Journal of the American College of Surgeons • July 2021 • Association Between Trimester and Outcomes after Cholecystectomy During Pregnancy

Vincent Cheng, MD, Kazuhide Matsushima, MD, FACS, Matthew Ashbrook, MD, Koji Matsuo, MD, PhD, Morgan Schellenberg, MD, FACS, Kenji Inaba, MD, FACS, Kulmeet Sandhu, MD, FACS 2021-06-16 01:33:35

Disclosure Information: Authors have nothing to disclose. Timothy J Eberlein, Editor-in-Chief, has nothing to disclose. Ronald J Weigel, CME Editor, has nothing to disclose.

Disclosures outside the scope of this work: Dr Matsuo receives honorarium payments from Chugai Pharmaceutical Co to reimburse textbook editorial expenses from Springer, and receives honorarium payments from VBL Therapeutics to reimburse investigator meeting attendance expenses. Other authors have nothing to disclose.

Presented virtually at the Western Surgical Association 128th Scientific Session, November 2020.

From the Divisions of Acute Care Surgery (Cheng, Matsushima, Ashbrook, Schellenberg, Inaba) and Upper GI and General Surgery (Sandhu), Department of Surgery, and the Department of Obstetrics and Gynecology (Matsuo), University of Southern California, Los Angeles, CA.

Correspondence address: Kazuhide Matsushima, MD, FACS, Division of Acute Care Surgery, Department of Surgery, University of Southern California, 2051 Marengo St, Inpatient Tower, C5L100, Los Angeles, CA 90033. email: kazuhide.matsushima@med.usc.edu

BACKGROUND: Conventional philosophy promotes the second trimester as the ideal time during pregnancy for cholecystectomy. However, literature supporting this belief is sparse. The purpose of this study is to examine the association of trimester and clinical outcomes after cholecystectomy during pregnancy.

STUDY DESIGN: The National Inpatient Sample was queried for pregnant women who underwent cholecystectomy between October 2015 and December 2017. Patients were categorized by trimester. Multivariable logistic and continuous outcome regression models were used to evaluate the association of trimester and outcomes, including maternal and fetal complications, length of stay, and hospital charges. The primary outcome was any complication—a composite of specific clinical complications, each of which were designated as secondary outcomes.

RESULTS: A total of 819 pregnant women satisfied our inclusion criteria. Of these, 217 (26.5%) were in the first trimester, 381 (47.5%) were in the second trimester, and 221 (27.0%) were in the third trimester. Median age was 27 years (interquartile range: 23─31 years). Compared with the second trimester, cholecystectomy during the first trimester was not associated with higher rates of complications (adjusted odds ratio [AOR] 0.88, 95%confidence interval [CI]: 0.47─1.63, p = 0.68). However, cholecystectomy during the third trimester was associated with a higher rate of preterm delivery (AOR 7.20, 95% CI 3.09─16.77, p < 0.001) and overall maternal and fetal complications (AOR 2.78, 95%CI 1.71─4.53, p< 0.001). Compared with the second trimester, the third trimester was associated with 21.3% higher total hospital charges (p = 0.003).

CONCLUSIONS: Our results suggest that cholecystectomy can be performed in the first trimester without significantly increased risk of maternal and fetal complications, compared to the second trimester. In contrast, cholecystectomy during pregnancy should not be delayed until the third trimester. (J Am Coll Surg 2021;233:29─38. © 2021 by the American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Cholecystectomy is one of the most frequently performed nonobstetric operations in pregnant women.^1,2 The recommended timing of cholecystectomy during pregnancy has a wavering history (eFig. 1). In 1992, the National Institutes of Health (NIH) recommended the second trimester as the optimal timing of cholecystectomy.³ While laparoscopic cholecystectomy was recommended as the treatment of choice in the general population, the NIH stated, “The use of laparoscopic cholecystectomy in patients in the first trimester of pregnancy is controversial because of the unknown effects of carbon dioxide pneumoperitoneum on the developing fetus.” In addition, the NIH stated, “patients in the third trimester of pregnancy should not usually undergo laparoscopic cholecystectomy, because of risk of damage to the uterus during the procedure.” Although women in their second trimester “may be candidates for laparoscopic cholecystectomy,” the NIH warned that these women should only be operated on “providing the operating surgeon is experienced in treating patients with complex laparoscopic cholecystectomy problems.” Six years later, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) published similar guidelines stating, “When possible, operative intervention should be deferred until the second trimester, when fetal risk is lowest.”⁴ At that time, cholecystectomy was considered the less preferable management option for gallbladder disease during pregnancy.^5-7

In 2008, SAGES revised its guidelines and published, “Laparoscopy can be performed safely during any trimester of pregnancy with minimal morbidity to the fetus and mother.”⁸ Furthermore, “Laparoscopic cholecystectomy is the treatment of choice in the pregnant patient with symptomatic gallbladder disease, regardless of trimester.” SAGES 2017 guidelines continue with the same recommendations. Accounting for new data and literature, it grades the former recommendation, deeming laparoscopy safe for all trimesters as “strong,” and laparoscopic cholecystectomy for treatment of symptomatic gallbladder disease regardless of trimester as “weak.”⁹ Despite this description of the evidence, rates of cholecystectomy have increased since SAGES updated its recommendations.^1,10,11

No consensus exists regarding the optimal timing of cholecystectomy during pregnancy. For example, the World Society of Emergency Surgery suggests the second trimester and early third trimester as the ideal time for laparoscopic cholecystectomy.¹² Contrary to these societal guidelines, Fong and colleagues¹³ published a large retrospective statewide database study of women in California showing higher rates of maternal complications associated with third trimester cholecystectomy compared with postpartum cholecystectomy.¹³ Existing data describing the optimal timing of cholecystectomy during pregnancy are not only sparse, but also conflicting. Therefore, the aim of this study is to compare the outcomes of cholecystectomy during pregnancy by trimester.

This is a retrospective cohort study using the National Inpatient Sample (NIS) database between October 2015 and December 2017. This time frame was chosen because October 2015 is when the NIS dataset first began using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), which is the first version to include pregnancy trimester codes. Data from December 2017 is the most recent available data. The study was approved by the Institutional Review Board at the University of Southern California. The NIS database is deidentified and approximates a 20% stratified sample of all US inpatient hospital discharges.¹⁴ The database was queried for all pregnant women with biliary disease during the study period using diagnostic codes from the ICD-10-CM. Table 1 summarizes the list of ICD-10-CM codes used for patient selection. The NIS database also contains an “elective” variable differentiating between elective and nonelective admissions. ICD-10 Procedure Coding System (ICD-10-PCS) codes were used to filter for patients who underwent laparoscopic or open cholecystectomy.

Baseline patient and hospital characteristics were abstracted from the NIS database. These included age, race, payer, income, and discharge year. Using coding algorithms validated for defining comorbidities in ICD-10-CM administrative data, the Charlson Comorbidity Index (CCI) was identified for each patient.¹⁵ Clinical outcomes variables included bile duct injury, maternal death, preterm delivery, preterm labor, abortion, premature rupture of membranes, amniotic infection, and other maternal and fetal outcomes (Table 1). An “Any Complication” outcome variable was created and defined as a composite of all these clinical complications. Given the anticipated infrequency of each specific clinical outcome, “Any Complication” was designated as the primary outcome, and the specific clinical outcomes were designated as secondary outcomes. Other secondary outcomes variables included hospital length of stay and total hospital charges. The latter outcome was adjusted for inflation using the consumer price index measured by the US Bureau of Labor Statistics.¹⁶

Using ICD-10-CM codes, study patients were divided into 3 groups based on trimester (Table 1). Patient baseline characteristics were compared across these 3 groups using univariate analysis (Table 2). As required by the Healthcare Cost and Utilization Project (HCUP) Data Use Agreement, summary data based on ≤ 10 observations were suppressed. A chi-square test was used to compare the 3 trimester groups to examine associations between treatment strategy (ie trimester when procedure was done) and dichotomous outcome variables. The Kruskal-Wallis test was used to examine associations between treatment strategy and continuous outcome variables. Multivariable logistic regression analysis was used to examine the associations between trimester and dichotomous outcome variables while adjusting for potential confounding factors including age, comorbidities, race, payer, and income quartile following the recommended methodologic standards for studies using the NIS database.¹⁷ Multivariable linear regression analysis was used for continuous outcome variables and adjusted for the same potential confounders. Hospital type and region were excluded from multivariable analyses because they had high percentages of missing values. To satisfy statistical assumptions necessary for linear regression, base 10 logarithmic transformations were required for hospital length of stay and total charges. The results from base 10 logarithmic transformations were then backtransformed to the original scale by exponentiating the coefficient, subtracting 1, and multiplying by 100 in order to interpret them as percent increases or decreases when comparing the 3 trimesters. Data were analyzed using SPSS version 20.0 (IBM Corporation). Statistical significance was defined as p < 0.05.

Included for analysis were a total of 819 pregnant women with biliary disease, who underwent cholecystectomy during the study period (Fig. 1). Of these patients, 217 (26.5%) were in their first trimester, 381 (46.5%) were in their second trimester, and 221 (27.0%) were in their third trimester. Table 2 compares patient and hospital characteristics among these 3 groups. The median age of all patients was 27 years (interquartile range [IQR]: 23─31 years). A total of 12 (1.5%) patients had a CCI ≥ 2. No significant difference in the proportion of patients with CCI ≥ 2 was found across the 3 trimesters in univariate analysis (p = 0.65). Compared with the second and third trimesters, the first trimester had a higher proportion of lowest income earners (41.1%) and a lower proportion of highest income earners (9.3%), though the overall comparison of income distributions did not differ significantly across the 3 trimesters (p = 0.47). The distribution of cholecystectomies performed at rural, urban nonteaching, and urban teaching hospitals differed significantly across the 3 trimesters (p = 0.004); a disproportionately high percentage of second and third trimester cholecystectomies were performed at urban teaching hospitals.

Figure 2 shows the distribution of the clinical diagnoses leading to cholecystectomy. Acute cholecystitis was the most common diagnosis associated with cholecystectomy, representing 46.2% of all cases. Elective cholecystectomy became more common in the second and third trimesters. Although 7.8% of cholecystectomies in the first trimester were performed in an elective setting, 21.8% and 33.2% were considered elective in the second and third trimesters, respectively. These percentages are not directory displayed elsewhere in this manuscript; they were based on the NIS characterization of each hospitalization and cannot derived from Figure 2.

The median number of days that elapsed after admission until cholecystectomy was 1 day (IQR: 0─3 days) in first trimester patients, 1 day (IQR: 0─2 days) in second trimester patients, and 2 days (IQR: 0─3days) in third trimester patients (p < 0.001). The median number of postoperative days before hospital discharge was less in second trimester patients (median 1 day, IQR: 1─2 days) compared with those of first trimester patients (median 2 days, IQR: 1e3 days) and third trimester patients (median 2 days, IQR: 1─3 days, p = 0.001). After adjusting for inflation, the median total hospital charges of all patients was $42,412 (IQR: $28,898─$62,489). The median charges for first, second, and third trimester admissions with cholecystectomy were $40,122 (IQR: $30,791─$65,353), $37,578 (IQR: $25,026─$55,926), and $47,515 (IQR: $30,995─$70,983, p = 0.003), respectively.

A total of 39 (4.8%) patients underwent open cholecystectomy. None of these open procedures was accompanied by an ICD-10-PCS code representing conversion from laparoscopic to open surgery. Multivariable logistic regression analysis showed that the third trimester was associated with significantly higher rates of open cholecystectomy compared with the second trimester (adjusted odds ratio [AOR]: 13.21, 95% CI: 3.19─54.60, p < 0.001). No significant difference in open cholecystectomy rates was found between the first and second trimesters (AOR: 1.75, 95% CI: 0.27─11.39, p = 0.56). Elective vs nonelective admission was not a significant predictor of open cholecystectomy. Neither maternal deaths nor bile duct injuries were observed in the dataset.

Table 3 illustrates the crude outcome frequencies; several secondary outcomes and specific complication rates were observed in fewer than 10 patients within a trimester. Multivariable logistic regression models also indicated that the third trimester was significantly associated with a higher rate of any complication (AOR 2.78, 95% CI: 1.71─4.53, p < 0.001) compared with the second trimester (Table 4). Overall complication rates did not differ between the first and second trimesters (AOR 0.88, 95% CI: 0.47─1.63, p = 0.68). Compared with the second trimester, the third trimester was also significantly associated with higher rates of preterm delivery, preterm labor, or abortion compared to the second trimester (AOR 7.20, 95% CI: 3.09─16.77, p < 0.001). Rates of premature rupture of membranes did not differ significantly across the 3 trimesters. Similarly, no significant difference was observed in rates of amniotic infection.

Compared with cholecystectomy performed in the second trimester, both the first trimester (regression coefficient [RC] 0.076, 95% CI: 0.040─0.111, p < 0.001) and third trimester (RC 0.119, 95% CI: 0.084─0.153, p < 0.001) were significantly associated with longer hospital stays after adjusting for patient characteristics using multivariable linear regression models (Table 5). After accounting for the logarithmic transformation required to normalize hospital days, these regression coefficients suggest that first and third trimester cholecystectomies were associated with 19.1% (95% CI: 9.6%─29.1%) and 31.5% (95% CI: 21.3%─42.2%) increases, respectively, in hospital stay compared with the second trimester. However, only the third trimester was significantly associated with greater hospital charges compared with the second trimester (RC 0.084, 95% CI: 0.030─0.139, p = 0.003). After accounting for the logarithmic transformation required to normalize hospital charges, this regression coefficient suggests that the third trimester was associated with a 21.3% (95% CI: 7.2%─37.1%) increase in total hospital charges compared to the second trimester.

The results of this study suggest that the frequencies of maternal and fetal complications after cholecystectomy during the first and second trimesters were not significantly different. However, cholecystectomy during the third trimester was significantly associated with increased maternal and fetal complications and greater economic burden (ie longer length of stay and greater hospital costs) compared with the second trimester. These findings suggest that the first and second trimesters of pregnancy may represent the optimal timing of cholecystectomy for the treatment of gallbladder disease in pregnancy.

Momentum in national guidelines^8,9,18 has swung in favor of laparoscopic cholecystectomy in any trimester to treat symptomatic gallbladder disease. However, this study shows that the second trimester is still the most common time for cholecystectomy during pregnancy. Of note, elective cholecystectomy was scheduled more frequently with each successive trimester. This finding likely reflects a combination of the natural pathophysiology^19-21 of symptomatic cholelithiasis to develop throughout pregnancy as well as the tendency to avoid or defer surgery until symptoms recur or worsen. In fact, more than 36% of pregnant women with acute cholecystitis were treated nonoperatively according to a recent study despite its nonelective indication.¹¹ It is unclear whether pregnancy augments aversion to surgery, despite literature showing that laparoscopic cholecystectomy during pregnancy is safe and associated with improved outcomes.^1,11,22-24 Furthermore, this study observed a disproportionately high percentage of second and third trimester cholecystectomies performed at urban teaching hospitals, which may reflect a referral pattern from rural and urban nonteaching hospitals to urban teaching or academic centers with higher acuity cases. Another possibility is that this distribution simply reflects the patient populations or practice patterns of the surgeons at these hospitals.

To date, few studies have incorporated pregnancy trimester into their analyses to evaluate its impact on clinical outcomes after cholecystectomy. Fong and colleagues¹³ used a large California database to compare clinical outcomes after cholecystectomy during the third trimester vs those in the postpartum period. They found significantly higher rates of maternal complications, longer hospital stays, and increased readmission rates after third trimester cholecystectomy compared to postpartum cholecystectomy. For patients presenting with symptomatic cholelithiasis during the third trimester, the authors recommended deferring cholecystectomy until the postpartum period. It is important to reiterate that this study neither refutes nor corroborates the study by Fong and associates,¹³ as our study did not include patients who underwent cholecystectomy in the postpartum period. However, it is possible that the results shown here may reconcile the results of studies by Fong and coworkers¹³ and Kuy and colleagues,¹ which showed significantly lower rates of maternal and fetal complications associated with laparoscopic cholecystectomy compared to nonoperative management of biliary disease during pregnancy. Improved outcomes associated with first and second trimester cholecystectomies may be driving the overall trend in favor of surgery observed in pregnant patients as a group.

This study has several limitations. First, the study may be underpowered to assess individual maternal and fetal complications. Although cholecystectomy is the second most common nonobstetric surgery performed during pregnancy after appendectomy,^1,2 the percentage of pregnant women undergoing cholecystectomy is low. Even with the nationally representative data source used in this study, only 819 cholecystectomies during pregnancy were included in this sample representing 10% of national discharges over a 27-month period. The small sample size and the low frequency of complications (Table 3) contribute to higher variability and lower precision in multivariable analyses. Unfortunately, the sample size could not be increased by extending the study period to previous years because ICD-9-CM codes were used before October 2015, and this system lacks codes assigned to each trimester. Second, this NIS dataset does not capture longitudinal follow-up information for individual cases. As a result, this study is unable to characterize complications that may be found in readmissions after cholecystectomy. This limitation is particularly restrictive when considering fetal complications. Third, the database does not include granular clinical details such as cholecystitis severity or number of episodes of biliary colic─qualities that may influence surgical outcomes. This lack of granularity also prevents parsing total hospital charges to determine whether they are related to surgical complications.

In conclusion, the results of this study favor the first and second trimesters for cholecystectomy for treatment of gallbladder disease in pregnant women. Though the second trimester was the most common time for cholecystectomy overall during the time period of this study, the third trimester was the most frequently scheduled time for elective cholecystectomy. Clinical outcomes may have improved if these operations had been performed during an earlier trimester. Additional research is required to develop a risk stratification that incorporates trimester to help guide the treatment of biliary disease during pregnancy.

Study conception and design: Cheng, Matsushima, Ashbrook, Matsuo, Schellenberg, Inaba, Sandhu

Analysis and interpretation of data: Cheng, Matsushima, Ashbrook, Matsuo, Schellenberg, Inaba, Sandhu

Drafting of manuscript: Cheng, Matsushima, Ashbrook Critical revision: Matsuo, Schellenberg, Inaba, Sandhu

CONTINUING MEDICAL EDUCATION CREDIT INFORMATION

Accreditation: The American College of Surgeons is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

AMA PRA Category 1 Credits^TM: The American College of Surgeons designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit^TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Of the AMA PRA Category 1 Credit^TM listed above, a maximum of 1 credits meet the requirement for Self-Assessment.

AOR = adjusted odds ratio
CCI = Charlson Comorbidity Index
ICDCM = International Classification of Disease-Clinical Modification
NIS = Nationwide Inpatient Sample
RC = regression coefficient SAGES = Society of American Gastrointestinal and Endoscopic Surgeons

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Discussion

DR KRISTA KAUPS (Fresno, CA): This was an examination of the National Inpatient Sample database during a 27-month period of cholecystectomy during pregnancy, with the conclusion that cholecystectomy can best be performed safely in the first and second trimesters of pregnancy, and should not be delayed to the third trimester.

Although the authors noted that the rate of open cholecystectomy was higher in the third trimester compared with procedures performed earlier in pregnancy, was there any difference in patients having open vs laparoscopic cholecystectomy with regard to elective vs emergent procedures? Was there any association with the diagnosis, whether it was acute vs other indications, and the incidence of complications? Again, because the National Inpatient Sample database was queried for all pregnant women with biliary disease, was any comparison made between patients undergoing operations vs those managed nonoperatively in terms of, for example, hospital length of stay and incidence of readmission?

Finally, in reviewing the indications for cholecystectomy by trimester, it appears that those done in the first trimester were less likely to be performed for elective indications. Is this potentially due to lingering concerns about teratogenesis or other fetal injury early in pregnancy?

In the analysis, preterm labor and miscarriage are grouped together, but did fetal loss differ by trimester?

DR KULMEET SANDHU (Los Angeles, CA): In regard to the operations being performed in elective and nonelective cases, we saw a trend toward increased rates of open cholecystectomy for nonelective cases, but it was not statistically significant. We saw about 4.1% open in elective cases and about 6.3% in nonelective cases, so that did show a trend, but it was not significant. In regard to the second question about comparing these patients for this study, we have only looked at differences in trimester. We did not compare these patients with patients who were treated nonoperatively.

This was done recently by our group in another article published recently in which we compared pregnant women who had acute cholecystitis and underwent cholecystectomy with those who received nonoperative management. In that article, we actually looked at a larger population because it covered more years. The reason we used this time period for this article is because it was this earliest time in which ICD-10 codes were used that could identify trimester for pregnant patients.

The sample before that time did not base the patient on trimester, just that they were pregnant or not pregnant. So we had a larger sample in this last article, looking at pregnancy but not at trimester. In that article, approximately 50% had laparoscopic cholecystectomy, approximately 4% had open operations, and approximately 36% had nonoperative treatment of their acute cholecystitis. This is looking at acute cholecystitis specifically.

The patients who had laparoscopic cholecystectomy had significantly lower rates of preterm labor, preterm delivery, and abortion. The patients who had open procedures did show an increased rate of preterm delivery, labor, and abortion, but, again, we did not have trimester data for those patients.

What is interesting is we also saw that every day of delay in doing the cholecystectomy came with increased risk of fetal complication. We did not see any significant difference in patient mortality in that case, but that last article suggested that laparoscopic cholecystectomy was recommended for pregnant patients based on those data. We did not compare operative and nonoperative management in this study. This study just looked at trimester to determine best timing for operation.

On the last topic, we do think that a lot of patients might say they want to hold off on the operation initially and wait until they have had more than 1 episode of biliary colic or issues with their gallbladder before they undergo an elective operation. It could also be because of their concerns about anesthesia. But we might also be seeing a larger number later in pregnancy if they had time to develop gallstones and had symptoms as well, so we may have a couple of reasons for seeing more patients having elective operations later.

In regard to fetal loss, we did see a higher rate in the third trimester. Second trimester was about 1% and third trimester was about 1.4%, but there was no statistical significance; again this might be due to low power because the numbers and rates were low for this.

DR DOUGLAS SCHUERER (St Louis, MO): Can these data really evaluate differences in longer-term complication after the first visit?

DR VINCENT CHENG (Los Angeles, CA): Unfortunately, the morbidity and complications assessed in this study include only those encountered during the admission associated with cholecystectomy.

DR RICHARD JAMISON (Portland, OR): Do you have information about whether the increasing rate of open cholecystectomy in the third trimester reflects planned open operation or conversion from laparoscopy?

DR VINCENT CHENG (Los Angeles, CA): There is an ICD-10 procedure code for laparoscopic converted to open cholecystectomy, but none of the records in our dataset use this code. Another way we tried to determine who had laparoscopic converted to open cholecystectomy is by identifying cases that listed an open cholecystectomy code with either diagnostic laparoscopy or laparoscopic cholecystectomy procedure codes. None of the records in our dataset listed both types of procedures either. Two possible explanations are that no laparoscopic converted to open cholecystectomies were performed in our sample or these conversions were not coded appropriately. The former explanation seems less likely to our group.

DR BENJAMIN JARMAN (LaCrosse, WI): Based on the relatively high rates of third trimester complication, is cholecystostomy an option that should be considered?

DR VINCENT CHENG (Los Angeles, CA): Our study concludes that laparoscopic cholecystectomy should be performed in either the first or second trimesters in comparison with the third trimester. In other words, if patients had a choice between trimesters, earlier is likely associated with fewer complications. However, our study does not compare operative and nonoperative management during the third trimester. As a result, our study can neither encourage nor discourage operation in a pregnant patient who presents with symptomatic cholelithiasis in the third trimester.