Perinatal Outcomes with Tamsulosin Therapy for Symptomatic Urolithiasis

Author's Accepted Manuscript Perinatal Outcomes with Tamsulosin Therapy for Symptomatic Urolithiasis George Bailey , Lisa Vaughan , Carl Rose , Amy Krambeck

PII: DOI: Reference:

S0022-5347(15)04312-8 10.1016/j.juro.2015.06.097 JURO 12738

To appear in: The Journal of Urology Accepted Date: 25 June 2015 Please cite this article as: Bailey G, Vaughan L, Rose C, Krambeck A, Perinatal Outcomes with Tamsulosin Therapy for Symptomatic Urolithiasis, The Journal of Urology® (2015), doi: 10.1016/ j.juro.2015.06.097. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.

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PERINATAL OUTCOMES WITH TAMSULOSIN THERAPY FOR SYMPTOMATIC UROLITHIASIS

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George Bailey, MD1; Lisa Vaughan2; Carl Rose, MD3; and Amy Krambeck, MD1 1

Department of Urology, Mayo Clinic, Rochester, Minnesota Health Sciences Research, Mayo Clinic, Rochester Minnesota 3 Department of Obstetrics and Gynecology, Mayo Clinic Minnesota

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Correspondence: Amy Krambeck, MD

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Mayo Clinic Department of Urology Mayo Clinic 200 First Street Southwest Rochester, Minnesota 55905 E-mail: [email protected] Telephone: 507-266-4446 Fax: 507-284-4951

Running Head: Tamsulosin use in Pregnancy Key Words: Tamsulosin, Pregnancy, Urolithiasis, Medical Expulsive Therapy Manuscript Word Count: 2090 Source of Funding: None

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ABSTRACT PURPOSE: Medical expulsive therapy (MET) represents an effective adjunctive treatment for nonpregnant patients with symptomatic urolithiasis. Tamsulosin is

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classified by the FDA as a category B medication; however no published data exists for human pregnancy. Our objective was to explore the safety and efficacy of tamsulosin therapy for symptomatic urolithiasis occurring during pregnancy.

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MATRIALS and METHODS: We retrospectively identified patients treated with

tamsulosin for stone disease during pregnancy at the Mayo Clinic during the 2000-2014

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interval. This MET cohort was matched 2:1 to pregnant women with symptomatic urolithiasis during pregnancy who did not receive MET. Groups were compared using linear mixed models for continuous variables and exact conditional logistic regression models for nominal variables, in order to take into account correlation due to matching.

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RESULTS: A total of 27 patients receiving MET comprised the study cohort. Median duration of antepartum tamsulosin exposure was 3 days (range 1-110), occurring during the first, second and third trimester in 3 (11%), 11 (40.7%), and 18 (67%) patients

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respectively. Mean gestational age at delivery was 38.1 weeks (SD 2.4); 6 (22%) infants were born preterm. All infant birthweights were considered appropriate for gestational

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age, and no cases of spontaneous abortion, intrauterine demise, or neonatal congenital anomalies were encountered. Comparison between the MET and control groups demonstrated no significant differences in maternal or infant outcomes for any of the examined variables.

CONCLUSIONS: Tamsulosin MET does not appear to be associated with adverse maternal or fetal outcomes, and may be considered as adjunctive therapy for urolithiasis during pregnancy.

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INTRODUCTION Although pregnancy does not intrinsically increase the risk of symptomatic episodes, management of urolithiasis during pregnancy can be challenging.1-3 In an

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effort to mitigate anesthetic and radiation exposure during gestation, initial management of clinically stable pregnant patients typically consists of a period of observation.

Several studies have reported the spontaneous passage rate in pregnant women to be

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as high as 70-80%.4-8, however, a more recent analysis has suggested that

overdiagnosis and suboptimal follow up may contribute to artificially inflated passage

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rates, with the true rate of spontaneous passage being as low as 48%.9 A significant number of patients will fail conservative management and consequently require procedural interventions with accompanying surgical and anesthetic risks. The addition of medical expulsive therapy (MET) could potentially increase the incidence of and

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decrease time to spontaneous stone passage in pregnant patients, but the safety of antepartum off-label use of tamsulosin, the most common alpha blocker medication, remains unstudied to date.

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MET using tamsulosin or nifedipine has been assessed in the non-pregnant population; a 2007 meta-analysis found a significantly higher rate and shorter time to

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spontaneous passage with tamsulosin therapy when compared to narcotic therapy alone.10 The Food and Drug Administration currently defines tamsulosin as a category B medication for pregnant patients: animal reproduction studies have failed to demonstrate risk to the fetus and there are no adequate, well-controlled studies in pregnant women. A PubMed search using terms “tamsulosin” and “pregnancy” revealed no reports of use during pregnancy; therefore we evaluated the safety of antepartum tamsulosin use and effects on neonatal outcomes.

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MATERIALS and METHODS After obtaining Internal Review Board approval, we retrospectively identified patients ≥18 years of age treated with tamsulosin for stone disease during pregnancy

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(MET group) between January 1, 2000 and January 1, 2014 with a minimum of 90 days postpartum follow-up. Potential patients were identified by searching for hospital

discharge ICD-9 codes V22, V23, 591, 592, and 788. Individual medical records were

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then abstracted for demographic information, presenting symptomatology, urologic

intervention, and previous medical, obstetrical, family, and social histories. Additionally

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we reviewed the timing, dose, and duration of tamsulosin use. Compliance with outpatient therapy was presumed. All patients were counseled pretreatment regarding the risks and benefits of off-label use of tamsulosin for MET. Outcome variables included medication side-effects, rates of spontaneous abortion and intrauterine fetal

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demise, and mode of delivery. Head circumference, congenital malformations, Apgar scores, intensive care unit admission, and mortality were also recorded. The MET cohort was matched 2:1 with a group of pregnant patients with

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symptomatic urolithiasis during pregnancy who did not receive MET (control group) based on the following variables: antepartum surgical stone procedure, maternal age

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<20 years, tobacco use during pregnancy, small for gestational age infant, and premature birth (gestational age <37 weeks). All selected variables, excluding postpartum surgical intervention, are identified risk factors for adverse neonatal outcomes. 11, 12

Score tests derived from exact conditional logistic regression models were used to compare dichotomous variables. F tests derived from linear mixed models were used to compare continuous variables.

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RESULTS A total of 27 women were treated with tamsulosin MET during the study interval. Maternal demographics and perinatal outcomes for the MET and control groups are

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displayed in Table 1. Onset of symptoms occurred in the first, second and third trimesters in 5 (19%), 10 (37%), and 12 (44%) patients in the MET group compared to 7 (13%), 26 (48%), and 21 (39%) control patients, respectively. Gestational age at

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symptom onset did not differ significantly between the two groups. All pregnancies were singleton.

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Presenting symptom (pain, nausea/emesis, sepsis, fever, urinary tract infection, dysuria, gross hematuria, urinary urgency, or urinary frequency) did not differ between the groups. One patient presented with a urinary tract infection without flank pain, but all other patients exhibited pain as their presenting symptom. Additional patient symptoms

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and testing are summarized in Table 2. In the MET group, median duration of tamsulosin use was 3 days (range 1-110), with exposure in the first, second and third trimester in 3 (11%), 11 (40%), and 18 (67%) patients respectively. Four women had

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tamsulosin exposure during multiple trimesters. Further details on timing and duration of tamsulosin exposure for each patient can be seen in Table 4. None of the tamsulosin-

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treated patients reported any medication-related side-effects. Mean number of admissions per days of remaining pregnancy after symptom

onset were similar for the MET and control groups (0.03 and 0.02, respectively, p = 0.32). Mean total of days of admission per days of remaining pregnancy after symptom onset were also similar for the MET and control groups (0.13 and 0.08, respectively, p = 0.44). Of the patients who did not undergo surgical intervention, 10 of the 19 (53%) women in the MET group, and 11 of the 38 (29%) women in the control group passed a

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stone fragment prior to delivery, yielding an absolute difference in stone passage rate of 24%. Mean time from presentation to stone passage in the MET group was 24 days and in the control group was 5 days.

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Of the 8 (29%) MET patients requiring surgical intervention during pregnancy, 1 (13%) required ureteral stent placement, 1 (13%) required ureteroscopy without stent placement, 5 (63%) required ureteroscopy with stent placement, and 1 (13%) required a

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nephrostomy tube. Of the 16 (29%) control patients requiring surgery during pregnancy, 9 (56%) required a ureteral stent and 7 (44%) required ureteroscopy with stent

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placement. Rates of obstetrical complications such as hyperemesis, pyelonephritis, gestational diabetes, placenta previa, gestational hypertension, and preeclampsia were not statistically different between the MET and matched cohort group (see Table 1). The incidence of cesarean delivery and median duration of postpartum hospitalization

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were also similar between groups (Table 1).

Table 3 describes the selected perinatal outcomes. All infant birthweights were considered appropriate for gestational age, and there were no instances of spontaneous

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abortion, intrauterine fetal demise, or neonatal congenital anomalies. In the MET group, 2 (7%) of the infants died of sudden infant death syndrome (SIDS) within 6 months of

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birth (deaths occurred at 2 and 3.5 months of life) compared with none in the control group, a difference which did not meet statistical significance (p = 0.11). Comparison between the MET and control groups demonstrated no significant differences in any maternal or infant outcome.

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DISCUSSION The two most common medications used for MET in non-pregnant patients are tamsulosin and nifedipine.10 In non-pregnant patients undergoing trial of passage,

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tamsulosin has been shown to increase the rate of stone passage, decrease the time to effect stone passage, and decrease pain in the interim.10 A meta-analysis evaluating MET examined randomized controlled trials of tamsulosin vs placebo and identified a

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statistically significant absolute increase in stone passage rate of 29%10; these results are similar to the absolute increase in stone passage rate of 24% observed in the

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current study. This same meta-analysis also evaluated randomized controlled trials comparing nifedipine to placebo in non-pregnant patients and demonstrated a nonsignificant absolute increase in stone passage rate of 9%.10 Additionally, the authors evaluated MET with tamsulosin vs nifedipine and found superior stone passage rates

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with tamsulosin. More recent studies have supported this finding, demonstrating superior stone passage rates with alpha blockers over calcium channel blockers.13, 14 Although time to passage in this study was longer for patients treated with tamsulosin,

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overall passage rate was higher; this longer time to passage may reflect eventual passage of stones that would not have passed at all if left untreated. It is intriguing that

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the median duration of tamsulosin use in the MET group was only 3 days, while the mean time to stone passage was 24 days. Every effort is made during pregnancy to limit medication exposure. Pregnant patients in this study were treated with tamsulosin based on symptoms. It is possible that intermittent, symptom directed tamsulosin use in this patient population facilitated stone passage at bottle neck points during stone migration, resulting in a superior stone passage rate. Currently the American Urological

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Association Nephrolithiasis Clinical Guideline Panel consensus recommends tamsulosin over nifedipine if MET is elected.10 The present study constitutes the initial description of antepartum MET for acute

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urolithiasis during pregnancy. Tamsulosin is a category B medication, primarily due to a paucity of data. By comparison, nifedipine and narcotics are a category C medications (animal reproduction studies have shown an adverse effect on the fetus and there are

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no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women). Calcium channel blockers are used during

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pregnancy for antihypertensive properties for patients with pre-existing hypertension, preeclampsia, and as a tocolytic agent for preterm labor.15 While animal studies have found limb anomalies associated with in-utero calcium channel blocker exposure,16, 17 similar outcomes have not been observed in human pregnancies. Prenatal exposure to

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calcium channel blockers for management of hypertension has been assessed by multiple studies, none of which found any association with fetal congenital malformations, miscarriage, or low birth weight.15, 18-21

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Our assessment of neonatal outcomes in infants with antepartum exposure to tamsulosin found no significant differences in any perinatal outcome measure. Tasian et

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al demonstrated the safety of tamsulosin use as MET in 449 pediatric patients.22; however, the mean age for patients in Tasian’s study was 14 years (IQR 12-16.7), thus the results may not be broadly applicable to the prepubertal population. Findings of the present study suggest safety of prenatal exposure as well. A non-significant numerical difference was noted in the incidence of SIDS in the MET group. The incidence of SIDS in the general population is less than one in a thousand.12 Two cases of SIDS seen in a cohort of 27 patients may be considered alarming. However, it is unclear if the two

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infants with SIDS in this series carried any other risk factors (sleeping position, sleeping arrangements, objects in the crib, infant overheating, or smokers in the home). Data on these SIDS risk factors were not readily available in this retrospective review. When

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patients were matched for SIDS risk factors available in the medical record (maternal age < 20 years, tobacco use during pregnancy, small for gestational age infant, and prematurity), no statistical difference was found. To date no antepartum medication

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exposure has been convincingly linked to SIDS. A pathophysiologic mechanism linking gestational tamsulosin use to SIDS is difficult to extrapolate, and likely this represents a

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circumstantial association. The use of any medication during pregnancy should prompt the treating physician to make a risk-benefit calculation, but there was no evidence in this analysis to support withholding tamsulosin therapy based on an increased risk of SIDS. Future studies with larger patient cohorts will further clarify the benefits of

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tamsulosin use during pregnancy.

Similar to other investigations into medication use during pregnancy, this study is limited by its retrospective design, inherent recall bias, and small sample size. Patients

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were assumed to have been compliant with prescribed medication. Retrospectively, medication compliance is difficult to confirm. Some patients in the MET cohort were

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treated with intermittent, symptom directed tamsulosin use, which differs from typical MET in non-pregnant patients. Most women with symptomatic nephrolithiasis manifest during the second and third trimesters.23 Our patient population reflects this trend. With only 3 of the 27 women in the MET group having first trimester exposure, it is challenging to make definitive conclusions on the potential risks of first trimester tamsulosin use. Since patients were matched based on pregnancy risk factors and not on stone characteristics, limited conclusions can be drawn on the statistical significance

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of stone passage metrics between the two groups. Additionally, most of the patients in this series were evaluated exclusively with ultrasound, which has a relatively poor sensitivity for urolithiasis and cannot reliably distinguish urolithiasis from gestational

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hydronephrosis.24 However, the rates of stone confirmation, either by surgical removal or spontaneous passage, and rates of stone detection on imaging were similar between

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CONCLUSION

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both groups, suggesting clinical homogeneity and comparable outcomes.

The diagnosis and treatment of the pregnant patient with acute urolithiasis entails unique challenges. Providers must balance symptomatic relief for the mother with limiting radiation and anesthesia exposure to the developing fetus.25-27 This study is the

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first investigation into the safety of tamsulosin use as MET in pregnancy. While the inherent limitations of a retrospective design make it difficult to draw definitive conclusions, the results of this study should provide reassurance for both the pregnant

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stone-former patient and the physician. Furthermore, tamsulosin appears to enhance stone passage rates in the pregnant patient, which has the potential to reduce necessity

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for surgical interventions. Additional data from larger patient cohorts is required before definitively declaring the safety of tamsulosin in the pregnant population.

ACKNOWLEDGMENTS

We would like to acknowledge and thank Eric Bergstralh for his expertise and assistance with statistical analysis.

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REFERENCES

7.

8.

9. 10. 11. 12. 13.

14.

15.

16. 17. 18.

19.

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6.

SC

5.

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4.

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3.

EP

2.

Drago, J. R., Rohner, T. J., Jr., Chez, R. A.: Management of urinary calculi in pregnancy. Urology, 20: 578, 1982 Harris, R. E., Dunnihoo, D. R.: The incidence and significance of urinary calculi in pregnancy. American journal of obstetrics and gynecology, 99: 237, 1967 Srirangam, S. J., Hickerton, B., Van Cleynenbreugel, B.: Management of urinary calculi in pregnancy: a review. Journal of endourology / Endourological Society, 22: 867, 2008 Parulkar, B. G., Hopkins, T. B., Wollin, M. R. et al.: Renal colic during pregnancy: a case for conservative treatment. The Journal of urology, 159: 365, 1998 Andreoiu, M., MacMahon, R.: Renal colic in pregnancy: lithiasis or physiological hydronephrosis? Urology, 74: 757, 2009 Maikranz, P., Lindheimer, M., Coe, F.: Nephrolithiasis in pregnancy. Bailliere's clinical obstetrics and gynaecology, 8: 375, 1994 Meria, P., Hadjadj, H., Jungers, P. et al.: Stone formation and pregnancy: pathophysiological insights gained from morphoconstitutional stone analysis. The Journal of urology, 183: 1412, 2010 Watterson, J. D., Girvan, A. R., Beiko, D. T. et al.: Ureteroscopy and holmium:YAG laser lithotripsy: an emerging definitive management strategy for symptomatic ureteral calculi in pregnancy. Urology, 60: 383, 2002 Burgess, K. L., Gettman, M. T., Rangel, L. J. et al.: Diagnosis of urolithiasis and rate of spontaneous passage during pregnancy. The Journal of urology, 186: 2280, 2011 Preminger, G. M., Tiselius, H. G., Assimos, D. G. et al.: 2007 guideline for the management of ureteral calculi. The Journal of urology, 178: 2418, 2007 Carpenter, R. G., Irgens, L. M., Blair, P. S. et al.: Sudden unexplained infant death in 20 regions in Europe: case control study. Lancet, 363: 185, 2004 Moon, R. Y.: SIDS and other sleep-related infant deaths: expansion of recommendations for a safe infant sleeping environment. Pediatrics, 128: 1030, 2011 Cao, D., Yang, L., Liu, L. et al.: A comparison of nifedipine and tamsulosin as medical expulsive therapy for the management of lower ureteral stones without ESWL. Scientific reports, 4: 5254, 2014 Ye, Z., Yang, H., Li, H. et al.: A multicentre, prospective, randomized trial: comparative efficacy of tamsulosin and nifedipine in medical expulsive therapy for distal ureteric stones with renal colic. BJU international, 108: 276, 2011 Weber-Schoendorfer, C., Hannemann, D., Meister, R. et al.: The safety of calcium channel blockers during pregnancy: a prospective, multicenter, observational study. Reproductive toxicology, 26: 24, 2008 Danielsson, B. R., Reiland, S., Rundqvist, E. et al.: Digital defects induced by vasodilating agents: relationship to reduction in uteroplacental blood flow. Teratology, 40: 351, 1989 Yoshida, T., Kanamori, S., Hasegawa, Y.: Hyperphalangeal bones induced in rat pups by maternal treatment with nifedipine. Toxicology letters, 40: 127, 1988 Davis, R. L., Eastman, D., McPhillips, H. et al.: Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. Pharmacoepidemiology and drug safety, 20: 138, 2011 Lennestal, R., Otterblad Olausson, P., Kallen, B.: Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. European journal of clinical pharmacology, 65: 615, 2009

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1.

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27.

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25. 26.

SC

24.

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23.

TE D

22.

EP

21.

Magee, L. A., Schick, B., Donnenfeld, A. E. et al.: The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. American journal of obstetrics and gynecology, 174: 823, 1996 Sorensen, H. T., Czeizel, A. E., Rockenbauer, M. et al.: The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta obstetricia et gynecologica Scandinavica, 80: 397, 2001 Tasian, G. E., Cost, N. G., Granberg, C. F. et al.: Tamsulosin and spontaneous passage of ureteral stones in children: a multi-institutional cohort study. The Journal of urology, 192: 506, 2014 Semins, M. J., Matlaga, B. R.: Kidney stones during pregnancy. Nature reviews. Urology, 11: 163, 2014 Lifshitz, D. A., Lingeman, J. E.: Ureteroscopy as a first-line intervention for ureteral calculi in pregnancy. Journal of endourology / Endourological Society, 16: 19, 2002 Guidelines for diagnostic imaging during pregnancy. Obstetrics and Gynecology, 104: 647, 2004 Lowe, S. A.: Diagnostic radiography in pregnancy: Risks and reality. Australian & New Zealand Journal of Obstetrics & Gynaecology, 44: 191, 2004 Wilder, R. T., Flick, R. P., Sprung, J. et al.: Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology, 110: 796, 2009

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Maternal Demographics and Outcomes Control Group

p-value

N

27

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Mean Maternal Age at Delivery (SD)*

28.42 (4.15)

29.42 (4.67)

0.35

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MET Group

29.14 (7.33)

26.22 (6.16)

0.60

0.04 (0.19)

0.09 (0.35)

0.46

Median Gravidity (IQR)

3 (2-5)

3 (2-4)

0.69

Median Parity (IQR)

1 (0-3)

Spontaneous Abortion

0

Alcohol Use During Pregnancy

2 (7.4%)

0.11

0

N/A

5 (9.3%)

1.00

5 (18.5%)

10 (18.5%)

1.00

0

2 (3.7%)

0.56

11 (42.3%)

1 (1.9%)

<0.0001

16 (59.3%)

16 (29.6%)

0.029

0 (0%)

2 (3.7%)

0.56

3 (11.1%)

4 (7.4%)

0.67

Placenta Previa

1 (3.7%)

0 (0%)

0.33

Preeclampsia

0 (0%)

1 (1.9%)

1.00

Gestational Hypertension

2 (7.4%)

0 (0%)

0.11

Pyelonephritis

0 (0%)

2 (3.7%)

0.56

11 (40.7%)

16 (29.6%)

0.48

2 (2-3)

2 (2-3)

0.43

Illegal Drug Use During Pregnancy Family History of Urolithiasis Prior Episode Urolithiasis Gestational Hyperemesis

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Gestational Diabetes

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1 (0-2)

Smoking During Pregnancy*

Cesarean Delivery

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Median Days Postpartum Hospitalization (IQR) *Variable used for matching

Table 1

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BMI (SD) Mean Charlson Comorbidity Index (SD)

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Patient Symptoms and Work up Control Group

N

27

54

Right-Sided Pain

17 (63%)

39 (72%)

0.48

Left-Sided Pain

9 (33%)

11 (20%)

0.30

Bilateral Pain

1 (4%)

3 (6%)

1.00

Nausea/Vomiting

17 (63%)

29 (53.7%)

0.43

Sepsis

0

1 (1.9%)

1.00

Fever

0

5 (9.3%)

0.16

Urinary Tract Infection

9 (33%)

9 (16.7%)

0.09

5 (18.5%)

10 (18.5%)

1.00

6 (22.2%)

3 (5.6%)

0.054

6 (22.2%)

9 (16.7%)

0.054

6 (22.2%)

12 (22.2%)

1.00

22 (82%)

43 (84.3%)

1.00

19 (70%)

36 (67%)

0.78

21 (78%)

47 (87%)

0.34

CT scan

5 (18.5%)

4 (7.4%)

0.26

Urolith Confirmed by Passage or Removal

14 (52%)

19 (35%)

0.20

Gross Hematuria Urgency Frequency Hydronephrosis

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Urolith Documented on Imaging (Ultrasound, CT, or MRI) Imaging Limited to Ultrasound

Table 2

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Dysuria

p-value

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MET Group

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Perinatal Outcomes

Infants Born to Mothers from MET Group

Infants Born to Mothers from Control Group

27

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Mean Gestational Age, weeks (SD)*

38.1 (2.4)

38.5 (2.2)

0.38

Preterm Delivery (<37 weeks)*

6 (22.2%)

12 (22.2%)

1.00

Mean Birthweight, kg (SD)*

3.47 (0.88)

3.4 (0.56)

0.63

Length, cm (SD)*

51.27 (4.38)

50.31 (2.44)

0.13

Mean APGAR 1 minute (SD)

8.46 (0.83)

7.94 (1.85)

0.21

Mean APGAR 5 minutes (SD)

8.92 (0.28)

8.91 (0.83)

0.98

Head Circumference, cm (SD)

34.8 (2.7)

34.54 (1.8)

0.56

2 (7.4%)

7 (13%)

0.59

2 (7.4%)

0

0.11

20.78 (18.76)

68.12 (36.61)

<0.0001

EP

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N

NICU Admission

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SIDS Mean Infant Follow Up, months (SD) *Variable used for matching

Table 3

p-value

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Gestational Tamsulosin Exposure (N=27)

28

Patient 2

4

Patient 3

3

Patient 4

1

Patient 5

1

Patient 6 Patient 7*

33 †

14

Patient 8 Patient 9

2 1 3 3

3

3

4

2

4

3

1

3

30

2

3

2

1

3

47

3

75

1, 2, 3

2

2

2

3

1

3

110

2, 3

2

2

2

3

Patient 23

2

3

Patient 24

31

3

Patient 25

1

1

Patient 26

2

2

Patient 27

15

3

Patient 10 Patient 11 Patient 12 Patient 13 Patient 14

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Patient 15 Patient 16 Patient 17 Patient 18

EP

Patient 19 Patient 20

Patient 21*

†

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Patient 22

*SIDS † NICU Admission

Table 4

2, 3

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4

2, 3

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Patient 1

Trimesters of Exposure

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Total Days of Exposure

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ABBREVIATIONS

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MET = medical expulsive therapy