Biliary Sludge and Gallstones in Pregnancy: Incidence, Risk Factors, and Natural History

Methods

Study Sample

From 1986 to 1988, we enrolled all women (n = 272) admitted to the obstetrics department of our hospital who were in the first trimester of pregnancy. All participants volunteered and gave written informed consent. Six women were excluded: three because of a previous cholecystectomy and three because of technically inadequate ultrasonograms. All women had clinical interviews and ultrasonographic examinations of the gallbladder at entry (month 3 of pregnancy), later during pregnancy (month 6), and 2 to 4 weeks after delivery.

We examined the following factors as possible predictors for the development of new sludge and new stones: age, previous use of oral contraceptives, previous pregnancy, number of previous deliveries, and percentage of body weight excess. The presence of sludge at the first-trimester examination (old sludge) was also considered as a predictor for the development of new gallstones. Age, breast-feeding, previous deliveries, and the diameter of stones found after delivery were considered as predictors for the disappearance of biliary sludge or gallstones. Body weight excess was defined as the percentage by which body weight exceeded ideal body weight [19]. Because of the high prevalence of -thalassemia in Sicily and its association with gallstones [20], we evaluated women for the presence of heterozygous -thalassemia by measuring hemoglobin A₂ concentrations. These measurements were done using column chromatography.

During follow-up, we assessed patients for vomiting, itching, biliary pain (colic pain in epigastrium or upper right abdomen that lasted more than 60 minutes and was not relieved by bowel movement), and dyspepsia (nausea, upper abdominal discomfort, and pyrosis). All clinical data were obtained by the examining physician before the ultrasonographic examination was done.

All women with biliary sludge or gallstones had follow-up after delivery. A clinical interview and ultrasonographic examination were done every 3 months for 1 year or until an empty gallbladder was found on two consecutive ultrasonographic examinations. During the study, no patient received medication to dissolve gallstones.

Ultrasonographic Examinations

The ultrasonographic examinations were done using a high-resolution real-time scanner with a 3.5-MHz linear array transducer. Two of us (AM and AO) served as examiners. After an overnight fast, patients were examined in the supine position, in the oblique position right side up, during the change from one position to another, and in the standing position. All patients were on an unrestricted diet.

An ultrasonic diagnosis of sludge was made when we found diffuse, low-amplitude echoes forming a fluid-fluid level [21]. Biliary sludge was characterized by homogeneous echoes or heterogeneous echoes of 2 to 5 mm with nonshadowing echogenic foci [22-24]. When heterogeneous echoes were present, sludge balls could not be differentiated from those gallstones [23] that do not completely deflect the ultrasonographic beam [25]. Consequently, the diagnosis of gallstones was made when shadowing, gravity-dependent, echogenic structures with a diameter of more than 2 mm were observed in the gallbladder [26]. We excluded slice-thickness artifact echoes, which can mimic sludge, using the criteria of Goldstein and Madrazo [27].

Before the study, the examiners had more than 5 years of experience with diagnostic ultrasonography and both had done more than 5000 examinations. For the first 100 women who enrolled in the study, the overall agreement between the observers was 97% and 100% for the diagnosis of sludge and stones, respectively. The value for chance-corrected agreement in the diagnosis of sludge was 91% (95% CI, 81% to 99%).

Statistical Analysis

The test for linear trend in proportions [28] was used to determine whether the frequency of variables at entry steadily increases or decreases as patients move from the best (empty gallbladder) to the worst (gallstones) ultrasonographic classes.

When appropriate, the t-test for continuous variables and the chi-square test for categorical variables were used to determine the statistical significance of differences. Crude rates for events are given with 95% CIs, which are reported according to Simon [29].

The cumulative incidence rates of biliary sludge and gallstones in pregnancy were calculated using an actuarial life-table method and are given with 95% CIs [30]. Because biliary sludge or gallstones were still present in the immediate postpartum period, we assumed that the examination at this time indicated the status of the gallbladder at the end of pregnancy. Actuarial analysis was also applied to the incidence rates for disappearance of sludge and stones after delivery.

A stepwise logistic regression analysis was done to identify the variables associated with the development of new sludge and new stones during pregnancy or with their disappearance after delivery, after adjusting for the effect of covariates [31].

Results

Findings in the First Trimester

We enrolled 272 women in the study during their first trimester of pregnancy (mean age SD, 27 5 years). Biliary sludge was found in 42 women (15%; CI, 11% to 20%) and gallstones were found in 17 women (6%; CI, 3% to 9%). Four women with gallstones also had biliary sludge. Eighty-one women (30%) had an excess body weight of more than 20%, 121 (44%) had had previous pregnancies, and 103 (38%) had used oral contraceptives. Only the presence of two or more deliveries before admission was associated with higher prevalence of biliary sludge or gallstones on the ultrasound examination done in the first trimester (Table 1).

Findings

Ultrasonographic Events and Symptoms

At the end of the second trimester the actuarial incidence rates for new sludge and new stones were 14% (CI, 9% to 18%) and 2% (CI, 0.1% to 3%), respectively. Between the first-trimester examination to the control examination done 2 to 4 weeks after delivery, new sludge and new stones developed in 67 (29.6%) and 6 (2.4%) women, respectively. Thirty-four women (12.5%) were lost to follow-up (26 with empty gallbladders and 8 with sludge) (Table 2). The actuarial cumulative incidence rate was 31% (CI, 25% to 37%) for new sludge and 2% (CI, 0.2% to 4%) for new stones.

Vomiting (32%) and dyspepsia (28%) were the most frequent symptoms. Twenty-eight women had itching (10%). No relation between vomiting, dyspepsia or itching and biliary sludge or gallstones was found. Eight patients (3%) experienced biliary pain. These patients had no relapses of pain during pregnancy, and no treatment was necessary. Biliary pain was significantly more frequent among women with gallstones (5 of 17) than among women with biliary sludge (2 of 42) or an empty gallbladder (1 of 213) (P < 0.0001). Biliary pain did not occur in patients with new stones or new sludge. Vomiting occurred more often during the first trimester (95%) than during the second (6%) or the third (2%), but dyspepsia was more prevalent during the third trimester (70%). No difference was observed in the incidence of itching and biliary pain in the different trimesters.

Predictors of Sludge and Gallstones

Women with new sludge were less obese than women without sludge (mean body weight excess [SD], 12.4% 7.2% compared with 17.3% 11.2%; P = 0.016). This finding was confirmed by stepwise logistic regression analysis; the detection rate for new sludge decreased by 2% for each additional percentage point of body weight excess (CI, 1% to 5%).

The number of patients who definitely formed gallstones during pregnancy was too small to assess predictive factors. However, the incidence of stones in women with formerly empty gallbladders (2 of 213 participants, 0.9%) was lower than in women with sludge (4 of 42 participants, 9.5%) (P = 0.0005).

Findings in the Postpartum Period

After delivery, 115 women were studied (92 with biliary sludge, 11 with gallstones and 12 with both sludge and gallstones) (see Table 2). Gallstones disappeared in seven women [30%, 3 women with stones only and 4 with both stones and sludge] after a mean follow-up of 9.7 4.6 months (range, 1 to 19 months). At this time, the rate of disappearance was 28% (CI, 10% to 46%). Four of these seven patients had old stones (stones detected at entry), whereas the other three women had new stones. The rate of sludge disappearance was higher. After a mean follow-up of 5.0 4.6 months (range, 1 to 23 months), sludge disappeared in 71 of 104 women (68.3%): in 65 of 92 with sludge only (70.7%) and in 6 of 12 with both stones and sludge (50%). At this time, the actuarial rate of disappearance was 61% (CI, 50% to 73%). Ten patients with sludge were lost to follow-up. We failed to find any relation between the time at which stones or sludge was detected and the disappearance of stones or sludge after delivery.

We did not observe any new occurrence of biliary sludge or gallstones in 115 women who had follow-up after delivery. Biliary pain, observed in eight patients during pregnancy, was recorded in three patients with gallstones and in two with biliary sludge after delivery. Each patient had only one episode, and neither surgery nor bile-acid therapy was needed. Dyspepsia was present in three patients with gallstones and in three with biliary sludge. No predictors of disappearance were identified by regression analysis in these 115 women. However, women in whom stones disappeared were older or had a smaller stone diameter at the beginning of the postpartum follow-up period (Table 3).

Discussion

Our prospective study corroborates and extends the findings of previous studies that assessed the influence of pregnancy on gallbladder disease. In our patients, the incidence rates for biliary sludge and gallstones were 31% and 2%, respectively, during the last 6 months of pregnancy. After delivery, sludge and stones spontaneously disappeared in 61% and 28% of women, respectively. During pregnancy, biliary pain was associated with only the presence of gallstones. The presence of sludge in the first trimester of pregnancy correlated with a higher risk for developing gallstones. Sludge was less frequent in obese women. After delivery, the disappearance of gallstones correlated with a smaller stone diameter and increasing age.

It is unlikely that selection bias operated in our study because patients were consecutively enrolled in the obstetrics outpatient service of a general hospital. We cannot rule out the possibility that women who attend the clinic for prenatal care may be better educated and less obese than women in the general population. However, the prevalence of gallstones was similar to that observed in previous Italian studies done in nonpregnant women [4, 32], which argues against the presence of major bias.

We used ultrasonography because it is more accurate than oral cholecystography in the diagnosis of gallstones [33] and is the only tool for diagnosing biliary sludge during pregnancy. The alternative technique involves the direct microscopic examination of crystals aspirated during endoscopic retrograde cholangiography or through a soft feeding tube mounted into the duodenum, after the intravenous administration of cholecystokinin [34, 35]. Both these procedures are inappropriate during pregnancy. However, if one considers the direct examination of crystals as the gold standard for diagnosis of sludge, ultrasonography has been shown to have a specificity close to 100% and a sensitivity ranging from 52% to 69% [34, 35]. The low sensitivity probably results from the ability to diagnose only discrete sludge. This low sensitivity would tend to underestimate the number of women with sludge and may explain the low prevalence of sludge and the low incidence of new sludge in obese patients. Obesity itself interferes with the diagnostic accuracy of ultrasonography in gallbladder disease [36]. To increase specificity in the diagnosis of small gallstones and to differentiate them from sludge balls, we made a diagnosis of gallstones when gravity-dependent, echogenic structures producing shadows were larger than 2 mm [26].

Our study is the first to show rapid formation of biliary sludge and gallstones during pregnancy. The incidence of gallstones in our sample (2% in 6 months) was greater than that in residents of Sirmione, Italy (3% in 5 years) [37], or in residents of Rochester, Minnesota (0.37/100 per year) [38].

The fluctuating course of biliary sludge and gallstones (present during pregnancy and absent after delivery) may be attributed to the impressive modifications of bile and gallbladder motility that occur during pregnancy. The changes in hepatic bile that occur in the last trimester of pregnancy are due to high estrogen levels [39]. The lithogenic bile [39] and the gallbladder stasis that is present during all of pregnancy [40] may favor the retention of bile, nucleation, and crystal formation that finally generate sludge and stones [41-43]. After delivery, biliary composition and gallbladder motility return to normal; thus, sludge and small stones may be eliminated or dissolved [17, 40, 44]. The spontaneous disappearance of sludge has also been shown by Lee and coworkers [14] in nonpregnant patients with abdominal pain. It is well known that gallstones may pass into the small bowel [45-47] or may be dissolved by medical treatment [48], but our study showed a high rate of gallstone disappearance in the first months after delivery.

In our study, vomiting, dyspepsia, and itching were not associated with the presence of sludge or stones. Biliary pain was associated only with the presence of stones. Only women with old stones experienced biliary pain, and in four women stones disappeared after pregnancy. Three of six women with new stones had an empty gallbladder at the end of follow-up. Our patients had a cumulative rate of biliary pain of 28% during pregnancy. This incidence rate is higher than that reported in the literature [49, 50] and supports the theory that most women with stones develop symptoms more frequently during pregnancy than at other times [2, 51].

Patients with sludge at admission had a greater risk for developing new stones during pregnancy. After delivery, increasing age and a small stone diameter were univariately correlated with the disappearance of stones. Decreased levels of circulating estradiol and progesterone in older women during the childbearing period [52] may reduce the lithogenicity of bile and gallbladder stasis, explaining the higher likelihood for small stones to disappear. However, the lack of confirmation by multivariate analysis suggests the need for larger studies.

We conclude that biliary sludge develops frequently during pregnancy, is usually asymptomatic, and spontaneously disappears after delivery. Gallstones may also occur during pregnancy. They are frequently associated with biliary pain and may spontaneously disappear after delivery. Additional studies are necessary to better assess the predictors for the development or disappearance of gallstones. However, our findings suggest that treatment for biliary sludge is not necessary during pregnancy or in the first year after delivery.

Presented in part at the Meeting of the American Association for the Study of the Liver Diseases, Chicago, Illinois, November 1990, and has been reported previously in abstract form.