Is there a human fetal gallbladder contractility during pregnancy?

Yasuko Tanaka1, Daisaku Senoh and Toshiyuki Hata

Department of Perinatology, Kagawa Medical University, Miki, Kagawa, Japan.


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The purpose of this study was to evaluate whether human fetal gallbladder contractility exists in the second half of pregnancy. Ultrasound examinations were performed on 54 normal pregnant women from 20 to 40 weeks of gestation. Fetal gallbladder volume was monitored every 30 min from 08:00 to 18:00 h in each patient. Maximum gallbladder volume was related linearly with gestational age between 20 and 32–35 weeks of gestation, after which a plateau was observed. Minimum gallbladder volume was unchanged throughout gestation. Functional capacity (maximum volume – minimum volume) of the fetal gallbladder increased linearly with advancing gestation until 32–35 weeks gestation, and thereafter was constant. Contractility rate [(maximum volume – minimum volume/maximum volume)x100] increased curvilinearly with advancing gestation (R2 = 30.7%, P < 0.0001). The daily change in fetal gallbladder volume showed a typical sinusoidal pattern, and the contractility cycle of gallbladder volume was unchanged during pregnancy (3.1 ± 0.6 h). These results suggest that there is an apparent gallbladder contractility in human fetuses in utero, and that maternal meals seem not to affect the volume of the fetal gallbladder. Further study is needed to clarify the physiological role of fetal gallbladder contractility during pregnancy.

Key words: contractility/fetus/gallbladder/gastro-intestinal/physiology/ultrasound


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The gallbladder, one of the organs among the extrahepatic biliary duct system, arises from the hepatic diverticulum in the fourth week of gestation, the cystic duct and gallbladder primordium being visible as a bud from the side of the diverticulum (Moore, 1982Go). At the beginning of the fifth week, the extrahepatic duct system, the gallbladder, cystic duct, hepatic ducts, common bile duct and pancreatic duct are demarcated. During this stage, the future duct system becomes a solid cord of cells. Re-establishment of the lumina of the ducts begins in the sixth week with the common duct, and progresses slowly in a distal direction. The lumina extends into the cystic duct by the seventh week, but the gallbladder remains solid until the 12th week (Gray and Skandalakis, 1972Go). Bile is formed by the fetal hepatic cells during the 12th week of gestation, and enters the duodenum via the bile duct after the 13th week of gestation (Moore, 1982Go).

There have been three reports on the growth of the fetal gallbladder measured by ultrasonography between 15 weeks gestational age and term (Hata et al., 1987Go; Goldstein et al., 1994Go; Chan et al., 1995Go). In two investigations (Hata et al., 1987Go; Chan et al., 1995Go), the fetal gallbladder size increased linearly until 30 weeks of gestation, and became constant. However, in a third investigation (Goldstein et al., 1994Go), a linear growth function between fetal gallbladder size and gestational age was observed throughout pregnancy. The cause of the disagreement on the growth of fetal gallbladder among these investigations is currently unknown. It was suggested in one case (Hata et al., 1987Go) that the fetal gallbladder occasionally appeared to be dilated in normal fetuses, and follow-up examination revealed a decrease in size. This served as a clue to assess the function of the fetal gallbladder.

Only two reports have been made on the contractility of the fetal gallbladder monitored by ultrasonography during pregnancy (Jouppila et al., 1985Go; Goldstein et al., 1994Go), and the changes in fetal gallbladder size were not significant during the observation period. However, the duration of observations reported in both studies was rather short (only 3 h), and both studies ignored the phase difference of each fetal gallbladder contractility cycle. The aim of the present study was to re-evaluate whether human fetal gallbladder contractility exists in the second half of pregnancy, and to evaluate whether its characteristics change with advancing gestation.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ultrasound examinations were performed on 54 normal pregnant women from 20 to 40 weeks of gestation (11 women at 20–23 weeks, 10 at 24–27 weeks, 12 at 28–31 weeks, nine at 32–35 weeks, and 12 at 36–40 weeks). Fetal gallbladder volume was monitored every 30 min from 08:00 to 18:00 h in each patient. The measurements were obtained by using the electronic callipers of the ultrasound machine (model SSD-1700; Aloka, Tokyo, Japan) equipped with 3.5 MHz transducers. The gallbladder volume calculation employed an ellipsoid approximation (volume = 0.52xgallbladder lengthxgallbladder heightxgallbladder width) (Jouppila et al., 1985Go).

These women were non-smokers, with neither indication of maternal complication nor incidence of drug administration. Those subjects with diabetes, multiple pregnancies, fetal hydrops, pre-eclampsia, previous pregnancy with pre-eclampsia or molar pregnancies were excluded from the study. Gestational age was estimated from the first day of the last menstrual period, and confirmed by first-trimester and early second-trimester ultrasound examinations (crown–rump length, biparietal diameter and femur length measurements). All infants were delivered vaginally and birth weights were in the normal ranges (between the 10th and 90th percentiles) to the standard growth curve for the Japanese (Sato et al., 1982Go). In no neonate were there congenital malformations or genetic disorders. The study was approved by the local ethical committee of Kagawa Medical University and standardized informed consent was obtained from each patient.

At 07:00 h, after an overnight fast of 12 h, the subjects had a 600 Cal breakfast. After resting for 30 min, the subjects were examined in the supine position. Fetal gallbladder volume was monitored every 30 min from 08:00 h to 18:00 h. Following the 12:00 h examination, the subjects had a 600 Cal lunch. All examinations were performed by one examiner (Y.T.). The intra-observer coefficient of variation for the measurement of gallbladder volume was <10%. Maximum and minimum gallbladder volume, functional capacity (maximum volume – minimum volume), contractility rate [(maximum volume – minimum volume/maximum volume)x100], contractility cycle of gallbladder volume, and frequency (1/contractility cycle) were calculated.

Statistical analysis
All values were reported as mean ± SD. Statistical analysis for comparison of each parameter at each gestational month was performed using an analysis of variance and Newman–Keuls multiple comparison test. A P-value < 0.05 was considered significant. Dataset regression analysis was carried out, testing the regression of contractility rate value on gestational age, using polynomials of the first to the third degree (Dunn and Clark, 1974Go; Rohatgi, 1976Go; Bertagnoli et al., 1983Go). Different models were tested and independent variable deletion carried out by analysis of variance applied to the regression was followed by calculation of the step-down method of coefficients (Snedector and Cochran, 1967). The choice of the optimal model was based on the following criteria: largest R2, all coefficients different from 0, and low standard deviation of regression (SDR) (Bertagnoli et al., 1983Go).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Maximum gallbladder volume was related linearly with gestational age between 20 and 32–35 weeks of gestation, after which a plateau was observed (Table IGo). Minimum gallbladder volume was unchanged throughout gestation (Table IGo). Functional capacity of the fetal gallbladder increased linearly with advancing gestation until 32–35 weeks gestation, and thereafter became constant (Table IGo). Contractility rate increased curvilinearly with advancing gestation (R2 =30.7%, P < 0.0001) (Figure 1Go). The daily change in fetal gallbladder volume showed a typical sinusoidal pattern (Figure 2Go). Therefore, maternal meals seemed not to affect the volume of fetal gallbladder. The contractility cycle of gallbladder volume was not changed during pregnancy (3.1 ± 0.6 h) (Table IGo), although it varied between fetuses. Frequency was also unchanged during pregnancy (Table IGo).


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Table I. Maximum and minimum volumes, functional capacity, contractility rate, contractility cycle and frequency of the fetal gallbladder across gestational age
 


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Figure 1. Contractility rate (CR) of fetal gallbladder and gestational age (GA). The optimal model for CR was: CR = 48.122 + 0.0005759(GA)3, R2 = 30.1%, P < 0.0001.

 


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Figure 2. Typical daily changes in fetal gallbladder volume at 20, 31 and 39 weeks gestational age, with measurements taken between 08:00 and 18:00 h.

 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In adults, gallbladder contraction is usually regulated by cholecystokinin, a polypeptide hormone that is secreted by duodenal mucosa cells after local stimulation by peroral meals. Although pure glucose is also capable of inducing gallbladder contractions (albeit to a lesser degree), little is known about the function of cholecystokinin or effect of glucose on fetal gallbladder contractility in humans. The fetal gastric and duodenal mucosa is capable of producing many important enzymes at the end of pregnancy, and therefore cholecystokinin production in fetal duodenal cells may also be possible (Kimura and Warshaw, 1981Go). In the guinea pig model, cholinergic and cholecystokinin receptors were present and functional on gallbladder smooth muscle before birth (Denehy and Ryan, 1986Go). It was also demonstrated that the size of fetal gallbladder remained constant for 3 h after maternal test meals (Jouppila et al., 1985Go). A later report (Goldstein et al., 1994Go) confirmed that fetal gallbladder dimensions remained relatively constant for 3 h periods of evaluation, although the gestational age varied. In the present study, however, the daily change in fetal gallbladder volume showed a typical sinusoidal pattern, and the cycle of gallbladder volume change was constant during pregnancy. The contractility rate increased curvilinearly with advancing gestation. This finding may suggest a reason for the decrease in association between fetal gallbladder volume and functional capacity with advancing gestational age. Moreover, the phase difference of each fetal gallbladder contractility cycle was specific to each fetus, and unaffected by maternal feeding. The cause of discrepancy in results of fetal gallbladder contractility between two previous investigations (Jouppila et al., 1985Go; Goldstein et al., 1994Go) and the present study is currently unknown. One possible explanation is that both studies ignored the phase difference of each fetal gallbladder contractility cycle, and averaged all values at each time point. However, further study is needed to clarify the physiological role of fetal gallbladder contractility in utero. Another important point to remember is that pathological gallbladder dilatation should not be diagnosed on the basis of a single observation of a prominently distended fetal gallbladder.


    Notes
 
1 To whom correspondence should be addressed at: Department of Perinatology, Kagawa Medical University, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan. E-mail: yasko{at}kms.ac.jp Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Bertagnoli, L., Lalatta, F., Gallicchio, R. et al. (1983) Quantitative characterization of the growth of the fetal kidney. J. Clin. Ultrasound, 11, 349–356.[ISI][Medline]

Chan, L., Rao, B.K., Jiang, Y. et al. (1995) Fetal gallbladder growth and development during gestation. J. Ultrasound Med., 14, 421–425.[Abstract]

Denehy, C.M. and Ryan, J.R. (1986) Development of gallbladder contractility in the guinea pig. Pediatr. Res., 20, 214–217.[Abstract]

Dunn, O.J. and Clark, V.A. (1974) Applied Statistics: Analysis of Variance and Regression. Wiley, New York, pp. 252–305.

Goldstein, L., Tamir, A., Weisman, A. et al. (1994) Growth of the fetal gall bladder in normal pregnancies. Ultrasound Obstet. Gynecol., 4, 289–293.[ISI][Medline]

Gray, S.W. and Skandalakis, J.E. (1972) Embryology for Surgeons. W.B.Saunders, Philadelphia, pp. 229–262.

Hata, K., Aoki, S., Hata, T. et al. (1987) Ultrasonographic identification of the human fetal gallbladder in utero. Gynecol. Obstet. Invest., 23, 79–83.[ISI][Medline]

Jouppila, P., Heikkinen, J. and Kirkinen, P. (1985) Contractility of maternal and fetal gallbladder: an ultrasonic study. J. Clin. Ultrasound, 13, 461–464.[ISI][Medline]

Kimura, R. and Warshaw, J. (1981) Intrauterine development of gastrointestinal tract function. In Lebenthal, E. (ed.), Textbook of Gastroenterology and Nutrition in Infancy. Raven Press, New York, pp. 39–46.

Moore, K.L. (1982) The Developing Human. 2nd edn. W.B.Saunders, Philadelphia, pp. 227–254.

Rohatgi, V.K. (1976) An Introduction to Probability Theory and Mathematical Statistics. Wiley, New York, pp. 506–512.

Sato, A., Akama, M., Yamanobe, H. et al. (1982) Intrauterine growth of live-born Japanese infants between 28 and 42 weeks of gestation. Acta Obstet. Gynaecol. Jpn., 34, 1535–1538.

Snedecter, W.G. and Cochran, W.G. (1967) Statistical Methods. 6th edn. Iowa State University Press, Ames, pp. 135–197.

Submitted on October 27, 1999; accepted on February 2, 2000.





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