Appendectomy, cholecystectomy and diagnostic laparoscopy conducted before pregnancy and risk of adverse birth outcomes: a nationwide registry-based prevalence study 1996–2015

This national prevalence study was based on a population of 5.7 million inhabitants in Denmark [9], with an average of 1.3 million female inhabitants aged 15-54 years each year in the years 1996-2015 [9]. All Danish citizens have free and equal access to hospital and specialist treatment through our tax-supported healthcare system [10]. Individual-level linkage of all Danish population-based registries was allowed for through the Civil Personal Registration-number assigned at birth or immigration [11]. This number contains information on birth date and sex. We used the Danish National Patient Registry (DNPR) [12] and the Danish Medical Birth Registry (DMBR) [13] to obtain information on appendectomy, cholecystectomy and diagnostic laparoscopy before pregnancy, surgical procedures during pregnancy, fetal outcomes and relevant covariates.

Through DMBR and DNPR, we identified all Danish female citizens aged 15-54 years who delivered during the period 1995-2016. We restricted to singleton births, because multiple births are associated with both lower fetal weight [14] and lower gestational age at birth [14]. Diagnosis codes are assigned to each patient at day of discharge from hospital or outpatient clinic and registration in the DNPR is mandatory for all Danish hospitals. Non-psychiatric hospital admissions have been recorded since 1977 and, emergency room contacts and contacts to hospital specialist clinics have been registered since 1995. Diagnoses are coded according to the International Classification of Diseases, 8th edition (ICD-8) until 1994 and the 10th edition (ICD-10) thereafter [15]. Surgical procedure codes are registered after surgery according to the Danish version of Nordic Medico-Statistical Committee Classification of Surgical Procedures [16] from 1996. From 1971 to 1995, they were registered according to the Danish Classification of Surgical Procedures and Treatments.

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We extracted information on birth weight and gestational age from the DMBR, which was established in 1973. It contains information on all home and hospital deliveries in Denmark. Livebirths regardless of gestational age and stillbirths > 22 weeks are included [17]. Data in the registry are collected prospectively by the midwife attending birth, with information on mother and child collected in one record. Available information on newborns include birth date, gender, birth weight, length at birth, fetal presentation, gestational age, multiple pregnancy, Apgar scores, birth presentation, and mode of birth. Maternal information include: number of previous births, parity, age, marital status, smoking status, pre-pregnancy body-mass index and citizenship [15]. We calculated the estimated first day of last menstrual period (LMP) as day of birth or abortion minus gestational age in days at birth or abortion. The LMP was used for calculation of gestational age at time of surgery.

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We then restricted the study population to women with appendectomy, cholecystectomy or diagnostic laparoscopy (see Additional file 2) as the latest surgical procedure before LMP in the years 1992-2015 and no major surgical procedures from date of LMP through pregnancy termination. Pregnancies with minor surgical procedures (eg skin procedures and all transluminal endoscopies) and with cesarean section were not excluded (see codes in Additional file 1). We excluded pregnancies with registration of birth within 139 days of the last birth in the same woman, pregnancies with LMP starting before birth in the last pregnancy in the same woman and births with birthweight above 6500 g or below 500 g.

We analyzed appendectomy, cholecystectomy and diagnostic laparoscopy separately. From each of the specific groups, we excluded pregnancies with any major surgical procedure not being appendectomy, cholecystectomy or diagnostic laparoscopy within 23 months before LMP, respectively (see Additional file 1). We computed time between date of surgery and date of LMP and divided it into 0-11, 12-23 and 24+ months before LMP. To assess potential difference in risk of the outcomes over calendar time due to changing guidelines and the technical development in surgery [18], we categorized calendar into year-groups (1996-1999, 2000-2003, 2004-2007, 2008-2011 and 2012-2015).

The outcomes of interest in our study were SGA, early preterm birth, late preterm birth and miscarriage occurring after gestational week 7.

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SGA was defined as births with a birth weight more than 2SD below an age- and sex-specific reference (19). We excluded pregnancies with gestational age (GA) < 22 weeks or missing information on birthweight (0.7%), when calculating the risk of SGA. Early preterm birth was defined as births with a GA between weeks 22-31 (both included) and late preterm birth as births between weeks 32-36 (both included). When information on GA was missing, we excluded the pregnancy. To evaluate the consequence of this exclusion, we performed a sensitivity analysis replacing missing GA with median GA. We defined miscarriage as having a diagnosis of miscarriage in the DNPR and a GA between 7 and 21 weeks (both included). We did not include miscarriages before week 7 because of incomplete registration of early abortions [20].

From the DMBR, we retrieved information on maternal age and smoking status. Infants born to smokers have lower median birth weight than those born to non-smokers [21] and smoking may be a risk factor for surgery [22]. Since smoking status was not available from the DNPR, we lacked smoking information for pregnancies resulting in miscarriages.

Statistical analyses

We tabulated maternal characteristics and fetal vital status for pregnancies with appendectomy, cholecystectomy and diagnostic laparoscopy 0-11, 12-23 and 24+ months before estimated day of LMP and calculated absolute risk (AR) and risk difference (RD) of SGA, early preterm birth, late preterm birth and miscarriage for all groups. We used logistic regression analysis to calculate odds ratios (ORs) of the association of timing of surgery (appendectomy, cholecystectomy and diagnostic laparoscopy, respectively), with surgery > 24 months before LMP as reference, and risk of SGA, late preterm birth, early preterm birth, and miscarriage after week 7, respectively. In the regression analysis, we adjusted for maternal smoking and maternal age using multiple imputation to account for missing information on smoking status. We tabulated diagnosis codes related to diagnostic laparoscopy and performed a regression analysis for the two main diagnosis groups. We performed an analysis with only complete cases of smoking status and an analysis with women with appendectomies performed more than 5 years before pregnancy as reference group as sensitivity analyses. For miscarriages, we adjusted for maternal age. We stratified the analysis by year of surgery (1996-1999, 2000-2003, 2004-2007, 2008-2011, 2012-2015) for appendectomies, cholecystectomies and diagnostic laparoscopies conducted anytime between 0 and 23 months compared with the same surgery > 24 months before LMP.

We used the statistical software package STATA (version 13, Stata Corp., College Station, Texas, USA) for data analysis.

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