Incidence,Treatment,and Implications of Kidney Stones During Pregnancy: A Matched Population-Based Cohort Study

Abstract

Purpose:

To determine the incidence of kidney stones in pregnancy, the risk of adverse birth outcomes, and treatment trends.

Methods:

We performed a population-based matched cohort study using Ontario's health care databases. All pregnancies in Ontario from 2004 to 2014 were identified. The study exposure was hospital admission, emergency room visit, or intervention for kidney stones during pregnancy. Each pregnancy with a stone was matched to up to six pregnancies without a stone based on age, region of residence, income quintile, year of cohort entry, prior births, and multibirths. The primary outcome was adverse birth outcome defined as preterm birth, low birth weight, or infant death. Secondary outcomes included premature rupture of membranes (PROM), pre-eclampsia, and cesarean section (C/S), as well as the type/frequency of intervention for stones in pregnancy. Logistic regression models, with generalized estimating equations, were used to assess any differences in study outcomes across groups.

Results:

Of 1.39 million pregnancies identified, there were 2863 pregnancies with stones (0.2%), which were matched with 17,171 pregnancies without stones. Pregnancies with stones had an increased risk for adverse birth outcome compared with matched pregnancies without stones (odds ratio [OR] 1.62, confidence interval [95% CI] 1.43–1.82, p < 0.0001). Pregnancies with stones also had a greater risk for pre-eclampsia (OR 1.42, 95% CI 1.02–1.99, p = 0.04) and C/S (OR 1.39, 95% CI 1.27–1.51, p < 0.0001), but not PROM. Twenty-six percent of pregnant patients admitted for a stone had an intervention, most commonly a stent or ureteroscopy.

Conclusion:

Our study demonstrated an increased risk of adverse birth outcomes in pregnancies with kidney stones. These results will be important for counseling pregnant patients with kidney stones and women of reproductive age who are at risk of developing stones.

Introduction

Based on the existing literature, a kidney stone event occurs in 1 out of every 200 to 1500 pregnancies, with 80% to 90% of patients presenting during the second and third trimesters.^1

–8 Although the incidence of nephrolithiasis is no higher in pregnant women than in the general female population, a stone event during pregnancy represents a unique clinical situation that poses risks to both the mother and the fetus, with specific diagnostic challenges and management strategies.

At present, there are relatively limited data on the contemporary incidence and outcomes of nephrolithiasis during pregnancy. Several single center retrospective studies have indicated that there is a higher risk of pregnancy complications in patients with symptomatic nephrolithiasis, including preterm premature rupture of membranes (PROM), recurrent spontaneous abortions, hypertensive disorders, gestational diabetes, and cesarean deliveries.^3,5,9 However, the lone existing population-based study only demonstrated an increased risk for preterm delivery.⁷

In the majority of cases, symptomatic stones in pregnancy can be managed conservatively, with spontaneous passage rates for kidney stones <1 cm ranging from 70% to 80%.^{5,7,9

–13} However, failing conservative management, contemporary ureteroscopic (URS) treatment of stones using laser lithotripsy has been shown to be feasible and safe in pregnancy in a number of single-institution retrospective studies.^14

–17 However, current real-world trends for the utilization of URS have not been reported.

Considering the documented increase in the incidence of stone disease in the general population over time,^18,19 it is important to evaluate the current frequency of symptomatic stones in the pregnant population. More importantly, given the conflicting evidence in the literature as to the risks for perinatal complications associated with nephrolithiasis, it is crucial to determine the risk of antenatal complications to appropriately counsel and manage such patients. The objectives of this study were to determine (1) the incidence of kidney stones resulting in hospital admission, emergency room visit, or intervention during pregnancy; (2) the risk of adverse perinatal and neonatal outcomes associated with symptomatic kidney stones; and (3) interventions utilized for kidney stones requiring hospital admission during pregnancy.

Subjects/Patients and Methods

Study design and setting

We conducted a population-based matched retrospective cohort study using Ontario's administrative health care databases that were linked using unique encoded identifiers and analyzed at the Institute for Clinical Evaluative Sciences (ICES). The province of Ontario, Canada, currently has ∼13 million residents who have universal access to hospital care and physician services. There is minimal loss to follow-up because of emigration from the province (0.5% per year).²⁰ We conducted this study according to a prespecified protocol that was approved by the Institutional Review Board at Sunnybrook Health Science Centre (Toronto, Ontario, Canada). Reporting of this study follows guidelines set for observational studies.²¹

Data sources

Multiple administrative databases were used to ascertain our cohort, baseline characteristics, covariate information, and outcome data. The Ontario Health Insurance Plan (OHIP) database contains information on inpatient, outpatient, and laboratory services based on billing claims from Ontario physicians. The Canadian Institute for Health Information Discharge Abstract Database (CIHI-DAD) has demographic, diagnostic, and procedural information for all inpatient admissions to acute care institutions. The Same Day Surgery database captures patient data for day surgery institutions in Ontario. The National Ambulatory Care Reporting System (NACRS) captures information on patient visits to hospitals and community-based ambulatory care centers, including outpatient clinics (cancer center clinics and renal dialysis clinics) and emergency departments. The Registered Persons Database (RPDB) contains demographic information on all Ontario residents, including their gender, date of birth, postal code, and vital status. All of these databases have been used extensively to research health outcomes.^22

–26 The ICES-derived MOMBABY database was used to obtain specific information relating to the birth admission about mothers and their newborns. We also used two validated ICES-derived cohorts to ascertain a diagnosis of hypertension and diabetes.

Study population

Our study population included all pregnancies from April 1, 2004 to December 31, 2014, in the province of Ontario, identified using the ICES-derived MOMBABY cohort. Pregnancies were excluded if the maternal age was <18 or >49 at the date of birth; the mother was a nonresident of Ontario; there was evidence of maternal death >2 days before the date of birth (filter out impossible/erroneous data); gestational age or birth weight was missing; birth weight was >7 kg; there was evidence of a maternal kidney stone (hospital admission, ER visit, or therapeutic intervention) in the year before the estimated date of conception; or where estimated conception date occurred during a previous pregnancy (filter out impossible/erroneous data). Pregnancies, and not the woman, were the unit of analysis; therefore, a single woman could be included multiple times, representing unique pregnancies with different index dates. To identify unique pregnancies, we followed each woman after their first date of delivery (birth date of the child) until end of the accrual period (December 31, 2014) for evidence of another birth. For women with more than one birth, it is a unique separate birth if the date of delivery occurs >140 days (20 weeks) after their most recent date of delivery.

Exposure

The primary exposure was a symptomatic kidney stone defined as hospital admission, emergency department visit, or intervention for nephrolithiasis during pregnancy. All such pregnancies were identified using the International Classification of Diseases (ICD)-10th revision codes N20.0-N20.9 or Canadian Classification of Health Interventions (CCI) codes from the CIHI-DAD and NACRS or physician billing claims in the OHIP database (Supplementary Table S1).

Any pregnancy included in our study cohort and not in the exposed group comprised the unexposed comparison cohort of pregnancies without kidney stones.

Matching

We matched each pregnancy with a kidney stone with up to six pregnancies without a kidney stone, without replacement. We matched based on age (within 2 years), year of cohort entry, region of residence (rural [population <10,000] vs urban), income quintile (five categories representing average neighborhood income on the index date), prior births, and multibirths. The unit of analysis was the pregnancy; as such a woman can be included in more than one matched set for each pregnancy they experienced. All exposed pregnancies were matched to at least two unexposed pregnancies, with >99.9% being matched to six unexposed pregnancies.

Covariates

In addition to the covariates upon which the cohorts were matched, a number of additional covariates representing comorbid medical conditions were assessed to ensure similarity of our exposed and unexposed cohorts. This included hypertension, diabetes mellitus, inflammatory bowel disease, gout, hyperparathyroidism, hypercalcemia, and gastric bypass surgery. We also used the Adjusted Clinical Group (ACG) scoring system to score comorbidity. The ACG is a population/patient case-mix adjustment system that provides a relative measure of the individual's expected consumption of health services.²⁷

Outcomes

The primary outcome was an adverse birth outcome defined as a composite of preterm birth (gestational age <37 weeks), low birth weight (<2500 g), or infant death (death within 1 year of birth). The secondary outcomes included assessment of each component of the primary outcome examined separately, including extreme prematurity (gestational age <28 weeks), as well as other adverse perinatal outcomes, including PROM and preterm PROM, pre-eclampsia, and cesarean section (C/S). For multiple births, as long as one of the births met the criteria for the outcome then the outcome was considered present. All perinatal outcomes were determined utilizing the CIHI-DAD, RPDB, and MOMBABY database (Supplementary Table S1).

Our secondary outcomes also included examination of the type and frequency of intervention for kidney stones during pregnancy, specifically, the incidence of stent insertion, URS and laser lithotripsy and percutaneous nephrostomy tube insertion. All interventions were identified using the CCI codes from CIHI-DAD and the physician billing claims in the OHIP database (Supplementary Table S1). Furthermore, the impact of the aforementioned interventions on the risk for the primary and secondary outcomes was investigated in the statistical analysis by comparing women with a stone intervention to their matched nonkidney stone pregnancies.

Statistical analysis

Baseline characteristics between the exposed and unexposed cohort were compared using standardized differences. This metric describes differences between group means relative to the pooled standard deviation; differences >10% reflect the potential for meaningful imbalance.²⁸

The unit of analysis is pregnancies, which means that women may enter into the study more than once. As such, logistic regression models with generalized estimating equations were used to assess for a difference in the primary and secondary outcome across the exposed and unexposed cohorts. Generalized estimating equations were used to account for matching and multiple potential pregnancies per woman.

Unadjusted analysis with the chi-square test was used to assess the risk of the primary and secondary outcomes in those pregnancies with a stone and urologic intervention compared with pregnancies with a stone and no intervention.

All statistical analyses were performed using SAS 9.4 software (SAS Institute, Inc., Cary, NC).

Results

Over the study time frame of April 2004 to December 2014, 1.39 million pregnancies were eligible for inclusion. There were 2863 pregnancies with a symptomatic kidney stone that were matched with 17,171 pregnancies without a kidney stone. The incidence of symptomatic kidney stones in pregnancy was 0.2059% (confidence interval [95% CI] 0.2055–0.2062). The baseline characteristics of the exposed and matched unexposed group were similar except for history of kidney stones and ADG score (Table 1). Certain covariates (hyperparathyroidism, hypercalcemia, and gastric bypass surgery) are not reported in Table 1 because of infrequent events. In accordance with ICES privacy policies, cell sizes less than or equal to five cannot be reported.

Table 1.

Baseline Characteristics for Pregnancies With a Kidney Stone and Matched Pregnancies Without a Kidney Stone in the Province of Ontario Between April 2004 and December 2014

	Matched not exposed pregnancies	Exposed pregnancies	St. Diff^a
	N = 17,171	N = 2863	St. Diff^a
Mother's age at estimated conception date
Mean (SD)	28.84 (2.16)	28.81 (5.4)	0.01
Median (IQR)	29 (25–33)	29 (25–33)
Mother's income quintile at estimated conception date^b
Quintile 1 (lowest income)	24.9%	24.9%	0
Quintile 2	22.0%	22.0%	0
Quintile 3	20.1%	20.1%	0
Quintile 4	19.1%	19.1%	0
Quintile 5 (highest income)	13.8%	13.8%	0
Year of pregnancy
2004–2006	25.1%	25.1%	0
2007–2009	28.5%	28.5%	0
2010–2012	30.0%	30.0%	0
2013–2014	16.4%	16.3%	0
Residential status at estimated conception date^c,d
Urban	82.2%	82.2%	0
Rural	17.8%	17.8%	0
Number of prior pregnancies at delivery date
0	47.1%	47.1%	0
1	33.6%	33.6%	0
2	13.0%	13.0%	0
3+	6.3%	6.3%	0
Multibirth (e.g., twins)
Yes	1.5%	1.5%	0
ADG score in 2 years before estimated conception date^e
Mean (SD)	7.79 (1.62)	8.71 (4.19)	0.29
Median (IQR)	8 (5–11)	9 (6–12)
Comorbidities in 5 years before estimated conception date
Remote history of kidney stones	0.3%	6.1%	0.33
Hypertension	2.3%	3.5%	0.07
Diabetes	1.6%	1.6%	0
Inflammatory bowel disease	0.8%	1.5%	0.07
Gout	0.0%	0.0%	0

This metric describes differences between group means relative to the pooled standard deviation; differences greater than 10% reflect the potential for meaningful imbalance.

Income quintile 3 includes missing values.

Urban includes missing values.

Rural is defined as a population <10,000.

Johns Hopkins ACG comorbidity scoring system: the ACG is a population/patient case-mix adjustment system that provides a relative measure of the individual's expected consumption of health services.²⁷ ICD-9/ICD-9-CM codes are categorized into 32 groups, called ADGs, on the basis of clinical similarity, chronicity, likelihood of required specialty care, and disability. These groups are further reduced to 12 “Collapsed ADGs,” or CADGs.

ACG = Adjusted Clinical Group; ADGs = Ambulatory Diagnostic Groups; St. Diff = standardized differences; ICD = International Classification of Diseases.

For the primary outcome, a pregnancy with a kidney stone had a significantly increased risk for an adverse birth outcome compared with matched pregnancies without a kidney stone (13.5% vs 8.8%, odds ratio 1.62, 95% CI 1.43–1.82, p < 0.0001). For those pregnancies with a symptomatic kidney stone the trimester of presentation, stratified by adverse birth outcome, is listed in Table 2.

Table 2.

Trimester of Symptomatic Stone Event in the Exposed Cohort Stratified by the Primary Outcome

Adverse outcome	Trimester of stone event^a
Adverse outcome	First	Second	Third	Total
No	387	1230	859	2476
Yes	70	156	161	387
Total	457	1386	1020	2863

If more than one stone event in the pregnancy, trimester of the last stone event before delivery listed.

For the secondary outcomes, a pregnancy with a kidney stone had a significantly increased risk of low birth weight, premature birth, pre-eclampsia, and C/S (Table 3).

Table 3.

Odds Ratio, Confidence Interval, and p-Values for the Risk of the Secondary Outcomes in Pregnancies With a Kidney Stone as Compared With the Matched Pregnancies Without a Kidney Stone

Outcome	Odds ratio (95% CI)	Absolute risk increase (95% CI)	p
Preterm birth^a	1.70 (1.50–1.94)	4.32% (3.10–5.54)	<0.0001
Extreme prematurity^b	1.20 (0.68–2.13)	0.08% (−0.19 to 0.35)	0.534
Low birth weight^c	1.52 (1.31–1.77)	2.61% (1.56–3.66)	<0.0001
Infant death^d	1.20 (0.59–2.46)	0.05% (−0.17 to 0.27)	0.618
PROM or preterm PROM	1.18 (0.92–1.53)	0.38% (−0.24 to 0.99)	0.202
Pre-eclampsia	1.42 (1.02–1.99)	0.44% (0.03–0.91)	0.039
Cesarean section	1.39 (1.27–1.51)	6.85% (4.99–8.70)	<0.0001

Preterm birth; <37 weeks gestation.

Extreme prematurity; <28 weeks gestation.

Low birth weight; weight is <2500 g.

Infant death; death within 1 year of birth date.

CI = confidence interval; PROM = premature rupture of membranes.

In 755 (26%) of the 2863 pregnancies with a kidney stone, at least one intervention was required during the pregnancy. A total of 1004 interventions were performed in these 755 pregnancies. This was most commonly a ureteral stent or URS (Table 4).

Table 4.

Type and Frequency of Kidney Stone Interventions in the 2863 Pregnancies with a Kidney Stone

Intervention type^a	N	%
Stent insertion	473	16.52%
PCN tube insertion	152	5.31%
Ureteroscopy and laser lithotripsy	379	13.24%

Patients may have had more than one intervention.

PCN = percutaneous nephrostomy.

Considering pregnancies with a kidney stone, the baseline characteristics for those with no intervention were similar to those who did undergo intervention, including age, income quintile, multibirth, and comorbidity score (ACG). When looking at the subset of pregnancies with a kidney stone that underwent an intervention (755) and their matched controls, there was an increased risk of an adverse birth outcome as compared with pregnancies with a stone that did not undergo intervention (2108) and their matched controls (Table 5). Pregnancies with a nephrostomy tube or stent had the largest magnitude of risk for an adverse birth outcome.

Table 5.

Odds Ratio, Confidence Interval, and p-Values for the Risk of the Primary and Secondary Outcomes in Pregnancies with a Kidney Stone Compared with Their Matched Controls, Stratified by Intervention

	No intervention (n = 2108)	Stent (n = 473)	PCN (n = 152)	URS (n = 379)
Adverse birth outcome	1.20 (1.04–1.39)	3.33 (2.62–4.23)	3.64 (2.49–5.33)	1.82 (1.34–2.47)
Preterm birth^a	1.23 (1.05–1.44)	3.81 (2.97–4.90)	3.79 (2.52–5.71)	1.96 (1.4–2.73)
Extreme prematurity^b	1.02 (0.52–2.00)	2.41 (0.75–7.75)	1 (0.12–8.42)	0.86 (0.1–7.00)
Low birth weight^c	1.22 (1.02–1.46)	2.91 (2.13–3.96)	2.59 (1.63–4.13)	1.26 (0.81–1.96)
Infant death^d	1.09 (0.46–2.61)	1.33 (0.29–6.22)	3.01 (0.27–33.64)	1.2 (0.14–10.33)
PROM and preterm PROM	1.02 (0.76–1.37)	2.93 (1.67–5.14)	0.86 (0.19–3.89)	1.46 (0.66–3.24)
Pre-eclampsia	1.54 (1.07–2.22)	0.96 (0.33–2.80)	2.42 (0.46–12.7)	0.37 (0.05–2.83)
Cesarean section	1.28 (1.16–1.41)	1.85 (1.52–2.26)	2.39 (1.7–3.34)	1.46 (1.16–1.84)

Preterm birth; <37 weeks gestation.

Extreme prematurity; <28 weeks gestation.

Low birth weight; weight is <2500 g.

Infant death; death within 1 year of birth date.

URS = ureteroscopy.

Discussion

Our study demonstrated that the contemporary incidence of symptomatic kidney stones in pregnancy is 0.2%. Importantly, symptomatic kidney stones were associated with an increased risk of preterm birth, low birth weight, pre-eclampsia, and C/S. Furthermore, we demonstrated an increased magnitude of risk for these outcomes in pregnancies with a stone that underwent intervention compared with pregnancies with a stone that did not undergo intervention. This study represents the largest cohort study to date on this topic. The universal health system of Ontario allows for excellent capture of our primary and secondary outcomes using standardized definitions. In addition, matching on several key covariates helped to reduce potential confounding. These results will be important for counseling pregnant patients with kidney stones and women of reproductive age who are at risk of developing stones in pregnancy.

These results are also important given the lack of contemporary literature on this topic. The majority of data have been from small single-institution retrospective case series. These case series have indicated that there is a higher risk of pregnancy complications in patients with symptomatic nephrolithiasis, including preterm PROM, recurrent abortions, hypertensive disorders, gestational diabetes, and cesarean deliveries.^3,5,9 However, conflicting results were reported by the only published retrospective population-based study (from Washington state, 1987–2003), which only demonstrated an increased risk for preterm delivery.⁷ Swartz et al. showed that women admitted for nephrolithiasis during pregnancy had nearly double the risk of preterm delivery compared with women without stones (adjusted odds ratio 1.8, 95% CI 1.5–2.1). Conversely, there was no higher risk for extreme prematurity (<28 weeks), low birth weight (<2500 g), infant death, PROM, and preterm PROM.⁷ Importantly, this study uses data that are now 15 to 30 years old and may not be applicable because of the documented increase in the incidence and prevalence of kidney stones worldwide, as well as the changes in prenatal care and stone treatment. Unlike this population-based study by Swartz and colleagues, our study demonstrated an association with a larger number of adverse pregnancy outcomes (preterm birth, low birth weight, pre-eclampsia, and C/S).

The results of our study must be viewed within the context of its limitations. First, given that we relied on administrative data for the determination of both the study exposure and outcomes there is a risk for misclassification. However, there is no reason to suggest that the risk for misclassification would differ between the two study cohorts. Second, it is an observational study and as such one cannot infer causation between symptomatic kidney stones and adverse birth outcomes. In addition, given the observational nature of the study there is the potential that unmeasured confounders could have accounted for the increased risk seen in the exposed cohort, although the groups were matched on important covariates in the main analysis. Similarly, our secondary analysis examining the risk associated with urologic intervention for stones in pregnancy may be susceptible to residual confounding. It is possible that the trigger for intervention (e.g., obstructing pyelonephritis, intractable nausea/vomiting) was also responsible for the adverse birth outcome, as opposed to the intervention itself. Accordingly, this finding must be interpreted with caution and based on this study no recommendation can be made about the safety of one intervention over another. This analysis was exploratory in nature and hypothesis generating for future studies, Such future studies, using population-based data and designed specifically to evaluate the safety and outcomes of urologic intervention in pregnancy, are needed to better understand the results of this study and provide more robust evidence given that the safety of URS in pregnancy is based on single-institution retrospective reports.

Conclusion

The incidence of symptomatic kidney stones in pregnancy is 0.2% in Ontario. Our population-based matched retrospective cohort study demonstrated an increased risk of preterm birth, low birth weight, pre-eclampsia, and C/S for pregnancies with a symptomatic kidney stone. Approximately one quarter of pregnant patients admitted for a kidney stone had some form of urologic intervention, most commonly a stent or URS. These data are important to help counsel pregnant patients who develop kidney stones in pregnancy.

Footnotes

Disclaimer

The opinions, results, and conclusions are those of the authors and are independent from the funding sources. No endorsement by ICES, AMOSO, SSMD, LHRI, or the MOHLTC is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions, and statements expressed in the material are those of the author(s), and not necessarily those of CIHI.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the Institute for Clinical Evaluative Sciences (ICES) Western site. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Core funding for ICES Western is provided by the Academic Medical Organization of Southwestern Ontario (AMOSO), the Schulich School of Medicine and Dentistry (SSMD), Western University, and the Lawson Health Research Institute (LHRI). The research was conducted by members of the ICES Kidney, Dialysis and Transplantation team, at the ICES Western facility, who are supported by a grant from the Canadian Institutes of Health Research (CIHR). The study was also supported by a research grant from the Canadian Urological Association Scholarship Foundation (CUASF) and the Canadian Urological Association. None of the aforementioned funders had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Supplementary Material

Supplementary Table S1

Abbreviations Used

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Supplementary Material

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