O r i ~ n aArticles

Pregnancy and Cholelithiasis: Pathogenesis and Natural

Course of Gallstones Diagnosed in Early Puerperium
VICENTE SIEGEL' AND FRANCISCO
VALDIVIESO,l CAEtMEN COVARRUBIAS,l FREDDY CRUZ'
Departments of 'Gastroenterology and 2Radiology, Universidad Catdica de Chile, School of Medicine, Santiago, Chile

Several recent reports have indicated an increased in teenagers it is 6.4and in 20- to 29-yr-olds it is 4.9 (1).
prevalence of gallstones in association with pregnancy. Recent publications have confirmed a significant asso-
If these reports are true, the early puerperium should ciation between parity and the prevalence of gallstones
be a favorable time to detect the disease in its initial (3).In addition, experimental studies have shown that in
stages and follow its natural course. Accordingly, the pregnant women the cholesterol saturation of bile
gallbladder was examined by ultrasound in 980 women increases and the fasting and postprandial volumes of
during the immediate postpartum period and in 150
nulliparous, age-matched healthy volunteers. Gall- the gallbladder are larger than in nonpregnant controls
stones were detected in 12.2% of the puerperal women (4).These data suggest that early puerperium is a
and in 1.3% of the control group. favorable period to detect gallstones in the earliest
In 70 patients who had stones in a functioning stages and to initiate follow-up studies concerning the
gallbladder, 22 (31%) had had attacks of biliary colic. natural history of this disease.
The history of pain was more common in patients with The aims of this study were fourfold: first, to de-
stones greater than 10 mm in diameter. Forty-one termine the frequency of gallstones in the early puer-
women with small stones (<lo mm) were followed perium; second, to look for a possible correlation
clinically and ultrasonographically for between 6 and between stone size and the occurrence of attacks of
24 (mean = 8.7) mo. All remained pain-free, and in biliary colic in stone patients; third, to examine and
twelve subjects (29%) the stones disappeared.
Gallbladder bile was examined in 11 normal volun- compare biliary lipid composition in the immediate and
teers (controls) immediately after delivery and in 19 late puerperium; and fourth, to follow the clinical and
women with small stones 39 f 6 days postpartum. Bile ultrasonographic evolution of patients with small stones
was saturated with cholesterol in the controls and was during the late postpartum period.
unsaturated in patients with gallstones.
We conclude that in our population pregnancy is a SUBJECTS AND METHODS
very important pathogenetic factor favoring gallstone This study was approved by the Institutional Review Board
formation. Attacks of biliary colic appear early and of the School of Medicine, Universidad Cat6lica de Chile.
frequently in young Chilean women with this disease. Participants gave informed oral consent, and 980 randomly
Unexplained disappearance of small stones frequently selected, middle-class women living in Santiago, Chile (mean
occurs: in some cases it is likely to be the result of age = 25 2 2 yr; range = 16 to 30 yr), were screened for
spontaneous dissolution because bile becomes unsatu- gallstonesby real-time ultrasound examination within 48 hr of
rated within a few weeks of delivery. (HEPATOLOGY their first (634 cases, 65%)or second (346 cases, 35%)delivery
1993;17:1-4.) (Fig. 1). The control group consisted of 150 age-matched,
nulliparous healthy volunteers (mean age = 24.1 -+ 3.1 yr;
Epidemiological studies performed on autopsy ma- range = 17 to 30 yr), chosen within the same socioeconomic
terial (1) and in living subjects (2) indicate that the level. Although the admixture of American Indian blood is
Chilean population experiences a very high frequency of common in Chile, none of the volunteers had the phenotypic
traits of pure Chilean Indians. Exclusion criteria included
cholesterol gallstones. In women the early appearance of delivery by cesarean section, awareness of gallstones and
the disease is particularly striking: in the general obesity defined as a body weight over 130% of a normalized
population the female to male ratio of gallstones is 2.5, standard (5).
Ultrasonography was performed by one of two experienced
radiographers using 3.5 and 5 MHz probes with patients in
Received April 23, 1992; accepted August 21, 1992. supine and left lateral decubitus positions. Gallstones were
Part of the data in this study was presented at the Meeting of the American identified by the presence of strong intraluminal, gravity-
Gastroenterological Association, May 1990, San Antonio, Texas. dependent echoes producing acoustic shadowing. All examina-
This study was supported by Grant FONDECYT 709/87 from the Comisidn
tions were performed after the patients fasted overnight.
Naciond de Investigacidn Cientifica y Tecnologica, Chile.
Address reprint requests to: Vicente Valdivieso, M.D., Department of
Four weeks after delivery the 120 volunteers in whom
Gastroenterology, School of Medicine, Universidad Cat6lica de Chile, Casilla gallstones had been detected were offered a standard oral
114-D, Santiago, Chile. cholecystography, with 6 gm of iodopanoic acid administered
31/1/42231 the night before. Eighty women accepted the study. In seven
0270-9139/93/$1.00+ $0.10 1
2 VALDIVIESO ET AL.
NON OBESE WOMEN (AGE 1 5 1 2 1 ~ 1
E X A M I N E 0 BY U S I L LB hs AFTER
1st OR 2a DELIVERY
WITH GALLSTONES
CHOLECISTOGRAPHV
30 DAYS AFTER DELIVERY
W l l H GALLSTONES IN
FUNCTIONING GALLBLADDER
INTERVIEW FOR ATTACKS
OF BILIARY COLIC
WITH STONES <lOrnrn
CLINICAL AND US FOLLOW UP
FOR 6 - 2 4 MONTHS
DETERMINATION OF
BlLlARY LIPIDS AND
CHOLESTEROLS CRYSTALS
39’6 D A I S
AFTER DELIVERY
FIG. 1. Diagram showing the breakdown of the study groups, Numbers in circles represent the number of women with each
characteristic.
patients, a radiological exclusion of the gallbladder was found
(five of them had had attacks of biliary colic, and only two were
asymptomatic). The results of cholecystography was normal in
10 women: in this group a second ultrasonographic study
showed a disappearance of small gallstones in three patients
and a persistence of stones in seven. Finally, in 63 patients the
cholecystogram showed gallstones in a functioning gall-
bladder.
The 70 patients with confirmed cholelithiasis in a func-
tioning gallbladder were subsequently interviewed for a
history of previous biliary colic. This history was defined
clinically in symptomatic patients as acute episodes of mod-
erate to severe continuous abdominal pain appropriate or
compatible in location with a duration of greater than 15 min.
Patients unable to recall such episodes were considered
asymptomatic. Forty-one women with small stones ( < 10 mm)
agreed to undergo a clinical and ultrasonographic follow-up
examination that was performed every 2 mo for at least 6 mo.
The follow-up period lasted up to 24 mo with a mean of 8.7 mo.
To determine the biliary composition, we obtained gall-
bladder bile from the duodenums of 11 fasting normal
volunteers 24 to 48 hr after delivery, 19 patients with small
gallstones during the late postpartum period 39 6 days after
delivery (range = 31 to 57 days) and a control group of 8
normal nulliparous women of similar age. Bile samples were
obtained by stimulating contraction of the gallbladder with an
intraduodenal infusion of 30 ml of an 8%amino acid solution,
and they were centrifuged at 3,000 rpm for 5 min. The
sediment was examined microscopically in polarized light for
cholesterol monohydrate crystals. Biliary cholesterol and
phospholipid were extracted from bile specimens with
chloroform - methanol (2 : 1,vol/vol)-and measured by color-
imetric methods (6, 7). Total bile acid concentration was
determined by Talalay’s method (8) as modified by Turley and
Dietschy (9). The theoretical cholesterol saturation index (CSI)
was calculated according to Carey (lo), assuming a total lipid
concentration of 10 gm/dl.
*
Results are expressed as mean S.D. Statistical methods
included x2 and Student’s t tests. Statistical significance was
achieved if the p value was less than 0.05.
RESULTS
Prevalence of Gallstones. Gallstones were detected in
120 of the 980 women examined after delivery and in 2
HEPATOLOGY
@ NULLIPAROUS. NON OBESE
WOMEN (AGE 2 4 l t 3 l y s )
1
IMMEDIATELY
AFTER DELIVERY
of the 150 women in the control group (12.2% vs. 1.3%;
p < 0.001). Stones were multiple in 76% of the patients
and were solitary in the remainder of patients. The
frequency of gallstones was similar in women examined
after their first or second delivery (761634 = 12% vs.
441346 = 12.7%; p = NS).
History of Biliary Pain. Twenty-two of the 70 pa-
tients with stones in functioning gallbladders (31%)had
had abdominal pain compatible with typical attacks of
biliary colic either before or during their last pregnancy.
Twenty-four patients had gallstones with a diameter of
10 mm or larger. Forty-six patients had stones smaller
than 10 mm in diameter. A history of biliary colic was
significantly more frequent in patients with the larger
stones (58%vs. 17%; p < 0.01).
Clinical and Ultrasonographic Follow-up. None of
the 41 patients with small gallstones had biliary pain
during the follow-up period. Stones disappeared without
symptoms in 12 of them (29%).All of these patients had
stones less than 6 mm in diameter.
* Biliary Lipid Composition. The proportion of biliary
lipids, the CSI and the presence of cholesterol crystals in
gallbladder bile are shown in Table 1.
In puerperal women with normal gallbladders ex-
amined immediately after delivery (group A), the per-
centage of cholesterol and the CSI were significantly
elevated; in contrast, the bile of patients examined in the
late puerperium (group B) was unsaturated despite the
presence of stones in their gallbladders.
A few cholesterol crystals were seen in only one
participant in group A and in only three patients in
group B.
DISCUSSION
The metabolic abnormalities that result in the se-
cretion of supersaturated bile and the biophysical
alterations that cause the nucleation of cholesterol
crystals in the gallbladder have been extensively studied.
In contrast, little is known about the initial stages of
gallstone formation and the earlier phases of their
Vol. 17,No. 1, 1993 GALLSTONES IN EARLY PUERPERIUM
TABLE1. Composition of gallbladder bile in group A (normal volunteers immediately after delivery), group B (gallstone
patients in late puerperium) and group C (normal, nulliparous volunteers)
Groups Bile acids Phospholipids
A (n = 11) 70.2 * 3.ab 20.6 ? 2.ab
B (n = 19) 72.4 ? 4.8b 21.5 f 4b
C (n = 8) 75.4 ? 3.96 18.9 ? 46
p Values
A vs. B NS NS
Avs. C < 0.01 NS
B vs. C NS NS
"Data expressed as no. of patients.
bData expressed as mean percentage -C S.D.
"Data expressed as mean f S.D.
natural history. Young pregnant Chilean women seem
particularly suitable for the study of these issues
because of their high incidence of cholesterol gallstones
(1,2).
We detected gallstones in 12.2% of 980 puerperal
women after their first or second delivery and in only
1.3% of 150 nulliparous, age-matched controls. This
striking difference suggests that the majority of our
patients formed the stones during pregnancy; moreover,
in a recent follow-up of 259 primigravidas done in our
department by Glasinovic et al. (111, the frequency of
gallstones in the first trimester (sixth to tenth week of
amenorrhea) was 3.1% vs. 11.2% immediately after
delivery. These data underscore the clinical importance
of gestation as the main pathogenetic factor somehow
influencing disease occurrence in our young female
population. Moreover, the frequency of cholelithiasis
observed in puerperal Chilean women is about twice that
found in a comparable group of 166 Italian women
studied with similar methods after their first or second
delivery (12).
The relatively high frequency and early occurrence of
biliary colic attacks reported by our patients contrasts
with several population surveys showing that choleli-
thiasis pursues a clinically silent course in most patients
(3, 13, 14). On the basis of the results of a previous
follow-up study (21, the natural evolution of the disease
is apparently more symptomatic in our country than in
the rest of the world. A recent population survey
performed in Britain (15) has also indicated that most
patients are asymptomatic, but in young women both
the occurrence of biliary pain and the cholecystectomy
rates were significantly higher than in the remainder of
the population studied.
In this study the appearance of biliary pain was
apparently related to size of the stones. Most patients
with small stones were asymptomatic and remained free
of pain during follow-up. On the other hand, 58% of
women with stones 10 mm or larger had experienced
attacks of biliary colic. This colic may be because their
gallstones had been present longer or because, above a
certain size, stones are more likely t o impact in the neck
of the gallbladder. Anyway, this observation contrasts
3
Cholesterol
Cholesterol CSI crystals"
9 ? 2.gb 131 ? 40' 1
6.1 f 1.7b 89 21" 3
5.6 ? l.lb *
89 25" 0
< 0.001 < 0.05 -
< 0.005 < 0.025 -
NS NS -
with previous reports that have not found an association
between gallstone size and the occurrence of pain (16,
17).
The frequency of gallstones was similar after the first
and second pregnancies; thus the high incidence of the
disease during pregnancy does not result in an accumu-
lative prevalence, at least for these two initial gestations.
This observation has also been documented in the
Italian study (12) and suggests that in their initial stages
gallstones frequently represent an intermittent phe-
nomenon. Actually, during our ultrasonographic
follow-up, stones disappeared silently in 29% of the
patients, all of whom had stones less than 6 mm in
diameter. This phenomenon has also been reported in a
recent survey on the incidence and evolution of gall-
stones in Denmark (18).
The disappearance of the stones may be explained by
either silent migration to the small intestine or sponta-
neous dissolution. Our study of biliary lipids tends t o
support the second possibility. During the third tri-
mester of pregnancy, bile becomes supersaturated with
cholesterol (4).We confirmed this phenomenon in the
bile samples obtained from the duodenum of normal
women within 48 hr postpartum. In contrast, bile
examined several weeks after delivery in patients with
small stones was unsaturated, and its composition was
similar to that observed in normal, nulliparous controls.
Cholesterol crystals are found in the duodenal bile of
50% to 60% of patients with gallstones (19, 20) and in
75% of the bile obtained by puncture of the gallbladder
during cholecystectomy in subjects with cholesterol
stones (21). In contrast with these observations, we
found only a few cholesterol crystals in only 3 of the 19
(16%)puerperal women with small stones studied in the
late puerperium.
These data indicate that the composition of gall-
bladder bile improves rapidly after delivery, even in
patients with gallstones, and this change probably favors
their dissolution.
Cholelithiasis is a multifactorial disease. Several
well-known pathogenic factors such as age, obesity and
genetic background may be important for the persis-
tence and further growth of the stones that develop
4 VALDMESO ET AL. HEPATOLOGY

during pregnancy. On the other hand, the mechanisms
that facilitate their disappearance must be elucidated
further if we wish to modify the natural course of the
disease in its initial stages.
Acknowledgments: We thank Andrea Vallespir and
Gloria Ramirez for their participation in the ultrasono-
graphic examinations and Miriem Aguad for assistance
in preparing the manuscript.
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