Pregnancy and Urolithiasis 

Although pregnancy-induced urinary stasis and hypercalcemia of pregnancy have been proposed as likely etiologic factors in urolithiasis, this has been disputed. Pregnancy-related events that tend to enhance stone formation include decreased ureteral peristalsis, physiological hydronephrosis, infection, and increased urinary calcium excretion. Augmented excretion of urolithiasis inhibitors, such as citrate, magnesium, and glycosaminoglycans, neutralize these phenomena in pregnant patients, who are no more likely to form urinary calculi than nonpregnant patients.[9] Coincident to the increased hypercalciuria in pregnancy is an increase in total circulating blood volume, making the relative supersaturation of calcium insignificant.

Anatomic and physiologic changes during pregnancy

Hydroureteronephrosis is the most significant renal alteration during pregnancy. Physiologic dilatation of the collecting system begins in the first trimester at 6-10 weeks' gestation and persists until 4-6 weeks following delivery.[10] Early theories suggest that hydronephrosis of pregnancy may be a hormonally induced phenomenon whereby ureteral smooth muscles relax in response to high levels of circulating progesterone. In early pregnancy, increased progesterone secretion dilates the ureters and reduces ureteral peristalsis, causing hydronephrosis. Alternatively, the predominant theory ascribes ureteric dilatation to compression of the ureter by the enlarging gravid uterus at the level of the pelvic brim, where the ureter crosses the iliac vessels.

Dilatation is greater on the right side than on the left because of pressure due to physiologic engorgement of the right ovarian vein and dextrorotation of the uterus.[11] Swanson and associates (1995) observed that hydroureteronephrosis was not routinely found below the pelvic brim and was altogether absent in patients who had undergone urinary diversion.[10]

Volume changes during pregnancy

Glomerular filtration rate (GFR) and renal plasma flow (RPF) increase by as much as 25-50% during pregnancy. Both of these changes are attributable to increases in cardiac output, decreases in renal vascular resistance, and increases in serum levels of progesterone, aldosterone, deoxycorticosterone, placental lactogen, and chorionic gonadotropin. GFR and RPF enhancements also contribute to the increase in glucose, amino acid, protein, and vitamin secretion. As a result of the GFR and RPF modulations, which peak at 9-11 weeks' gestation, renal volume increases during pregnancy by as much as 30% above the reference range. The sustained elevation of prolactin levels in the pregnant patient has a growth hormone–type effect by increasing the glomerular surface area, which also contributes to an increase in renal volume.

Along with increases in GFR and RPF, the filtered load of sodium, calcium, and urate increases. Although calcium and urate excretion increases, sodium excretion remains unchanged. The urinary excretion rate of calcium stone inhibitors, such as citrate and magnesium, also increases in the pregnant patient; likewise, increased glycosaminoglycans and acidic glycoproteins inhibit oxalate stone formation (eg, nephrocalcin). This explains why pregnancy is not associated with a net increase in the rate of stone formation relative to nonpregnant patients. The net effect of these physiologic changes is a stable relative supersaturation of important ions such as calcium oxalate, urate, and phosphate.

Uric acid stone formation

The formation of uric acid stones requires continued and excessive oversaturation of urine with uric acid or extreme aciduria. Dehydration, hyperuricosuria, and significantly acidic urine contribute to uric acid supersaturation and stone formation. However, during gestation, urine tends to be more alkaline, probably because of greater intrinsic purine use and increased urinary citrate excretion. Thus, renal units are generally protected against uric acid stone formation during pregnancy.

Calcium oxalate and calcium phosphate stone formation

Stone composition in pregnant women is predominantly (74%) calcium phosphate, with only 26% being calcium oxalate. With nonpregnant stone formers, in contrast, nearly 75% of stones are of calcium oxalate composition. The exact reasons remain unclear but may be pH related, which may explain why stone disease during pregnancy has remained stable while rising in nonpregnant women.[12]

Although pathologic calcium oxalate supersaturation has been identified in the urine of pregnant women, the incidence of crystalluria is no higher than in women who are not pregnant. In the pregnant patient, physiologic absorptive hypercalciuria is due to elevated levels of serum 1,25 dihydroxycholecalciferol (1,25 vitamin D). This hormone, which is secreted by the placenta, augments calcium absorption in the GI tract and suppresses parathormone production, increasing renal excretion of calcium.

Additionally, dietary supplementation of calcium during gestation further augments calcium excretion. Some reports suggest that calcium excretion increases 200-300% compared with that in healthy patients who are not pregnant. However, increased concentration of the aforementioned urolithiasis inhibitors present in urine during gestation and increased urine fluid output counters the increased risk imposed by any hypercalciuria.

Struvite stones

Struvite stones form only when the urinary tract is infected with urea-splitting organisms (eg, Proteus species). These infected stones are usually composed of pure magnesium ammonium phosphate but may be formed around a coexisting calcium, uric acid, or cystine stone. Struvite stones appear to develop more commonly in the presence of a congenital abnormality of the collecting system.

Stone formation during pregnancy does not appear to have any etiologic factors that are unique to pregnancy. Risk factors associated with urolithiasis in general include the following:

• Family history
• Age (third to fifth decades of life)
• Decreased water intake
• Increased environmental temperature and/or dry climate
• Diet (eg, high in calcium, sodium, and red meat consumption)
• Excessive weight or obesity (apparently a risk factor in women but not in men)
• Diabetes

The incidence of urolithiasis in pregnancy vary widely from 1:188 to 1:4600, with lower incidences typically found in unreferred populations.[3] The incidence of symptomatic nephrolithiasis complicating pregnancy has been reported as 1 in 3300 pregnancies.[4]  

While in the past, rates of urolithiasis were similar in pregnant women and age-matched nonpregnant women, a 2014 review of two decades of data from a tertiary women's hospital found that while the number of patients with nephrolithiasis increased significantly, the number of pregnant patients with nephrolithiasis did not. From 1991-2000 to 2001-2011, the number of patients with nephrolithiasis increased significantly, from 78 to 226 a year (P = 0.004). However, the rise in the number of pregnant patients with nephrolithiasis, from 36 to 47 (P = 0.1), was not significant.[12]

Approximately 80-90% of pregnant patients with urinary calculi present with symptoms during the second or third trimester, because spontaneous stone passage is more difficult at this stage of pregnancy.[5]  Ureteral stones occur twice as often as kidney stones in pregnant patients.[3]

White women are more commonly predisposed to the development of urinary calculi. Hispanic, black, and Asian women exhibit less incidence and prevalence of calculi formation. The exact cause of this discrepancy is not known, but variations in dietary patterns may contribute. Calculi in black individuals are more likely to become infected than those in white individuals.[3]

Urinary stones in women usually manifest during the third to fifth decades of life, with an average age of 24.6 years. The reported incidence of urolithiasis is higher in men, with a male-to-female ratio of 3:1, although this ratio is decreasing, possibly because of dietary or obesity trends in the United States.[12]  

 

Diagnosis and treatment of urolithiasis in pregnancy is complex. However, advances in technology and experience allow urologists to provide accurate evaluation and succeed with either temporizing or definitive treatments. These can be accomplished safely, with little risk to the mother or fetus. With prompt evaluation and expeditious treatment, the prognosis is excellent.

Approximately 64-84% of renal calculi pass spontaneously with conservative management,[6, 7] especially if they 4 mm or smaller. Stones that are 7 mm or larger are much less likely to pass without intervention and often require some type of treatment.

Symptomatic urolithiasis does not appreciably worsen pregnancy outcome. Occurring in about 10-20% of patients, urinary tract infection is the most common nonobstetric complication of urolithiasis in pregnancy. Premature labor associated with renal colic is rare but can occur. In the past, spontaneous abortion has been associated with a history of urolithiasis but it is extremely rare today.

Urolithiasis associated with ureteral obstruction and upper urinary tract infection mandates immediate treatment; this is a true urologic emergency that can potentially lead to urosepsis, perinephric abscess formation, or even death in pregnant women. Urolithiasis in a pregnant patient may precipitate premature labor or interfere with the progression of normal labor, which poses a significant health risk to the fetus.[3]

Urolithiasis in pregnancy poses a diagnostic challenge. Clinical manifestations of urolithiasis in pregnant patients often resemble signs and symptoms of pregnant patients without stones, not to mention many other sources of abdominal pathology (see DDx).[13]

Flank pain (89%) and hematuria (95%) are the most common symptoms of kidney stones[7] ; however, these findings may also represent physiologic changes of pregnancy. Pregnancy-induced hydronephrosis can cause flank pain and even mimic renal colic,[14] and microanatomic alterations in venous fragility of the collecting tubules may cause hematuria.[15] Aside from its presentation in normal conditions, hematuria without discomfort is rare in the presence of a calculus.[10]

Alternatively, pregnant patients with ureteral stones may report pain in atypical locations or the pain of premature labor. Signs of premature labor, ectopic pregnancy, or complicated labor often mimic clinical symptoms of renal-ureteral calculi. Therefore, maintaining a high degree of suspicion in all pregnant women with abdominal or pelvic pain, hematuria (gross or microscopic), or unresolved urinary tract infections is imperative.

The most common symptoms of urolithiasis of pregnancy include the following:

• Flank pain
• Pain radiating to the groin or labia
• Nausea
• Dysuria
• Gross hematuria

Less-common symptoms of urolithiasis include the following:

• Lower abdominal pain
• Fever/chills
• Vomiting

Other important historical findings pertinent to urolithiasis include the following:

• Recurrent or persistent urinary tract infection (especially during the current pregnancy)
• History of previous calculi, either in a previous pregnancy or in the nonpregnant state
• Prior urologic surgery
• History of prior complicated pregnancy or premature delivery

Sites of urolithiasis may be localized based on the patient's description of pain, as follows:

• Urolithiasis that obstructs at the ureteropelvic junction generally manifests as deep flank pain without radiation to the groin

• Urolithiasis within the mid-portion of the ureter can cause severe and intermittent pain, pain in the flank, and ipsilateral lower abdomen pain with radiation to the vulvar area

• Urolithiasis in the distal ureter or ureterovesical junction may manifest as pain that radiates to the labia, and irritative voiding symptoms such as urinary frequency and dysuria

Patients with renal colic are often extremely restless, exhibiting active movement on presentation.  On inspection, the abdomen may be moderately distended, especially if the patient has coexisting ileus.  On palpation, the abdomen is soft and tender in the upper quadrant. This differs significantly from the motionless presentation and rigid abdomen of a patient with peritonitis.

On auscultation, bowel sounds do not provide helpful clues because they may range from hyperactive to markedly diminished because the patient may have concurrent ileus. Other possible signs and symptoms include the following:

• Costovertebral angle tenderness
• Generalized flank tenderness
• Voluntary guarding of the abdominal musculature

Laboratory studies in pregnant patients with possible urolithiasis include the following:

• Urinalysis -To assess for microscopic hematuriaSerum chemistry studies, including a renal panel
• Urine culture - To identify the offending bacteria and determine antibiotic sensitivities
• Complete blood cell (CBC) count - To determine the presence or absence of systemic infection
• Metabolic studies - To guide stone prevention

Urinalysis

Consider the following:

• The presence of red blood cells may suggest a calculus
• Using both dipstick and microscopic analysis can identify microscopic hematuria in 95% of patients with urinary stones
• Pyuria, which can result from an inflammatory reaction to a stone or infection, mandates evaluation for a coexisting urinary tract infection. Urinary tract infection is present in approximately 31% ^[7]
• Urine pH greater than 7 may signal the presence of infected stones (magnesium-ammonium-phosphate) with urea-splitting organisms (eg, Proteus and Klebsiella species)
• Acidic urine (pH < 5) suggests the presence of a uric acid stone

Renal panel

Decreased serum bicarbonate and potassium levels suggest an underlying renal tubular acidosis that may result in the formation of calcium phosphate stones. Elevated serum calcium levels might suggest possible primary or secondary hyperparathyroidism. Hyperuricemia suggests possible gouty diathesis and hyperuricosuria, which can increase the risk for both uric acid and calcium stone formation.

Elevated serum creatinine levels suggest azotemia due to ureteral obstruction or chronic renal insufficiency. The physiologic increase in glomerular filtration rate (GFR) during pregnancy dictates that the serum creatinine and BUN levels should be nearly 25% less than levels in the nonpregnant patient.[17]

Metabolic studies

For patients with a sincere interest in reducing their risk of developing additional urinary stones, a 24-hour urine collection for stone prevention analysis is recommended. However, because of the physiologic and electrolytic changes associated with pregnancy, metabolic studies should be postponed until completion of pregnancy. Patients undergoing metabolic analysis studies should be willing to make long-term changes in their diet or lifestyle and take medications and/or supplements to help reduce their risk of new stone formation.

The metabolic evaluation should include, as a minimum, a 24-hour urine collection and determination of total volume and sodium, oxalate, citrate, uric acid, calcium, phosphate, and magnesium. Various commercial programs are available from laboratories such as Mission Pharmacal, LabCorp, Litholink, Dianon Systems, Nichols, and UroCor. All of these provide accurate and reliable results from the 24-hour urine collections.

The cornerstone of the metabolic evaluation is the stone analysis. All patients should be encouraged to strain urine until the stone passes or repeat imaging is performed.

Radiologic diagnosis of urolithiasis in pregnant patients is complicated by the physiologic and hemodynamic changes of pregnancy, such as increased renal blood flow (RBF) and GFR, in addition to the concern for fetal radiation exposure. Delay in diagnosis or inappropriate therapy may risk maternal renal damage, premature labor, spontaneous abortion, pyonephrosis, and/or maternal hypertension. Tailor the diagnostic evaluation and management of the gravid patient to the individual.[18]

The use of ionizing radiation during pregnancy is a complicated and controversial issue. Radiographic studies should be used judiciously and avoided when possible, particularly during the first trimester. The guidelines available from the American College of Obstetricians and Gynecologists (ACOG) stress the need to weigh the risks of exposure to radiation and contrast agents with the risk of nondiagnosis and worsening of disease.  Fetal risk of anomalies, growth restriction, or abortion have not been reported with radiation exposure of less than 50 mGy, a level above the range of exposure for most diagnostic procedures.  In rare cases in which there are exposures above this level, patients should be counseled about associated risks to the fetus.[19]

Estimated fetal radiation exposure for common diagnostic procedures used in the workup of urolithiasis in pregnancy are as follows[20] :

• Ultrasonography: None
• MRI (< 1.5 T): None
• Kidneys, ureters, and bladder (KUB) radiograph: 0.5–1 microSieverts (mSV)
• Intravenous urography (IVP): 1.3–3.5 mSV
• Regular-dose noncontrast computed tomography (CT): 4.5-5 mSV
• Low-dose noncontrast CT: 0.97-1.9 mSV
• Enhanced CT: 25-35 mSV

Renal ultrasonography, with or without Doppler studies, is recommended as the primary imaging modality in pregnant women. In the event that ultrasonography findings are equivocal and clinical symptoms strongly suggest renal calculi, a limited IVP with reduced films and radiation exposure may be performed. If the ultrasonography and limited IVP test findings are unclear, additional tests or procedures may be indicated, depending on the clinical scenario. However, many experts suggest proceeding directly to ureteroscopy for diagnosis and treatment when this procedure is indicated, especially in the first and second trimesters.[21, 22, 23] Radiation exposure in the third trimester is less of a risk to the fetus.

Ultrasonography

Renal ultrasonography is the first-line screening tool for urolithiasis in pregnant patients. Stothers and Lee (1992) found that renal ultrasonography provided a sensitivity of 34% and specificity of 86%,[7] yet Parulkar et al (1998) reported 95% and 87%,[6] respectively. The sonogram may not actually show the stone.

However, false-positive results may occur in the setting of extrarenal pelvis, vesicoureteral reflux, a high urine-flow rate, parapelvic cysts, and crossing vessels within the renal sinus. Up to 35% of patients with documented acute ureteral obstruction may not demonstrate any significant hydronephrosis, which makes standard ultrasonography less useful. Furthermore, differentiating hydronephrosis caused by an obstructing calculus due to physiologic dilation of pregnancy may be difficult.

Advantages of renal ultrasonography include avoidance of radiation exposure to the fetus, no pain, avoidance of proallergenic intravenous contrast material, and the ability to examine coexisting abdominal or pelvic disease etiologies.

Vaginal ultrasonography

This has been found valuable in revealing stones in the distal ureter that are not visualized with renal ultrasonography. Laing et al (1994) reported that distal ureteral stones were identified in 13 of 13 patients; renal ultrasonography revealed the distal stones in only 15% of the 13 patients. Laing et al also observed that patients tolerated the procedure well.[24] Loughlin and Ker (2002) endorse the use of a transrectal ultrasonography probe if a vaginal transducer is unavailable.[25]

Renal ultrasonography with Doppler sonography

In contrast to standard renal ultrasonography, ultrasonography with Doppler studies enables recording of waveform tracings of the renal vasculature. Ureteric obstruction increases renal vascular resistance, resulting in a reduction of diastolic blood flow and a rise in renal resistance. Based on waveform tracings, a resistive index (RI) value is calculated (RI = peak systolic velocity - peak diastolic velocity / peak systolic velocity), providing improved sensitivity and specificity for differentiating obstructed from nonobstructed dilated collecting systems. An elevated RI value of greater than 0.70 is specific for ureteral obstruction. Alternatively, a difference in the RI of 0.04 or more between the affected and contralateral kidney also suggests an obstruction in the side with the higher RI value.

Shokeir and Abdulmaaboud (1999) also evaluated the change in RI, which showed increased sensitivity (88%) and specificity (98%) in diagnosing ureteral obstruction.[26]

Color Doppler renal sonography is a new addition to sonographic visualization of calculi, with a reported sensitivity of 100% and a specificity of 91% for diagnosing ureteral obstruction. This important study demonstrates the presence of ureteral jets (streams of densely opacified urine) flowing into the bladder (containing dilute nonopacified urine). The absence of these jets may suggest ureteral obstruction, while symmetric jets indicate the absence of obstruction. In addition, color Doppler studies also aid in differentiating iliac vessels from a dilated ureter.

Equivocal sonographic results that do not suggest either physiologic hydronephrosis of pregnancy or urolithiasis require further imaging with limited excretory urography.

Summary

Disadvantages of renal sonography include the following:

• Suboptimal determination of the level of obstruction

• Difficulty in showing the ureters and intraureteral calculi

• Possible difficulty differentiating physiologic hydronephrosis of pregnancy from acute obstructive hydronephrosis

• Unable (in most cases) to determine the size or shape of the urinary calculi

• Difficulty visualizing calculi obscured by overlying bony structures, fetal skeleton, or fecal material

• Operator dependent

Disadvantages of renal sonography with color Doppler include the following:

• Relies on elevated urine output and density differences between urine in the bladder and urine existing within the ureter

• Degree of asymmetry of the ureteral jets unaltered from reference range because of calculi causing low-grade or no obstruction

• Operator dependent

Normal findings on renal sonography are as follows:

• Degree of renal and ureteral dilation consistent with pregnancy

• RI value of less than 0.70 in both kidneys

• Symmetric ureteral jets

• No specific calculus identified

The following results indicate a high probability of urolithiasis during pregnancy:

• Greater degree of dilatation disproportionate to hydronephrosis of pregnancy in collecting system

• RI value greater than 0.70 in the symptomatic kidney or change in RI greater than 0.60[26]

• Dilated ureter extending below the level of the iliac arteries

• Asymmetry of ureteral jets

• Identification of calculus

Excretory urography

Excretory urography remains an important diagnostic modality for stone detection in nonpregnant women, allowing the investigator to accomplish the following:

• Establish the presence of an obstruction

• Locate and determine the size of the offending calculus

• Estimate renal function

• Identify anatomic abnormalities that may alter the treatment algorithm

• Detect altered renal physiology secondary to obstruction

Intravenous urography (IVU or IVP) consists of initial KUB film followed by a second radiograph obtained 20-30 minutes after the intravenous injection of a contrast medium. The initial KUB radiograph exposes the fetus to 0.002 Gy; however, because the standard IVU necessitates four or five films, the patient may be exposed to a total of 0.004-0.01 Gy. The dose of radiation during IVU has been reported to be safe to the fetus during the second and third trimesters.

Limited IVP, however, has been shown to successfully reveal calculi without the high radiation dose of full IVP. Stothers and Lee (1992) recommend a scout film, a 30-second film, and a 20-minute film. They report successful visualization of 16 of 17 stones in pregnant patients who presented with acute renal colic.[7] See the image below.

Indications for excretory urography in a pregnant patient may include the following:

• Sonography results that are equivocal for pregnancy dilatation or urolithiasis

• Azotemia suggestive of postrenal obstruction

• Persistent fever or persistent positive finding on urine culture despite 48 hours of parenteral antibiotic treatment

• Massive hydronephrosis on abdominal ultrasonography

Disadvantages of IVU include the following:

• Risk of intravenous contrast allergy in the mother and fetus

• Risk of radiation exposure to the mother and fetus

• Possible ambiguous differentiation between delayed excretion of contrast material from calculus obstruction and pathologic hydronephrosis, especially in the third trimester

• Small ureteral calculi obscured by enlarged uterus during IVU studies, especially in the third trimester

Magnetic resonance imaging

MRI provides high-quality images of the kidneys and urinary tract with obstruction and is used by some as second line to ultrasonography.  However, MRI visualizes stones poorly; it cannot demonstrate the actual stone, only the point of obstruction. MRI does provide a benefit in its ability to reveal non–urinary-tract pathology that may manifest with similar symptoms (ie, ovarian torsion, appendicitis)[27]

Using T2-weighted imaging, MRI urography can be used to differentiate a physiological upper tract dilatation from a pathologic ureterohydronephrosis during pregnancy and to ascertain whether the obstruction is intrinsic or extrinsic

MRI does not use ionizing radiation or iodinated contrast, but its use during the first trimester is not recommended because the effect of MRI on fetal development is not clear. Other disadvantages include expense, discomfort for the pregnant patient, and a lack of availability.

Nuclear renal scan

Nuclear renal scan using Tc 99m DTPA (technetium-99 diethylene-triamine-pentaacetate) is an excellent study for objectively establishing the differential renal function and the efficiency of drainage of the dilated collecting system (washout times). DTPA is cleared almost exclusively by glomerular filtration. The rate of clearance provides an excellent estimate of GFR. However, nuclear studies do not allow visualization of stones and provide very limited illustration of anatomy. Differing opinions exist on its utility in the diagnosis of urolithiasis in pregnancy.[11, 17]

Interpretation is as follows:

• A drainage half-time of 20 minutes or more indicates obstruction, whereas a drainage half-time of 10 minutes or less indicates nonobstruction

• Washout or drainage half-times of 10-20 minutes are considered indeterminate

Computed tomography

Unenhanced helical CT scanning is reported to be highly sensitive (96-97%) and specific (96-99%) and has become the criterion standard in the diagnosis of urinary calculi. It is also effective in differentiating calculi from tumors or blood clots. Despite these benefits, this study has traditionally been avoided in pregnant patients and guidelines recommend restricting CT to selected cases.[19, 28]

Ureteroscopy has emerged as a safe and efficient way to treat urolithiasis during pregnancy.[21] Ulvik and associates (1995) have used ureteroscopy to successfully treat urolithiasis and consider it as a diagnostic procedure in difficult cases.[23] Rigid or flexible ureteroscopes may be used, but Ulvik et al feel that flexible scopes may be better suited in diagnosis during pregnancy.

Rittenberg and Bagley reported the use of ureteroscopy for diagnosis with local anesthesia alone in 1988.[29] Currently available ureteroscopes are small and may be used with minimal or no anesthesia.[21, 30] Lemos and coworkers (2002) feel that ureteroscopy used solely for diagnosis may be aggressive but agree that it can be used as a single modality for diagnosis and removal of ureteral calculi in pregnancy.[22] Ureteroscopy offers clear-cut diagnosis, with direct visualization, as well as definitive therapy in the same encounter.

Retrograde pyelography

This can successfully reveal ureteral stones in cases with ambiguous sonography and IVU results. However, this study is performed only during stent placement because of the invasiveness of the examination, possible introduction of bacteria and risk of sepsis, and the need for radiation, sedation, and cystoscopy. Routine retrograde pyelography is not recommended for documentation of ureteral calculi in pregnant patients.

The initial management of urolithiasis in pregnancy should be conservative. Intravenous hydration and analgesia have been shown to result in spontaneous passage of symptomatic calculi in 64-84% of patients.[6, 7]  Bed rest, antiemetics, and antibiotics are also important, when indicated. Some stones may simply become asymptomatic, allowing delay of further treatment. Symptomatic urolithiasis is more likely to resolve when calculi are located in the renal pelvis as opposed to the distal ureter.[31]

Extracorporeal shockwave lithotripsy (ESWL) is contraindicated in pregnancy due to animal studies associating this treatment with fetal death and malformations.[32]

Treatment goals in the remaining patients are to reduce maternal discomfort, to prevent renal damage and sepsis due to obstructing calculi, and to minimize risks to the fetus. If conservative measures fail to relieve clinical symptoms or to pass calculi, appropriate surgical intervention should be undertaken.

Urine should be strained to obtain stones when they are passed. Chemical analysis should then be performed to guide postpartum treatment and diet modifications to prevent future stone formation. However, because of the physiologic and electrolytic changes associated with pregnancy, metabolic studies should be postponed until completion of pregnancy.

Pain management 

Several narcotics have been tested for use during pregnancy. Morphine sulfate, hydromorphone, butorphanol, meperidine, and acetaminophen provide temporary symptomatic relief without harming the fetus. However, avoid codeine during pregnancy because of its association with fetal defects. Long-term use of narcotics in pregnancy can lead to fetal narcotic addiction and even intrauterine growth retardation (IUGR) or premature labor.[33]

Nonsteroidal anti-inflammatory drugs (NSAIDs) are also contraindicated because of an increased risk of miscarriage when used in the first trimester. In addition, fetal renal anomalies, fetal pulmonary hypertension, and premature closure of the ductus arteriosus are risks when NSAIDS are prescribed close to term.

Medical expulsive therapy (MET) 

Medical expulsive therapy (MET) is a pharmacologic approach thought to augment the spontaneous passage of ureteral calculi. Ureteral stone passage may be facilitated by alpha-adrenoceptor blockers. These agents promote relaxation of ureteral smooth muscle and have been found to increase rates of stone passage, to hasten stone passage, and to decrease the amount of pain associated with stone passage.[34, 35]

Small retrospective studies of women receiving the alpha adrenergic blocking agent tamsulosin as medical expulsive therapy found no significant differences in maternal or infant outcomes for any of the examined variables compared with the control group. These results suggest it may be considered as adjunctive therapy for urolithiasis during pregnancy.[36, 37]

However, the usage of MET drugs in pregnancy has not been well studied, and both their safety and utility are still unknown. The super-selective alpha blockers tamsulosin and alfuzosin are considered Pregnancy Category B drugs, while the nonselective alpha blockers terazosin and doxazosin, calcium channel blockers, and glucocorticoid are all considered Pregnancy Category C. Selective alpha 1a blockers have not been approved by the US Food and Drug Administration (FDA) for use during pregnancy; thus, their use in the treatment of stone disease is also considered off-label.[38]  

Calcium stone disease

Medical management for reduction of calcium stone disease is contraindicated. Thiazide diuretics, which markedly reduce calciuria and resultant stone formation, are a viable treatment option for urolithiasis in the general population. However, thiazide diuretics are contraindicated during pregnancy because they may induce fetal thrombocytopenia, hypoglycemia, and hyponatremia. Additionally, diuretics are generally dangerous because they may interfere with the normal extracellular volume expansion of pregnancy.

The safest method of medically managing calcium stone disease during pregnancy is to increase fluid intake and to avoid excessive calcium intake (including calcium-fortified prenatal vitamins). Typically, calcium intake should not exceed 1000-1200 mg/d during pregnancy. This treatment may prevent or reduce the risk of urolithiasis during pregnancy. Sodium intake and protein consumption should also be curtailed.

Uric acid disease

In uric acid stone disease, xanthine oxidase inhibitors (eg, allopurinol) prevent uric acid stone formation by inhibiting the final step in human purine metabolism, thereby decreasing both serum and urinary uric acid levels. However, use of xanthine oxidase inhibitors is contraindicated during pregnancy because the effects of the drug on the fetus are unknown. Alternative treatment modalities for uric acid stones during pregnancy include increasing fluid intake, limiting dietary purine intake, and increasing urinary alkalinization.

Cystine stone disease

Patients with cystine stone disease often have known cystinuria prior to conception. Despite contraindications to the use of common drug therapy, research has shown that careful medical management can allow women with cystinuria who form stones to safely undergo pregnancy without increased risk.

Penicillamine reduces cystine stone formation by interchanging disulfide bonds with cystine residues, thereby separating cystine-cystine bonds and allowing increased cystine solubility. Severe or serious adverse effects occur in about 50% of patients. Because penicillamine has been reported to cause fetal abnormalities in rats, it is contraindicated during pregnancy.

Increasing urinary volume to 3000 mL and urine alkalinization to an optimal urinary pH of around 7.5 are alternative means to treat cystinuria during pregnancy. However, patients with high urinary excretion of cystine (ie, >300 mg/24 h) may need low-dose penicillamine treatment. Studies performed by Gregory and Mansell (1983) suggest that the risk of recurrent stone formation may outweigh the theoretical risks of penicillamine exposure in this particular situation.[8]

Alpha-mercaptopropionyl glycine (alpha-MPG) is an alternative to penicillamine. It has the same mechanism of action and is roughly equal in efficacy, with somewhat fewer and milder adverse effects. Like penicillamine, it is contraindicated in pregnancy.

Surgical intervention is required in 20-30% of pregnancies complicated by urolithiasis.[11] Surgical strategies include placement of a ureteral stent or percutaneous nephrostomy, to provide temporizing drainage of an obstructed system until completion of the pregnancy, or ureteroscopic methods to definitively diagnose and treat the stone.

A broad spectrum of interventions, ranging from ureteral stent placement to open lithotomy, have been used to successfully treat urolithiasis in pregnancy[9] ; however, regardless of the mode or invasiveness of the surgical intervention (eg, endoscopic, percutaneous, open), each carries an element of risk to the mother and fetus. Thus, surgical intervention is reserved for pregnant patients in whom conservative management fails or when surgery is otherwise indicated. Admission of these patients by the obstetrician service for consultation with a urologist is not unusual. As a result, most if not all, of these women undergo noninvasive fetal monitoring.

Indications

Indications for surgical intervention include the following:

• Ureteral obstruction associated with increasing azotemia
• Obstruction in a solitary kidney
• Intractable pain despite maximal conservative measures
• Urosepsis
• Renal colic–induced premature labor unresponsive to tocolytics

Temporizing measures

Traditional treatment has consisted of initial placement of a percutaneous nephrostomy tube or insertion of a ureteral stent for temporary drainage.[9] Ureteral stents and/or nephrostomy tubes are then changed at periodic intervals until delivery, thus allowing delay of definitive treatment until completion of pregnancy.

Ureteroscopy

Ureteroscopy is gaining favor as a first-line approach to urinary calculi that require intervention.[21, 39, 30, 23] Improved instruments and increased experience have led to successful outcomes with few complications. Disbanding of supposed limitations (anatomical distortion late in pregnancy) and resolution of many associated concerns (anesthesia, radiation) has resulted in advocacy from previous opponents.[40, 17] These significant changes represent a paradigm shift in intervention for urolithiasis in pregnancy that is unresponsive to conservative treatment.

A study of serial stenting vs ureteroscopy for treatment of urolithiasis during pregnancy found that ureteroscopy was less costly and more effective for urolithiasis, irrespective of gestational age at diagnosis but most beneficial for women who received the diagnosis early during pregnancy.[41]

Ureteral stent placement

Internal stents are usually placed with ultrasound guidance or limited fluoroscopy with local anesthesia. This minimizes risks of radiation and anesthesia to the fetus. Increasing oral hydration and decreasing calcium intake is recommended to prevent stent encrustation secondary to urinary stasis, hypercalciuria, or infection. Replacing stents every 3-4 weeks and antibiotic prophylaxis are suggested to avoid urinary tract infection and calcification.[9] Insertion of percutaneous nephrostomy tubes or ureteral stents is considered a minor procedure, yet repeated insertions or changes may carry risks comparable with those of definitive ureteroscopy in a single setting.[23] The obstetrician should be involved for fetal monitoring.

Ureteral stents often cause irritative voiding symptoms and chronic discomfort.[42] The physiologic hydroureteronephrosis of pregnancy has been found to aggravate that by allowing more frequent stent migration within the dilated system.[43] Parulkar and coworkers (1998) studied a group of 70 pregnant patients with urolithiasis; 19 patients required intervention, 15 of whom had ureteral stents placed. They reported that 5 of 15 patients (>30%) required subsequent manipulation because of migration, encrustation, or severe irritative symptoms.[6]

Denstedt and Razvi (1992) recommend limiting ureteral stent placement until after 22 weeks of pregnancy, with use of a percutaneous nephrostomy prior to that point.[9] If a ureteral stent is indicated but cannot be placed with ultrasound guidance or if urosepsis is present, a percutaneous nephrostomy tube should be placed instead.

Disadvantages to internal ureteral stent include the following:

• Urinary tract infections and promotion of ascending infections
• Hematuria
• Irritative voiding symptoms and renal colic due to stent
• Stent migration due to hydroureteronephrosis of pregnancy
• Multiple procedures to change stent to avoid encrustation
• Need for patient compliance and vigilant follow-up for stent change

Percutaneous nephrostomy

Use this treatment modality in patients with urosepsis or pyonephrosis. This procedure can be performed with local anesthesia and ultrasound guidance. Nephrostomy tube placement allows for rapid and adequate decompression of the upper urinary tract, control of pain due to acute obstruction, and resolution of the infected hydronephrosis. Another advantage of placing a percutaneous nephrostomy tube is that it may be used for antegrade irrigation with an antibiotic solution to decrease the risk of infection and tube encrustation.[44] Internalization of a double-J stent can be performed after recovery from the original illness. This procedure needs to be performed by a physician experienced in percutaneous procedures. Disadvantages to percutaneous nephrostomy include the following:

• Bacteruria despite preventive antibiotics
• Frequent obstruction, requiring change and/or flushing
• Cumbersome external appliance
• Risk of bleeding
• Discomfort

Percutaneous nephrolithotomy

Percutaneous nephrolithotomy (PCNL) is usually considered contraindicated in the pregnant patient due to the prolonged use of fluoroscopy and general anesthesia, and the need for the patient to be in a prone position.[32] However, there have been case reports of successful use of PCNL to treat urolithiasis during pregnancy with no major complications.  A review of 16 cases of PCNL during pregnancy concluded that the procedure was feasible if performed by an experienced endourologist as part of a multidisciplinary medical team.[37]

Ureteroscopy and stone manipulation

Ureteroscopy allows for complete visualization of the entire ureter and renal pelvis, enabling accurate diagnosis and definitive treatment for urolithiasis. Anatomic distortion near the completion of pregnancy has long been thought to make ureteroscopy impossible; however, ureteroscopy has been found to be safe and effective in all stages of pregnancy.[21, 39, 30, 23] Scarpa et al also found that rigid ureteroscopy could be performed on the entire urinary tract, even in advanced pregnancy.[30] The above group of series, along with the work of Lemos and associates,[22]  represent 68 patients who underwent ureteroscopy for diagnosis and/or treatment; no obstetrical complications were reported, and only one ureteral perforation was reported. The one perforation[23] was treated successfully with a stent, and the child was born healthy at term.

Most ureteroscopies are performed without use of radiation. In the above studies, radiation was used sparingly in only a few patients; furthermore, Ulvik et al (1995)[23] and Scarpa et al (1996)[30] used no radiation. Physiologic hydroureteronephrosis of pregnancy allows entry of the ureteroscope under direct vision without dilation of the ureteral orifice; dilation is rarely performed.[11, 30, 23]

General anesthesia is rarely used. The vast majority of procedures have been performed with epidural or spinal analgesia with an element of sedation. Scarpa et al performed ureteroscopies in five patients without anesthesia and used only neuroleptic anesthesia (fentanyl or propofol and atropine) in 10.[30] Ulvik et al concluded that sedation analgesia may be preferred to spinal or general anesthesia.[23] Both rigid and flexible scopes have been used successfully.

In a study by Rivera et al of 26 women with urolithiasis during pregnancy, the number of anesthetic events and the anesthesia time were no different in patients treated with temporizing stents than in those who underwent ureteroscopic stone extraction. In the ureteroscopy group, the median number of anesthetic exposures was 1.18 and the median total anesthetic time was 80 minutes. In the stent group, six of the 15 required multiple stent exchanges for a median of 1.47 anesthetic events and a median total anesthetic time of 70 minutes.[45]

Kavoussi and associates (1998) suggest that definitive ureteroscopy may be preferable to stenting in select patients (particularly patients >6 wk prior to term).[43] Ulvik and associates[23] found that hospital stay was significantly shorter in patients who underwent ureteroscopy patients (mean, 2.7 d) compared with those who received ureteral stents (mean, 7 d).[7]

Stone retrieval via ureteroscopy has been performed successfully in many forms.[46, 21, 30, 23] These include holmium YAG Laser, pulsed dye laser, ballistic lithotriptor, ultrasonic lithotriptor, basket retrieval, and forceps crush and retrieval; all were used successfully without known complications. The holmium YAG laser, with less than 1 mm of penetration, has been used most frequently in the more recent studies.[46, 21, 39]  Akpinar and associates reported that routine stent placement with a string for 72 hours postoperatively reduced pain and analgesic requirements in pregnant patients who underwent ureteroscopy and holmium laser lithotripsy.[46] \

Contraindications to ureteroscopy include the following[11] :

• Stones larger than 1 cm
• Multiple calculi
• Sepsis
• Transplanted kidney
• Ureteroscopic inexperience or inadequate instruments
• Absence of general obstetrical services or high-risk obstetrical services

Open surgery

In the past, pregnant patients who required intervention for urolithiasis underwent open lithotomy or blind stone manipulation under general anesthesia, similar to the general population. However, more modern procedures for surgical treatment of urolithiasis are performed without anesthesia or radiation and carry lower morbidity rates while maintaining equal or greater success rates. Consequently, open surgery is now used as a last resort. Open surgery is used if a stone must be removed before delivery because of complications of conservative or invasive management of urolithiasis, or if contraindications to ureteroscopy are present.

Percutaneous nephrolithotomy (PCNL), when indicated, is best postponed until postpartum because of the risks to the fetus of anesthesia and radiation.[11]

Extracorporeal shockwave lithotripsy (ESWL) is frequently used in the nongravid population; however, it requires frequent use of ionizing radiation, and the potential adverse effects of energy dispersion on the fetus are unknown. At this time, ESWL is contraindicated during pregnancy.[47]

Surgical risk

Physiologic organ system changes increase specific perioperative risk factors in the pregnant patient. Special attention to these risk factors can help prevent associated morbidity to the mother and fetus.

Thromboembolism

Pregnancy-related changes in the cardiovascular and hematologic systems create a hypercoagulable state and place the patient at increased risk of venous thromboembolism and pulmonary embolism. The risk of venous thromboembolism is progressive throughout gestation and, in the third trimester, is estimated to be 5-6 times greater than that for a nongravid female.[17]

The increasing size of the gravid uterus changes the hemodynamics in the lower extremities. Compression of the great vessels by the uterus reduces the velocity of venous blood return, increases pressure, and increases the risk of stasis in the lower extremities.[17] Hematologic changes include increased plasma levels of clotting factors VII, VIII, and X and fibrinogen[33] , as well as a decrease in fibrinolytic activity[17] .

Low-dose heparin is considered safe and effective by some researchers and is recommended in patients with a history of thromboembolism.[48]

Aspiration

Pregnancy-related changes in gastrointestinal function and relative anatomy increase the risk of inadvertent perioperative aspiration. These changes include compromised integrity of the gastroesophageal sphincter, decreased gastrointestinal motility, and a decrease in the pH of gastric secretions.[33] Intravenous proton pump inhibitors provide acid suppression and may be used in the perioperative period as prophylaxis for acid aspiration syndrome during induction of anesthesia.[49]

Fetal risks of anesthesia

Inhalation anesthetics readily cross the placenta because of their lipid solubility. These agents have been shown to increase risk of teratogenicity. General anesthesia should be avoided during the first trimester, after which the risk is minimal.[11]

Management of pregnant patients with urolithiasis should always involve the obstetrician. When treatment beyond conservative measures is indicated, for the fetus' safety, coordinated care with a neonatologist, an anesthesiologist, and a radiologist is appropriate.

Dietary modification is the cornerstone of preventing urolithiasis. General recommendations include dietary moderation of high-oxalate foods and purines with an increase in fluid intake. Salt and sodium intake should also be moderated because of their tendency to increase fluid retention and hypercalciuria. Low-calcium diets frequently cause a paradoxical rise in calcium stone formation and are discouraged.

Specific long-term dietary changes should ideally be based on objective information from the stone composition analysis and 24-hour urine chemistry determinations.

A low-oxalate diet tends to prevent calcium oxalate stone formation. Common foods that are high in oxalate include chocolate, nuts, green leafy vegetables, coffee, spinach, beets, and tea. Moderation and proportionate reductions are suggested rather than complete avoidance of high-oxalate foods that the patient enjoys.

While excessively high calcium ingestion is discouraged, unusually low-calcium diets can also increase stone production by allowing increased oxalate absorption from the gastrointestinal tract. Low calcium intake may also lead to a decrease in calcium deposition in bone, with associated osteopenia and osteoporosis. In general, one calcium meal per day is suggested. If a calcium supplement is being used by the patient, calcium citrate seems to be the least likely to increase calcium stone production because of a compensatory increase in urinary citrate excretion with this particular supplement.

Drinking at least 2 qt of water per day decreases the risk of stone formation. Actually, recommending a fluid intake sufficient to generate a 24-hour urine volume of 2000 mL per day may be better. A patient guide to maintaining an increased urinary volume developed by Stephen W. Leslie, MD, FACS, may be helpful. This recommendation applies to stones of all types. In patients unable to drink the required amount of water, lemonade is a reasonable substitute. Lemon juice is high in citrate, which is a natural inhibitor of kidney stone formation.

A low-methionine diet has been reported to decrease the risk of cystine stone formation. Methionine is a dietary precursor of cystine. However, this diet is unpalatable, and patient compliance is poor. 

Diets that are high in purines and green vegetables may increase the likelihood of stone formation. A low-purine diet decreases the risk of both uric acid and calcium stone formation. This diet requires avoidance of red meats, beef, chicken, fish and peanuts.

Complications secondary to surgical interventions are more common in the pregnant population; however, they are becoming increasingly infrequent with increased experience and improved technology. Physiologic changes of pregnancy are associated with an increase in perioperative risk. Complications of any surgical procedure may include the following:

• Aspiration
• Deep vein thrombosis
• Pulmonary embolism
• Premature delivery

Complications of internal stent placement may include the following:

• Stent incrustation, which may be accelerated in pregnancy and require change every 3-4 weeks ^[9]
• Infection
• Sepsis
• Stent migration

Complications of percutaneous nephrostomy may include the following:

• Recurrent obstruction necessitating frequent flushing or replacement
• Infection or sepsis secondary to tube obstruction
• Fetal harm secondary to prolonged anesthesia requirements and ionizing radiation
• Premature delivery ^[50]
• Risk of bleeding caused by nephrostomy tube placement, tube dislodgement, and erosion

According to recent studies, complications of ureteroscopy and intracorporeal lithotripsy in pregnancy are rare in experienced hands.[22, 21, 39]  The risk of complications may be mildly increased because of the anatomic changes of pregnancy; however, the possible complications do not differ from those in the general population. These types of risks include the following:

• Ureteral injury
• Perforation
• Subsequent stricture formation

Complications of open surgery include an increased risk of premature delivery. The rate of premature delivery after surgery is 6.5% during the first trimester, 8.6% during the second trimester, and 11.9% during the third trimester. Intrauterine growth restriction or premature birth (complication of receiving general anesthesia during pregnancy) is more likely.

Prevention is the best cure for urolithiasis, and multiple investigators have suggested prophylactic measures to prevent the difficult course of treating urolithiasis in pregnancy. Denstedt and Razvi (1992) suggested prophylactic treatment of asymptomatic caliceal stones in women of childbearing age who are planning pregnancies.[9]  Biyani and Joyce (2002) recommended metabolic evaluation in known stone formers, as well as prophylactic treatment of asymptomatic stones prior to pregnancy.[11]  In support of their recommendation, they cited Glowacki et al (1992), whose study monitored 107 asymptomatic patients with renal calculi over 31.6 months and found that 31.8% became symptomatic over that period.

 

Diagnosis

The European Association of Urology (EAU) guidelines recommend ultrasonography (US) as the treatment of choice for the diagnosis of urolithiasis during pregnancy. However, the guidelines note that normal physiologic changes in pregnancy can mimic ureteral obstruction and the role of US is limited in acute obstruction because it cannot properly differentiate causes of dilation. Magnetic resonance imaging (MRI)  is recommended as a second-line imaging study, but use of low-dose computed tomography (CT) is restricted to selected cases.[28]

The American College of Obstetricians and Gynecologists (ACOG) makes the following general recommendations regarding diagnostic imaging procedures during pregnancy[19] :

• Ultrasonography and MRI are the imaging techniques of choice, but should be used prudently and only when use is expected to answer a relevant clinical question or otherwise provide medical benefit to the patient.
• With few exceptions, radiation exposure through radiography, CT scan, or nuclear medicine imaging techniques is at a dose much lower than the exposure associated with fetal harm. If these techniques are necessary, they should not be withheld.
• The use of gadolinium contrast with MRI should be limited; it may be used as a contrast agent only if it significantly improves diagnostic performance and is expected to improve fetal or maternal outcome.

​Treatment

Both the American Urological Association (AUA) and the European Association of Urology (EAU) have released guidelines for the treatment of urolithiasis that include specific recommendations for management during pregnancy.[20, 51, 52]

The AUA recommends that treatment be coordinated with the obstetrician. First-line therapy for patients with well-controlled symptoms is observation. Ureteroscopy (URS) should be offered to patients in whom observation fails. Ureteral stent and nephrostomy tube are alternative treatment options, with frequent stent or tube changes usually being necessary.[51, 52]

The EAU guidelines concur that conservative management should be first-line treatment for all noncomplicated cases of urolithiasis in pregnancy. (except those that have clinical indications for intervention). If spontaneous passage does not occur or if complications develop, placement of a ureteral stent or a percutaneous nephrostomy tube is recommended.  Regular follow-up until final stone removal is needed due to the higher encrustation tendency of stents during pregnancy. URS is an alternative for patients with who have poor tolerance for those temporary therapies.[20]

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are not recommended during the first 20 weeks of pregnancy. They have been shown to be associated with an 80% increased risk of miscarriage over non-use in a study of 1055 women.[53] NSAID use is also linked to congenital renal abnormalities and fetal pulmonary hypertension[54] and may cause premature closure of the ductus arteriosus[55] .

Class Summary

These agents are used to treat pain and provide patient comfort.

Butorphanol (Stadol)

Mixed agonist-antagonist narcotic with central analgesic effects for moderate to severe pain. Causes less smooth muscle spasm and respiratory depression than morphine or meperidine. Weigh advantages against increased cost of butorphanol.

Meperidine (Demerol)

Analgesic with multiple actions similar to those of morphine but may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.

Morphine sulfate (Oramorph, MS Contin, Duramorph)

Criterion standard for relief of acute severe pain; may be administered in various ways; commonly titrated until desired effect obtained. IV morphine demonstrates half-life of 2-3 h; however, half-life may be 50% longer in elderly patients.

Hydromorphone (Dilaudid)

A hydrogenated ketone of morphine. Hydromorphone is a narcotic analgesic. Analgesic action of parenterally administered Dilaudid is apparent within 15 min and usually remains in effect for >5 h.

Class Summary

These agents are used to treat pain and to provide patient comfort.

Acetaminophen (Tylenol)

Inhibits prostaglandin synthesis in the CNS and peripherally blocks pain impulse generation. Produces antipyresis from inhibition of hypothalamic heat-regulating center.

Class Summary

These agents relax smooth muscle to facilitate ureteral stone passage.

Tamsulosin (Flomax)

This alpha-1 selective blocker is indicated for the treatment of lower urinary tract symptoms due to prostatic enlargement. An off-label use, as discussed above, is to facilitate passage of ureteral stones. Only short-term therapy (10 d) should be considered for this indication.