuria.31, 32 Urine pH is also higher during pregnancy due to a progesterone-induced chronic respiratory alkalosis.15, 16
Hypercalciuria and higher urine pH during pregnancy explain the propensity toward calcium phosphate stones.15, 16 This study found 89% of pregnant first-time stone formers had calcium phosphate stone, consistent with prior studies.24, 33, 34 After delivery, there was a trend toward less calcium phosphate and more calcium oxalate over time consistent with the decrease in urine pH after pregnancy.15, 16 Pregnancy is thus one of the reasons hydroxyapatite stones are disproportionately more common among younger women compared to older women or men.22, 35
Consistent with the current study, prior studies have reported that 80–90% of symptomatic kidney stones during pregnancy manifest in the second and third trimester.3, 5, 7, 8, 24, 36 The current study further shows that the risk remains elevated during the first year after delivery, even though the physiological changes with pregnancy (hypercalciuria and hydronephrosis) have resolved.15–18 This is likely explained by a timing lag between the asymptomatic formation and growth of a kidney stone during pregnancy, and the migration into the ureter after delivery resulting in symptomatic renal colic. The preferential use of ultrasound to avoid radiation exposure in pregnant women may lead to under-detection of small kidney stones during pregnancy. Pain and hydronephrosis from a stone may be difficult to distinguish from the pregnancy itself. In one study of pregnant women admitted for kidney stones, only 60% of stones were visualized using ultrasound.37 Due to our strict requirements for a seen stone, it is possible that some symptomatic kidney stones during pregnancy were missed because of the preferential use of ultrasound. A symptomatic kidney stone that had migrated to the ureter but not passed during pregnancy may be diagnosed post-delivery when CT scans are more commonly used. Nonetheless, we likely underestimated the true risk of kidney stones with pregnancy.
There were several potential limitations to these findings. Because this was a case-control study design, the rate of stone events with pregnancy cannot be determined from these data. We only studied pregnancies that were >20 gestational weeks and resulted in a livebirth or stillbirth delivery. Further studies are needed to determine whether pregnancies that end in an abortion or miscarriage (<20 gestational weeks) are associated with a kidney stone episode. There was no increased risk of kidney stones observed during the first trimester in this study, and most spontaneous and elective abortions or miscarriages occur during the first trimester. Detection of asymptomatic stones may increase in women during pregnancy due to more frequent ultrasounds. Thus, we required kidney stone episodes to involve stone migration and attempted passage with symptoms that resulted in clinical care in order to minimize ascertainment bias. Calcium and vitamin D intake (dietary or supplement) was not available to study as it is not well-documented in the medical record. The study sample was predominantly white, which is a high risk population for kidney stones.38, 39 Our stratified analysis in white versus non-white women did not detect a difference in stone risk with pregnancy.
In conclusion, pregnancy confers an increased risk of a first-time symptomatic kidney stone that peaks just after delivery and decreases substantially by 1 year after delivery. However, risk is still slightly higher with a prior pregnancy even when the delivery was more than 1 year ago. Besides the pain, kidney stones are associated with adverse birth outcomes3–5 and there are challenges with their surgical management during pregnancy.1 Thus, prenatal counseling of kidney stone risk with pregnancy may be warranted, particularly in women with other risk factors for kidney stones (e.g., family history of stones, obesity, or diabetes).40 Further studies are needed to determine the risk of a symptomatic kidney stone during pregnancy among women with past symptomatic kidney stones or asymptomatic radiographic stones.
Supplementary Material
Table S1. Association of a first-time symptomatic kidney stone with prior pregnancies that had a delivery date more than 1 year ago.
Table S2. Kidney stone compositions, radiographic findings, and urology interventions of stone formers during different time periods.
Support:
This project was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (Mayo Clinic O’Brien Urology Research Center, DK100227 and DK83007) and made possible by the Rochester Epidemiology Project (AG034676) from the National Institutes of Health, U.S. Public Health Service, and the CTSA Grant UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Funders did not have a role in study design, data collection, analysis, reporting, or decision to submit for publication.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Association of a first-time symptomatic kidney stone with prior pregnancies that had a delivery date more than 1 year ago.
Table S2. Kidney stone compositions, radiographic findings, and urology interventions of stone formers during different time periods.