Swartz, Mia A. MD, MS1; Lydon-Rochelle, Mona T. PhD2; Simon, David MD, MPH3; Wright, Jonathan L. MD, MS1; Porter, Michael P. MD, MS1
Nephrolithiasis is an uncommon event in pregnancy, but previous small case series have suggested that premature rupture of the membranes (PROM), preterm labor, and preterm birth occur in women with symptomatic kidney stones.1–3 The current evidence characterizing these risks in women with symptomatic nephrolithiasis is incomplete, and clinicians are reticent to perform therapeutic procedures on gravid women due to potential fetal risks. Therefore, the pregnant patient with kidney stones presents a challenge to obstetricians and urologists.
Improved understanding of these risks may facilitate clinical decisions, and provide the basis for informed counseling. The objective of this study was to describe the relationship between hospital admission for symptomatic nephrolithiasis during pregnancy and adverse birth outcomes using population-based hospital discharge and birth certificate data. In addition, we sought to describe the association between surgical procedures for nephrolithiasis and risk of preterm delivery.
MATERIALS AND METHODS
We conducted a population-based retrospective cohort study of women who had a prenatal or intrapartum admission for urinary tract stones from 1987 through 2003 who subsequently delivered a liveborn, singleton infant. All women admitted for kidney stones in Washington State were identified with the Comprehensive Hospital Abstract Reporting System based on International Classification of Diseases, 9th Revision (ICD-9) codes 592.0 (nephrolithiasis), 592.1 (ureterolithiasis), and 592.9 (unspecified stone). These records were linked to statewide birth certificate data to identify those who gave birth during that hospitalization or within 270 days of their discharge (n=2,239). To minimize misclassification, women were excluded if time from discharge to birth was inconsistent with gestational age at delivery (n=4).
Comparison women without nephrolithiasis who delivered a liveborn, singleton infant were randomly selected in a 3:1 ratio and frequency-matched by year of delivery (n=6,729). Based on an estimated 11% and 7.5% prevalence of preterm delivery and low birth weight, respectively, the study had 80% power (α=.05) to detect an odds ratio of 1.45 for preterm delivery and 1.54 for low birth weight. Permission was obtained from the Washington State Department of Health to access these databases and University of Washington human subjects review board approval was obtained.
The primary exposure was intrapartum or prenatal hospital admission for nephrolithiasis during pregnancy. Outcomes of interest included preterm birth (less than 37 weeks), extreme prematurity (less than 32 weeks), low birth weight (less than 2,500 grams), and infant death (death within one year of birth). We also examined risk of PROM (rupture that occurs 12–24 hours before clinical onset of labor) and preterm PROM (PROM that occurs at less than 37 weeks gestation).
Two estimates of gestational age were available from the data source: gestational age in weeks (determined by ultrasonography) and gestational age in days (determined by date of last menstrual period). To classify gestational age, we used the age determined by ultrasonography when available (n=2,072). In the remaining cases (n=127), gestational age was classified using date of the last menstrual period.
Logistic regression was used to generate odds ratios (ORs) and 95% confidence intervals (95% CIs) as estimates of relative risk for adverse birth outcomes associated with hospital admission for symptomatic nephrolithiasis during pregnancy. Potential confounding variables selected to be in the final model a priori were ethnicity (white, African-American, Hispanic, and other), age (3-year groupings) and insurance status, as determined from the birth certificate. Other covariates considered were pyelonephritis (determined from ICD-9 codes), presence of maternal hypertension (any type), renal disease (determined by maternal discharge ICD-9 codes and birth certificate data), obesity (determined from maternal discharge ICD-9 codes), and parity (determined from the birth certificate). Confounding variables were chosen for inclusion in the model using a change in estimates approach and retained in the final model if they changed the risk estimate by 10% or more.4 Analyses were performed using Stata 8 (StataCorp, College Station, TX).
Polytomous logistic regression was used to perform two subgroup analyses to further characterize the risk of preterm birth.5 First, we compared risk of preterm birth among women who underwent procedures for nephrolithiasis, women who did not have these procedures, and women without an admission for stone. Procedures were identified using ICD-9 procedure codes from the discharge records (n=532). Sixty-one women (11%) had a procedure during the birth hospitalization and were excluded from this analysis because the timing of procedures with delivery date (ie, before or after delivery) could not reliably be ascertained. We then evaluated the risk of preterm birth based on trimester of admission for nephrolithiasis. Trimester was classified based on gestational age at time of admission, with less than 13 weeks gestation classified as first, 13–26 weeks classified as second, and more than 26 weeks classified as third. Statistical significance was tested using the likelihood ratio test. In short, a polytomous regression model that allowed separate odds ratios for nephrolithiasis patients based on procedure status (or trimester of stone admission) was tested against a nested polytomous regression model in which procedure status (or trimester of admission) was constrained to a common odds ratio. We used a χ2 distribution and degrees of freedom equal to the difference in the number of model parameters.
During 1987–2003, there were 2,239 pregnant women admitted for nephrolithiasis who subsequently delivered a live singleton infant. Over the same time period, there were 1,297,625 births, which resulted in an overall incidence of 0.17% or 1.7 admissions per 1,000 pregnancies annually. Characteristics of the women admitted for stones and the sampled control cohorts are shown in Table 1. Women admitted with stone were slightly younger, more likely white, and multiparous. They were also more likely to have renal disease and hypertension.
Women admitted for nephrolithiasis during pregnancy delivered 232 (10.6%) preterm infants compared with 423 (6.4%) preterm infants for those without nephrolithiasis (P<.001). The preterm infants born to women with kidney stones had a mean gestation of 34.7 weeks (range 24–36.9 weeks, standard deviation 1.9 weeks). There were 190 (81.9%) infants born at 34–36 weeks of gestation and 21 (9.1%) each at 32–33 weeks and before 32 weeks of gestation. Of those women with kidney stones who delivered prematurely, 161 (69.4%) were spontaneous, 49 (21.1%) were induced, 17 (11.6%) had premature rupture of the membranes, and in 5 (2.2%) the cause was unknown. Pregnant women admitted for nephrolithiasis were more likely to have labor induced and receive tocolytic therapy (Table 2). Administration of tocolytic agents was highly correlated with premature delivery (P<.001).
Of those women admitted for kidney stones, 1,547 (69.1%) were admitted before the delivery hospitalization, 423 (18.9%) occurred during their delivery hospitalization, and 269 (12.0%) were admitted with nephrolithiasis both before and at delivery hospitalization. Most were admitted with a stone diagnosis during the third trimester (67.5%) followed by second trimester (26.5%) and first trimester (4.5%). There were 378 (16.9%) women admitted with kidney stones before the delivery hospitalization who had concomitant pyelonephritis. During the delivery hospitalization, 176 (7.9%) of the women with nephrolithiasis had a diagnosis of pyelonephritis compared with 115 (1.7%) of the control women (P<.001). A total of 471 (25.9%) women underwent one or more surgical procedures for their kidney stones before the delivery. There were 623 procedures identified and included: 363 ureteral catheterizations (58.3%), 158 procedures to remove ureteral obstruction (25.4%), 58 cases of ureteroscopy (9.3%), 29 percutaneous nephrostomies (4.7%), six ureterotomies (1.0), four nephrostomy procedures (0.6%), four ureteral procedures not otherwise specified (0.6%), three percutaneous nephrostomies followed by stone fragmentation (0.5%), and two cases of ultrasonic fragmentation (0.3%).
The odds of preterm delivery among women admitted for kidney stones during pregnancy compared with those who did not have kidney stones were 1.79 (95% CI 1.51, 2.13). Adjustment for a concomitant diagnosis of pyelonephritis at the time of delivery did not change the risk estimate, nor did exclusion of women with pyelonephritis. Extreme prematurity, low birth weight, PROM, preterm PROM, and infant death were not significantly associated with admission for nephrolithiasis (Table 3).
In the subgroup analysis, women who were admitted with nephrolithiasis in all trimesters were at an increased risk of preterm delivery compared with those who were never admitted for kidney stones (Table 4). No single trimester posed a significantly increased risk compared with the other trimesters (likelihood ratio test, P=.93). Women who did and did not undergo procedures for nephrolithiasis both had an increase in risk of preterm delivery compared with women without admission for nephrolithiasis. Having a procedure did not significantly change the risk of preterm delivery (likelihood ratio test, P=.68).
We observed an 80% increased risk of preterm delivery among pregnant women admitted for nephrolithiasis in the state of Washington. Notably, no change in risk of preterm delivery was found based on trimester of admission or for those women who underwent procedures to manage nephrolithiasis during hospitalization.
To our knowledge, there are only two small studies in the literature since 1965 that suggest an association between nephrolithiasis symptoms and preterm labor, and our study supports their findings. A complete literature search was performed to identify studies that addressed the incidence of preterm birth or other birth outcomes in gravid women with kidney stones. We reviewed PubMed from January 1965 to January 2007 for publications in English, and keywords used for the search were nephrolithiasis and pregnancy. In one case series, Drago et al noted that six out of nine pregnant women admitted for symptomatic kidney stones (67%) experienced preterm labor.3 This ceased with treatment of nephrolithiasis symptoms. In another series, 15 pregnant women were admitted for nephrolithiasis and 6 (40%) of the women delivered a premature infant.1 Premature delivery was less common in our study but may reflect the fact that the previous report was based on a single tertiary center experience.
Recently, a small case-control study (n=86) investigated multiple pregnancy complications and birth outcomes in women admitted for nephrolithiasis in Louisiana.2 In contrast to our study, the authors concluded there was increased preterm PROM in gravid women with symptomatic nephrolithiasis. This difference is likely because we were able to perform multivariate analysis with adjustment for gestational age. Interestingly, there was no elevated risk for low birth weight in the current study, but this may reflect that most premature infants were late preterm deliveries. Although we did not demonstrate an increase in extreme prematurity, the finding of increased mild and moderate preterm deliveries is important because there is an increased risk of morbidity and mortality in this infant population.6–8 In a study of US and Canadian infants, late preterm deliveries (34–36 weeks) had a five-fold increase in early neonatal death and nearly three-fold increase in total infant mortality compared with infants delivered at term.6 Therefore, the increased incidence of premature delivery among women who have been admitted for kidney stones is clinically significant.
Our results have important cautionary implications for the management of women who have asymptomatic, small kidney stones during their reproductive years. Previous studies have suggested that 43% of small stones (≤4mm) will become symptomatic and 77% of larger kidney stones (1 cm) will have disease progression.9,10 Small stones are often observed with a goal of spontaneous passage, but urologists may consider definitive treatment for those women planning pregnancy. This information also provides a basis for informed counseling of those women who are not currently attempting pregnancy but elect for stone observation.
The etiology of the association between symptomatic nephrolithiasis and preterm delivery is unknown. Increased labor induction in the nephrolithiasis group suggests the possibility that women have labor induced to receive definitive treatment of their kidney stones. This may account for some cases of elective preterm delivery. On the other hand, significantly increased tocolytic use in women admitted for nephrolithiasis suggests spontaneous preterm labor as one possible etiology. Tocolytic agents may not always be administered in the setting of true preterm labor, but in this population their use was highly correlated with preterm delivery. It has been suggested that dehydration from vomiting may precipitate preterm labor mediated by secretion of anti-diuretic hormone and oxytocin.2,11 Preterm labor from symptomatic kidney stones may also be a prostaglandin mediated process. The role of prostaglandins in ureteral obstruction has been documented,12–14 and they also promote labor by stimulating uterine contractions and ripening the cervix.15 11
In the present study, nephrolithiasis requiring admission occurred most commonly in the second and third trimesters and trimester at admission did not appear to affect risk of preterm delivery. In addition to progesterone mediated dilation of the right ureter, there is also a mechanical obstruction secondary to right ovarian vein enlargement and uterine dextro-rotation. This may explain the onset of nephrolithiasis symptoms and admission later in pregnancy. Previous reports have suggested that most kidney stones will pass spontaneously,1,16 but in Washington State, over one fourth of the women admitted in the prenatal period had at least one procedure related to their stone. Although there is reticence to perform surgical procedures in gravid women, our findings did not demonstrate a change in the risk of preterm delivery in those receiving surgical intervention. However, given the observational nature of the data and potential for confounding by indication, it is difficult to draw a firm conclusion about surgical interventions and the risk of preterm delivery in this patient population.
There are few risk factors identified for nephrolithiasis in the general population. The condition is more commonly seen in white individuals and our study results concur. Women admitted for kidney stones were younger (P<.001), but this age difference is not clinically significant. More recently, body mass index and hypertension have been identified as risk factors in women,17–19 and some have raised the possibility of multiparity as a risk factor for kidney stones.20 Pregnant women in Washington State admitted for kidney stones were more likely to have renal disease and hypertension. Although there were minor differences in parity between cohorts, this was not a confounder in age-adjusted analyses. Therefore, the association of parity may reflect increasing age, a known stone risk factor. We were unable to reliably classify obesity in this study and therefore could not examine the relationships among obesity, nephrolithiasis, and adverse birth outcomes.
This study has several limitations. First, misclassification can occur due to coding errors. In Washington, hospital discharge data has been reported to be accurate for reporting in-hospital procedures. Thus, use of hospital discharge data decreases the likelihood of misclassification for procedures recorded during hospitalization.21,22 Another limitation is the possibility that some women may not have been pregnant at the time of stone admission. We attempted to minimize this by eliminating those with inconsistent timing of gestational age with admission. These errors in exposure measurement are likely nondifferential, and if present, would bias the relative risk toward the null and falsely attenuate our risk estimates. In addition, our study only includes women that were admitted for nephrolithiasis. Pregnant women treated for nephrolithiasis as outpatients could not be identified because Comprehensive Hospital Abstract Reporting System is based on discharge information. However, pregnant women with symptoms of nephrolithiasis would generally be admitted for analgesia, observation, and hydration. Therefore, most of the symptomatic cases of nephrolithiasis were likely identified. Last, pregnancy rates in Washington State are among some of the lowest in the United States23 and this may affect the generalizability of the results.
The diagnostic approach to the gravid woman with nephrolithiasis has been well documented,24,25 but management of these patients remains a challenge. Studies such as this one are the first step in understanding how nephrolithiasis alters the risk of adverse birth outcomes as well as the seriousness of this diagnosis in the gravid woman. These results should allow for more informed counseling of these women and may prompt urologists to more aggressively treat small, asymptomatic stones in women during their reproductive years.
1. Hendricks SK, Ross SO, Krieger JN. An algorithm for diagnosis and therapy of management and complications of urolithiasis during pregnancy. Surg Gynecol Obstet 1991;172:49–54.
2. Lewis DF, Robichaux AG 3rd, Jaekle RK, Marcum NG, Stedman CM. Urolithiasis in pregnancy. Diagnosis, management and pregnancy outcome. J Reprod Med 2003;48:28–32.
3. Drago JR, Rohner TJ Jr, Chez RA. Management of urinary calculi in pregnancy. Urology 1982;20:578–81.
4. Maldonado G, Greenland S. Simulation study of confounder-selection strategies. Am J Epidemiol 1993;138:923–36.
5. Thomas DC, Goldberg M, Dewar R, Siemiatycki J. Statistical methods for relating several exposure factors to several diseases in case-heterogeneity studies. Stat Med 1986;5:49–60.
6. Kramer MS, Demissie K, Yang H, Platt RW, Sauve R, Liston R. The contribution of mild and moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System. JAMA 2000;284:843–9.
7. Seubert DE, Stetzer BP, Wolfe HM, Treadwell MC. Delivery of the marginally preterm infant: what are the minor morbidities? Am J Obstet Gynecol 1999;181:1087–91.
8. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants. Pediatrics 2004;114:372–6.
9. Burgher A, Beman M, Holtzman JL, Monga M. Progression of nephrolithiasis: long-term outcomes with observation of asymptomatic calculi. J Endourol 2004;18:534–9.
10. Streem SB, Yost A, Mascha E. Clinical implications of clinically insignificant store fragments after extracorporeal shock wave lithotripsy. J Urol 1996;155:1186–90.
11. Stan C, Boulvain M, Hirsbrunner-Amagbaly P, Pfister R. Hydration for treatment of preterm labour. Cochrane Database Syst Rev 2002;2:CD003096.
12. Lowry PS, Jerde TJ, Bjorling DE, Maskel JL, Nakada SY. Obstruction alters the effect of prostaglandin estradiol (E2) on ureteral contractility. J Endourol 2005;19:183–7.
13. Chou SY, Cai H, Pai D, Mansour M, Huynh P. Regional expression of cyclooxygenase isoforms in the rat kidney in complete unilateral ureteral obstruction. J Urol 2003 170:1403–8.
14. Lang RJ, Davidson ME, Exintaris B. Pyeloureteral motility and ureteral peristalsis: essential role of sensory nerves and endogenous prostaglandins. Exp Physiol 2002;87:129–46.
15. Mohan AR, Loudon JA, Bennett PR. Molecular and biochemical mechanisms of preterm labour. Semin Fetal Neonatal Med 2004;9:437–44.
16. Horowitz E, Schmidt JD. Renal calculi in pregnancy. Clin Obstet Gynecol 1985;28:324–38.
17. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA 2005;293:455–62.
18. Gillen DL, Coe FL, Worcester EM. Nephrolithiasis and increased blood pressure among females with high body mass index. Am J Kidney Dis 2005;46:263–9.
19. Madore F, Stampfer MJ, Willett WC, Speizer FE, Curhan GC. Nephrolithiasis and risk of hypertension in women. Am J Kidney Dis 1998;32:802–7.
20. Jones WA, Correa RJ Ansell JS. Urolithiasis associated with pregnancy. J Urol 1979;122:333–5.
21. Lydon-Rochelle MT, Holt VL, Nelson JC, Cardenas V, Gardella C, Easterling TR, et al. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol 2005;19:460–71.
22. Lydon-Rochelle MT, Holt VL, Cardenas V, Nelson JC, Easterling TR, Gardella C, et al. The reporting of pre-existing maternal medical conditions and complications of pregnancy on birth certificates and in hospital discharge data. Am J Obstet Gynecol 2005;193:125–34.
23. Minino AM, Heron MP, Smith BL. Deaths: preliminary data for 2004. Natl Vital Stat Rep 2006;54:1–49.
24. Biyani CS, Joyce AD. Urolithiasis in pregnancy. II: management. BJU Int 2002;89:819–23.
25. Biyani CS, Joyce AD. Urolithiasis in pregnancy. I: pathophysiology, fetal considerations and diagnosis. BJU Int 2002;89:811–8.