Metabolic and Hypertensive Complications of Pregnancy in Women with Nephrolithiasis

Abstract

Background and objectives

Kidney stones are associated with future development of hypertension, diabetes, and the metabolic syndrome. Our objective was to assess whether stone formation before pregnancy was associated with metabolic and hypertensive complications in pregnancy. We hypothesized that stone formation is a marker of metabolic disease and would be associated with higher risk for maternal complications in pregnancy.

Design, setting, participants, & measurements

We conducted a retrospective cohort study of women who delivered infants at the Massachusetts General Hospital from 2006 to 2015. Women with abdominal imaging (computed tomography or ultrasound) before pregnancy were included in the analysis. Pregnancy outcomes in women with documented kidney stones on imaging (stone formers, n=166) were compared with those of women without stones on imaging (controls, n=1264). Women with preexisting CKD, hypertension, and diabetes were excluded.

Results

Gestational diabetes and preeclampsia were more common in stone formers than nonstone formers (18% versus 6%, respectively; P<0.001 and 16% versus 8%, respectively; P=0.002). After multivariable adjustment, previous nephrolithiasis was associated with higher risks of gestational diabetes (adjusted odds ratio, 3.1; 95% confidence interval, 1.8 to 5.3) and preeclampsia (adjusted odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6). Infants of stone formers were born earlier (38.7±2.0 versus 39.2±1.7 weeks, respectively; P=0.01); however, rates of small for gestational age offspring and neonatal intensive care admission were similar between groups (8% versus 7%, respectively; P=0.33 and 10% versus 6%, respectively; P=0.08). First trimester body mass index significantly influenced the association between stone disease and hypertensive complications of pregnancy: in a multivariable linear regression model, stone formation acted as an effect modifier of the relationship between maximum systolic BP in the third trimester and body mass index (P interaction <0.001).

Conclusions

In women without preexisting diabetes, hypertension, and CKD, a history of nephrolithiasis was associated with gestational diabetes and hypertensive disorders of pregnancy, especially in women with high first trimester body mass index.

Introduction

Kidney stones are common, and the incidence of kidney stone disease is increasing, especially in younger populations (1,2). Although risk factors, such as diet, hydration, and urine composition, have long been associated with stone risk, epidemiologic studies have linked nephrolithiasis with common systemic conditions, such as metabolic syndrome and cardiovascular disease (3–5). A history of nephrolithiasis increases the risk of hypertension and diabetes mellitus (6–8). There are sex-specific differences in both risk factors and complications of stone disease (9,10). Although nephrolithiasis is more common in men, the incidence of stone disease in young populations (<30 years old) is higher in women (11). Women who present with symptomatic nephrolithiasis during pregnancy are more likely to have complications, including preterm delivery (12,13). Although the rate of incident stone disease during pregnancy is not increased compared with in the nonpregnant population, increasing parity is associated with higher stone risk. Studies assessing pregnancy risk in women with known stone disease before pregnancy are limited to small historic cohorts (14).

Pregnancy offers a unique window to study both metabolic and cardiovascular risk factors in women. During pregnancy, there are dramatic alterations in maternal metabolism and systemic hemodynamics that are important for fetal development. These changes may unmask subclinical disease in women. Transient disorders of pregnancy, such as gestational diabetes and gestational hypertension, predict the later development of diabetes, hypertension, and cardiovascular disease (15–17).

The objective of our study was to determine if a history of kidney stone disease increases the risk of metabolic and hypertensive complications in pregnancy in women without preexisting chronic disease. We hypothesized that a history of kidney stone disease would identify women at higher risk for gestational diabetes and hypertension.

Materials and Methods

Subjects and Data Collection

The Massachusetts General Hospital (MGH) obstetrics service provides both community and high-risk obstetrics care for women from Boston and New England. We performed a cohort study of all pregnancies in the MGH obstetric service birth database between January 1, 2006 and December 31, 2015. Clinical information, including medical histories, prenatal BP measurements, and delivery information, was abstracted into the medical record prospectively by obstetric providers and directly transferred into the study database.

Singleton pregnancies that continued beyond 20-weeks gestation were included in the analysis. Women missing baseline BP, urine dipstick, weight, or glucose testing (all standard of care) were excluded. Women with preexisting hypertension, defined as a BP before 20-weeks gestation ≥140/90 mm Hg or the use of antihypertensive medications before the start of pregnancy, were excluded. Women with preexisting diabetes, defined on the basis of documentation in the obstetric medical record at the initial prenatal visit or the use of oral hypoglycemic agents or insulin before pregnancy, were excluded. Women with preexisting kidney disease, including structural kidney disease, GN, AKI, or eGFR<90 ml/min per 1.73 m² before pregnancy, who were identified during chart review (including review of nephrology documentation, imaging, laboratory results, and kidney biopsy reports) were excluded. Women who presented for initial prenatal care after 20-weeks gestation were excluded (Figure 1). Detailed past medical information, including previous medical imaging, laboratory results, inpatient and outpatient medical documentation, and prior billing data, was obtained for the 10 years before pregnancy through the Partners Longitudinal Medical Record and the Partners Research Patient Data Registry (18).

Figure 1.

Flow chart of inclusion into study. DM, diabetes mellitus; HTN, hypertension.

Ascertainment of Exposures and Outcomes

We included all women who had imaging of the kidneys (abdominal ultrasound or abdominal computed tomography scan) before the start of pregnancy (n=1430). Examinations were obtained as part of medical care, including inpatient hospital admissions, ambulatory care, or emergency room visits. Radiology reports were used to identify stone formers and included the location and number of kidney stones. Written radiology reports were reviewed manually without knowledge of the outcome by the reviewer; 166 women met criteria for kidney stone disease. For women with multiple pregnancies, only the first pregnancy after documentation of stone disease was considered. The control population included 1264 pregnancies in women without evidence of stone disease on imaging. In a secondary analysis, we included all women in the MGH obstetric database who delivered during the study period who met the clinical inclusion criteria but did not have previous abdominal imaging (n=14,878).

Gestational diabetes was defined as a 1-hour glucose load test value of >140 mg/dl and two abnormal values on a 3-hour 100-g glucose tolerance test using Carpenter–Coustan criteria (19). Preeclampsia was defined on the basis of BP and spot urine protein measurements made at prenatal visits. Gestational hypertension was defined as BP≥140/90 mm Hg after 20-weeks gestation (20). Preeclampsia was defined as the presence of gestational hypertension and 2+ or greater proteinuria after 20-weeks gestation or gestational hypertension and 1+ proteinuria after 20-weeks gestation with confirmation of the diagnosis in the electronic delivery record. Preterm preeclampsia was defined as preeclampsia requiring delivery before 37-weeks gestation. Small for gestational age and large for gestation age were defined as birthweight less than the 10th percentile or greater than the 90th percentile, respectively, for the completed week of gestational age on the basis of national standards (21). The composite fetal outcome was defined by preterm delivery (<37 weeks), neonatal intensive care unit admission, or small for gestational age offspring.

Statistical Analyses

Baseline characteristics and primary pregnancy outcomes of women with and without kidney stones were compared using t tests for continuous variables and Fisher exact tests for categorical variables. Univariable and multivariable logistic regressions were used to compare the odds of gestational diabetes, gestational hypertension, preeclampsia, and preterm delivery between stone formers and nonstone formers. Covariates in the multivariable logistic models were selected on the basis of prior knowledge of their association with adverse pregnancy outcomes and included maternal age, baseline systolic BP, race, and parity. It was hypothesized a priori that the relationship between stone history and gestational hypertensive disorders may differ with respect to body mass index (BMI). To formally test for this association, multiplicative interactions between stone disease and BMI were formally tested, and stratum-specific point estimates for the association between stone disease and the primary outcome of preeclampsia were reported.

Multivariable linear regression was used to compare maximum systolic BP during the third trimester of pregnancy in women with and without stones. Multiplicative interaction terms between stone history and BMI (treated as both a continuous variable and a categorical variable) were formally tested. Statistical analyses were conducted using STATA 14 (Stata Corporation, College Station, TX).

Results

Baseline Characteristics

From the initial population of 25,280 deliveries at the MGH during the study period, 1430 women met inclusion criteria (Figure 1). Of women meeting the inclusion criteria, 166 (12%) had documented kidney stones (stone formers), and 1264 had no documented kidney stones (nonstone formers). At the first prenatal visit, stone formers were of similar age, BMI, and parity compared with nonstone formers (Table 1). The groups were similar with respect to baseline systolic and diastolic BPs at first prenatal visit.

Table 1.

Main baseline characteristics of stone formers versus nonstone formers

Characteristic	Stone Formers, n=166	Nonstone Formers, n=1264
Age at first prenatal visit, yr	32±5	32±6
Nonwhite Race, n (%)	84 (51)	597 (47)
Body mass index, kg/m2	27±6	27±6
Nulliparous, n (%)	49 (30)	393 (31)
Parity	1 [0–2]	1 [0–2]
Baseline systolic BP, mm Hg	108±11	107±10
Baseline diastolic BP, mm Hg	66±8	66±7
Imaging modality, n (%)
Ultrasound	50 (30)	386 (29)
CT scan	116 (70)	896 (71)
Imaging location, n (%)
Inpatient	22 (13)	164 (13)
Ambulatory	104 (62)	702 (56)
Emergency room	40 (24)	398 (31)
Multiple or bilateral stones, n (%)	73 (44)	n/a
Hydronephrosis, n (%)	35 (21)	n/a
Time from imaging to conception, yr	1.9 [0.8–4.2]	2.2 [0.9–4.3]
Preconception laboratory values, mg/dl
Serum creatinine	0.73±0.16 (n=166)	0.72±0.15 (n=1264)
Serum calcium	9.2±0.5 (n=91)	9.3±0.4 (n=711)
Uric acid	4.3±1.2 (n=83)	4.5±1.5 (n=372)

Data are presented as n (%), mean±SD, or median [interquartile range]; n reflects the number of subjects in each group with prepregnancy laboratory values available. CT, computed tomography; n/a, not applicable.

Metabolic Complications of Pregnancy

In women with normal glucose loading tests (<140 mg/dl), mean serum glucose levels were significantly higher in stone formers versus nonstone formers (111±18 versus 107±18 mg/dl, respectively; P=0.04) (Table 2). Gestational weight gain was lower in stone formers compared with nonstone formers (11.9±6.0 versus 12.9±5.2 kg, respectively; P=0.03). Stone formers were at higher risk for gestational diabetes compared with nonstone formers (18% versus 6%, respectively; P<0.001). After multivariable adjustment, stone formers were at threefold higher odds for gestational diabetes (odds ratio [OR], 3.1; 95% confidence interval [95% CI], 1.8 to 5.3) (Figure 2).

Table 2.

Main pregnancy outcomes between stone formers and nonstone formers

Characteristic	Stone Formers, n=166	Nonstone Formers, n=1264	P Value
Maternal outcomes
Metabolic complications of pregnancy
Average GLT glucose, mg/dl	111±18	107±18	0.04
Gestational diabetes, n (%)	28 (18)	65 (6)	<0.001
Gestational weight gain, kg	11.9±6.0	12.9±5.2	0.03
Hypertensive complications of pregnancy
Maximum systolic BP, mm Hg	126±14	121±10	<0.001
Maximum diastolic BP, mm Hg	78±9	77±8	0.15
Gestational hypertension, n (%)	37 (22)	162 (13)	0.001
Preeclampsia, n (%)	25 (16)	70 (8)	0.002
Cesarean section, n (%)
All	49 (30)	408 (32)	0.50
Elective	13 (27)	192 (48)	0.01
Neonatal outcomes
Gestational age at delivery, wk
Preterm delivery, wk, n (%)	38.7±2.0	39.2±1.7	0.01
<37	27 (16)	96 (8)	<0.001
<34	4 (3)	16 (1)	0.24
Baby weight, g	3286±634	3415±541	0.01
Small for gestational age, n (%)	13 (8)	86 (7)	0.33
Large for gestational age, n (%)	15 (9)	122 (10)	0.80
Neonatal ICU admission, n (%)	16 (10)	77 (6)	0.08
Composite fetal outcome, n (%)	35 (21)	191 (15)	0.05

Data are presented as n (%) or mean±SD. Average GLT glucose results are only presented for women who had normal testing on GLT (<140 mg/dl; n=876). Maximum systolic and diastolic BPs were recorded in the third trimester. Small for gestation age is defined as <10 percentile birthweight adjusted for gestational age at delivery. Large for gestational age is defined as >90 percentile birthweight adjusted for gestational age at delivery. GLT, glucose loading test; ICU, intensive care unit.

Figure 2.

Previous stone disease increases risk for adverse maternal, but not fetal, complications in pregnancy. Association of adverse pregnancy outcomes with stone formation from multivariable logistic regression. Boxes reflect adjusted odds ratio estimates, and lines represent 95% confidence intervals. ICU, intensive care unit.

Hypertensive Complications of Pregnancy

Stone formers were at higher risk for developing gestational hypertension and preeclampsia compared with nonstone formers (22% versus 13%, respectively; P=0.001 and 16% versus 8%, respectively; P=0.002). After multivariable adjustment, stone formation remained significantly associated with hypertensive complications in pregnancy. Stone disease was associated with twofold higher odds of gestational hypertension and preeclampsia compared with in women without stone disease (adjusted OR for gestational hypertension, 2.0; 95% CI, 1.3 to 3.1 and adjusted OR for preeclampsia, 2.2; 95% CI, 1.3 to 3.6) (Figure 2). Maximum systolic BP but not diastolic BP was significantly higher in stone formers compared with nonstone formers (126±14 versus 121±10 mm Hg, respectively; P<0.001 and 78±9 versus 77±8 mm Hg, respectively; P=0.15).

After stratification by BMI, the risk of preeclampsia was only significantly elevated among obese (BMI>30 kg/m²) women (OR, 2.6; 95% CI, 1.2 to 5.8). There was a significant interaction between stone-forming status and BMI category on the risk for preeclampsia (P interaction =0.01) (Supplemental Table 1). In a multivariable linear regression model, stone formation acted as an effect modifier of the relationship between maximum systolic BP in the third trimester and BMI (P interaction <0.001) (Figure 3).

Figure 3.

Stone disease modifies the relationship between body mass index and blood pressure in late pregnancy. Relationship between maximum systolic BP in the third trimester and body mass index in stone formers and nonstone formers. The black lines represent linear fitted estimates. Gray bands represent 95% confidence intervals. P interaction in multivariable models is <0.001.

Delivery Complications and Fetal Outcomes

Mean gestational age at delivery in stone formers was 38.7±2.0 versus 39.2±1.7 weeks in nonstone formers (P=0.01). Mean neonatal weights at birth in stone formers and nonstone formers were 3286±634 and 3415±541 g, respectively (P=0.01). Rates of small for gestational age and large for gestational age offspring were similar between groups (8% versus 7%, respectively; P=0.33 and 9% versus 9%, respectively; P=0.80). In offspring of women with stone disease, 21% developed the composite adverse fetal outcome versus 15% in those without stones (P=0.05).

Sensitivity Analyses

As an additional method to control for potential confounders of adverse pregnancy outcomes, we performed three sensitivity analyses: (1) an analysis comparing stone formers with a cohort including women without previous abdominal imaging (“general cohort”), (2) an analysis restricted to nulliparous women, and (3) an analysis restricted to women without gestational diabetes.

Women with previous abdominal imaging represented approximately 10% of the women who delivered at our center during the study cohort period. As a secondary analysis, we compared the 166 women with documented kidney stones with the 14,878 women in the general cohort without reported stones, regardless of previous imaging status. Stone formers had a higher first trimester BMI and were more likely to be multiparous and of nonwhite ethnicity than those in the general cohort (Supplemental Table 2). After multivariable adjustment, stone formers had 2.5-fold higher odds for gestational hypertension and threefold higher odds for preeclampsia and preterm delivery (Supplemental Table 3).

Because we did not have complete information on gestational diabetes or preeclampsia in pregnancies that occurred outside of our institution or before the start of the MGH obstetric cohort in 1998, we also performed an analysis restricted to nulliparous women in the cohort to exclude the possibility that adverse outcomes were related to prior gestational diabetes or preeclampsia. In nulliparous women, stone formation remained significantly associated with higher risk of gestational diabetes (21% versus 6%, respectively; P=0.002; OR, 3.6; 95% CI, 1.5 to 8.9). Although the rates of preeclampsia were higher in nulliparous stone formers versus nulliparous controls, they were not statistically significant (14% versus 10%, respectively; P=0.30; OR, 1.5; 95% CI, 0.6 to 3.5). Given the reduced sample size in this analysis, we were only powered to detect an estimated effect size difference of 15% or an OR>3.0.

Because insulin resistance and gestational diabetes are associated with higher rates of preeclampsia, we performed a sensitivity analysis looking at the rates of preeclampsia only among women who did not develop gestational diabetes to determine if higher rates of gestational diabetes explained the association between stone disease and preeclampsia. In this restricted analysis, stone disease remained significantly associated with preeclampsia after adjustment for baseline confounders (OR, 2.2; 95% CI, 1.4 to 4.0).

Discussion

We observed a higher risk for gestational diabetes and hypertensive disorders of pregnancy in women with a history of nephrolithiasis at our institution. This association persisted after controlling for maternal age, BMI, systolic BP, race, and parity. Notably, we excluded women with preexisting diabetes, chronic hypertension, and CKD, which are well described risk factors for pregnancy complications, including preeclampsia and preterm delivery.

To our knowledge, we are the first to address the association of nephrolithiasis before gestation with adverse pregnancy outcomes since modern imaging technologies have been used for diagnosis of stone disease. Coe et al. (14) reported that stone disease before pregnancy did not influence pregnancy outcomes; however, this was a cohort of 40 women followed in a specialized stone clinic in the 1960s–1970s and differs from modern stone-forming populations. Previous studies have shown a higher risk of preterm delivery in women presenting with symptomatic stones during pregnancy. In a study of pregnant women in the state of Washington between 1987 and 2003, women who were admitted to the hospital for management of symptomatic nephrolithiasis had an 80% higher risk of preterm delivery (13). In a study of births from 1989 to 2010 at a large obstetric hospital in Israel, symptomatic nephrolithiasis in pregnancy was associated with a higher risk of preeclampsia and gestational diabetes (12).

Kidney stones are linked with systemic disorders, including diabetes and metabolic syndrome. Obesity is independently associated with a higher risk of kidney stone formation, especially in women (22). The average BMI in women with stone disease was similar to that of other women who had received imaging at our institution but higher than that in the general pregnancy cohort. In the nonpregnant population, the relationship between stones and diabetes is bidirectional. Diabetes is an independent risk factor for incident stones, and stones are a risk factor for incident diabetes (7). It is hypothesized that insulin resistance results in prolithogenic changes in urinary composition (23–26). In pregnancy, insulin resistance is a normal phenomenon resulting from increased placental secretion of diabetogenic hormones, such as human chorionic somatomammotropin, corticotrophin releasing hormone growth hormone, and progesterone (27). Gestational diabetes develops when maternal pancreatic function fails to compensate for this normal insulin resistance. One hypothesis is that stone formers have subclinical insulin resistance before pregnancy that is unmasked by the normal physiologic changes during gestation.

In our study, the association between kidney stone disease and gestational hypertension risk was most pronounced among obese pregnant women. In obese women, maximum systolic BP in the third trimester was, on average, 10 mm Hg higher in stone formers compared with nonstone formers, even when adjusted for age, race, parity, and first trimester BP. The relationship between obesity, nephrolithiasis, and hypertension risk has been reported previously in nonpregnant women. In the Third National Health and Nutrition Examination Survey, Gillen et al. (28) reported 1.7 higher odds of self-reported hypertension outside of pregnancy in women with a history of kidney stones. Among obese women, both systolic and diastolic BPs were higher in stone formers versus nonstone formers. The association was not significant in nonobese women. In our study, we found that stone disease acted as an effect modifier on the relationship between BMI and systolic BP in late pregnancy. This finding may warrant more vigilant screening or prevention measures for hypertensive disorders of pregnancy in obese women with a history of nephrolithiasis.

Subclinical kidney disease is increasingly recognized as a risk factor for gestational hypertensive disorders. Recent studies have reported that women with congenital solitary kidneys, kidney transplant donors, and women with recovered AKI are at 1.5- to fivefold increased risk for preeclampsia or gestational hypertension (29–31). Kidney stone formers may also have subclinical kidney function impairments, despite normal serum creatinine. Nephrolithiasis has been linked with incident CKD and ESKD (32,33). In a series from the Mayo Clinic, asymptomatic stone formers undergoing evaluation for living kidney donation were more likely to have kidney parenchymal thinning and focal scarring (34). Subclinical kidney injury in the form of either reduced nephron number or elevated vascular resistance may impair normal kidney adaptation to pregnancy, including plasma volume expansion, and result in impaired placental development.

We did not identify stone formation as a risk factor for fetal complications, such as intrauterine growth restriction or need for neonatal intensive care unit admission. Although preterm delivery was more common among stone formers, most stone formers with preeclampsia delivered at term. The fact that stone formers developed preeclampsia more often but were not more likely to have neonatal complications suggests that the preeclampsia that tracks with stone disease is associated with milder degrees of placental dysfunction. Preeclampsia is now recognized as a heterogeneous group of disorders and can be classified on the basis of timing of onset (preterm versus term) or angiogenic profile (35,36). Studies investigating these distinct phenotypes have shown that women who develop preeclampsia after 37 weeks or with a normal angiogenic profile are more likely to be overweight and have comorbid diabetes. Kidney stone formation in these women may be a marker of endothelial dysfunction, and women who form stones may be more likely to manifest the clinical syndrome of preeclampsia with milder degrees of placental pathology. We also excluded women with preexisting hypertension and kidney disease, a group at greater risk for marked placental dysfunction.

Our study has several limitations meriting discussion. Most notably, we relied on available imaging for classification of stone formation status. Although this increases the specificity of our exposure of interest and allowed us to identify women with subclinical stone disease, it is possible that we missed cases of stone disease in women without imaging available. Because women who have had abdominal imaging had different baseline characteristics and risks for pregnancy complications than women who have never had abdominal imaging, we selected our control population from women who had also had imaging to reduce the risk of confounding by indication. We acknowledge that imaging technology has improved with time, leading to higher rates of incidental stone detection. We found no difference in the year of radiology examination between stone formers and nonstone formers, and the duration between imaging procedure and pregnancy was similar between groups. Including year of examination in our final models did not change the effect estimate of stone formation and risk for gestational diabetes or preeclampsia. We were also unable to determine stone type or control for baseline dietary factors. Hyperuricemia has been linked to both preeclampsia and gestational diabetes (37,38). Although uric acid levels were similar between stone formers and nonstone formers, this information was available in <50% of the cohort. Additionally, we did not have information on maternal smoking status. Another important limitation is that we did not have complete information on gestational diabetes or preeclampsia in pregnancies that occurred at other institutions or before implementation of the MGH obstetric cohort in 1998. We hypothesize that the rate of previous gestational hypertension is low, because we excluded women who ever received an antihypertensive medication before the index pregnancy. Although we observed a similar trend between stones and preeclampsia in nulliparous women, our analysis was limited in statistical power. Because the risk of incident kidney stone disease increases with parity, it is not surprising that a majority of stone formers were multiparous (39).

In conclusion, our findings show that a history of kidney stones identifies women at higher risk for metabolic and hypertensive complications in pregnancy. This finding supports the link between stone disease, diabetes, and hypertension and identifies a new population that may be differentially affected by stone disease. Additionally, our study highlights the importance of obesity in its interaction with stone disease and pregnancy complications. Given the increasing prevalence of stone disease in young women, additional research aimed at identifying modifiable risk factors as well as novel treatment and prevention strategies for these women should be encouraged.

Disclosures

None.