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Safety of digoxin for fetal demise before second-trimester abortion by dilation and evacuation
Contraception 85 (2012) 144 – 149
Original research article
Safety of digoxin for fetal demise before second-trimester abortion by dilation and evacuation Gillian Deana,⁎, Lisa Colarossia, Britt Lundeb, Adam R. Jacobsc, Lauren M. Porscha, Maureen E. Paula a Planned Parenthood of New York City, New York, NY 10012, USA Department of Obstetrics and Gynecology, University of Illinois, Chicago, IL, USA c Department of Obstetrics, Gynecology, and Reproductive Sciences, The Mount Sinai Medical Center, New York, NY 10029, USA Received 1 February 2011; revised 19 May 2011; accepted 21 May 2011 b
Abstract Background: Digoxin is used to induce fetal demise before dilation and evacuation (D&E) abortion. Published data on the safety of digoxin in abortion care are limited. Study Design: We conducted a retrospective cohort study with historical controls at a large family planning center. We reviewed the records of patients at 18 to 24 weeks' gestation who received digoxin before D&E from May 15, 2007 (date the center initiated digoxin use), through March 31, 2008. We also reviewed the records of patients who presented for D&E without digoxin from February 22, 2006, through May 12, 2007. We compared the rates of immediate complications. Results: We included 566 digoxin patients and 513 controls. Eleven spontaneous abortions occurred in the digoxin cohort; none occurred among controls (pb.001). We found 19 cases of infection in the digoxin cohort and three among controls (odds ratio 5.91; 95% confidence interval 1.74–20.07). Eleven digoxin patients were admitted to a hospital after the preoperative visit; no controls were admitted (pb.001). Conclusions: Patients who received digoxin before D&E were more likely to experience spontaneous abortion, infection and hospital admission than controls who underwent D&E without digoxin. © 2012 Elsevier Inc. All rights reserved. Keywords: Digoxin; Abortion; Safety; Dilation and evacuation; Feticide
1. Introduction Since the 1980s, physicians have used digoxin to induce fetal demise before dilation and evacuation (D&E) abortion for a variety of reasons. Following the 2007 Supreme Court decision Gonzales v. Carhart upholding the Partial Birth Abortion Act of 2003, routine use of digoxin before later second-trimester D&E increased. Gonzales v. Carhart outlaws abortion procedures in which the physician intentionally removes a “living fetus” to or past the point of various anatomic landmarks [1,2]. Feticide prior to abortion is one means of ensuring compliance with the ban. Research to date has not shown medical benefits of digoxin before abortion, although one study found patient preference for preoperative fetal demise [3]. Despite widespread use, published data on the safety of digoxin in abortion care are limited. We conducted a ⁎ Corresponding author. Tel.: +1 212 274 7324; fax: +1 212 274 7218. E-mail address: [email protected] (G. Dean). 0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.05.016
retrospective cohort study with historical controls to compare complication rates in patients who received digoxin before late second-trimester D&E to complication rates in patients who underwent D&E without digoxin. We hypothesized that patients who received digoxin would have higher rates of certain complications, particularly spontaneous abortion and infection, but not other surgical complications, such as hemorrhage and perforation.
2. Materials and methods We conducted this study at a large urban family planning center. The center instituted routine use of digoxin for abortion patients with viable pregnancies at 18 to 24 weeks' gestation on May 15, 2007, and discontinued digoxin on March 31, 2008. After discontinuing digoxin use, physicians at the center relied on surgical techniques to comply with Gonzales v. Carhart. Patients who received digoxin (the digoxin cohort) were compared with all patients with viable
G. Dean et al. / Contraception 85 (2012) 144–149
pregnancies at a similar gestational age range who had D&E without digoxin from February 22, 2006, through May 12, 2007 (the control cohort). We limited our control period to the 15 months immediately prior to the initiation of digoxin use in order to limit the number of physicians included in the analysis; physician movement into and out of employment by the facility was at its lowest during the period included in the analysis. The Institutional Review Board of the Mount Sinai School of Medicine approved the study. All patients who received digoxin were eligible for inclusion. We identified the digoxin cohort using the digoxin log maintained by the charge nurse. All patients with viable pregnancies at 18 to 24 weeks' gestation who presented for D&E in the control period were eligible for inclusion; we used computerized billing records to identify control patients. We also reviewed the Office of Quality Management's Occurrence Log that listed all serious adverse events associated with D&E, including hospitalizations, spontaneous abortions and failures to return for D&E. All patients had osmotic dilators inserted on the preoperative day, Day 1. The standard procedure included applying povidone-iodine to the cervix, injecting 10–20 cc of 1% lidocaine paracervically and inserting laminaria or Dilapan® tents. All patients received doxycycline 200 mg after osmotic dilator placement in recovery (or azithromycin 1 g if doxycycline allergic or if lactating) and were observed for at least 30 min before being discharged home. Patients in the digoxin cohort received digoxin injection using an 18- or 20gauge spinal needle on Day 1 immediately before osmotic dilator insertion. Physicians administered digoxin according to a standard protocol under ultrasound guidance. Physicians used 1 mg of digoxin (4 mL of undiluted digoxin at a concentration of 250 mcg/mL) per fetus if the injection was intrafetal or 1 mg per sac if intraamniotic. Other than paracervical block prior to osmotic dilator placement, patients were not routinely administered analgesia for the preoperative visit. Patients with contraindications to digoxin were referred elsewhere. Digoxin patients underwent ultrasound on Day 2; digoxin injection was repeated at the physician's discretion before D&E for persistent fetal cardiac activity. On Day 2, patients routinely received buccal misoprostol 600–800 mcg 90 min before D&E. In rare cases of inadequate dilation, the patient received additional misoprostol or osmotic dilators; for markedly poor cervical dilation, the patient returned for D&E on Day 3. The center staff recorded preoperative body temperatures routinely before misoprostol administration and per physician discretion after D&E. If a patient experienced a complication outside the center between dilator placement and D&E, the staff obtained details from the patient or treating physician and requested records from the hospital where she received care. Failure of a patient to return for D&E prompted rigorous attempts to contact her by phone. Attending physicians were all experienced providers of D&E in high-volume settings. The Medical Director observed all physicians performing digoxin injections before granting
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privileges to provide this service. All but one, a general surgeon, were obstetricians/gynecologists with prior training in amniocentesis; the general surgeon was trained in digoxin administration by the Medical Director. Attending physicians performed over 90% of digoxin injections, osmotic dilator placements and D&E procedures; in the remainder, resident physicians in obstetrics and gynecology provided care under the direct supervision of the attending physician. We reviewed the medical records for all study subjects and the occurrence reports and available hospital records for patients with adverse events. We collected data on patient demographic and background characteristics, the preoperative visit, the D&E procedure and any complications that occurred during the period from osmotic dilator placement through the recovery room stay after D&E. We did not collect data on delayed complications. Double data abstractions were conducted on a subsample of 10 charts from each cohort to assess the interrater reliability of data abstraction; no major discrepancies in data abstraction were identified. Our primary outcomes were infection, spontaneous abortion and hospitalization. The diagnosis of infection was not standardized in the medical record. Therefore, we created two variables to measure infection and one variable that was a composite of these two as follows: (a) temperature N38°C on Day 2 or 3 and (b) antibiotics administered at the center on Day 2 or 3 other than those used for routine prophylaxis or treatment of vaginal or cervical infections, or administration of parenteral antibiotics at a hospital and (c) any sign of infection, from presence of either of the first two indicators. Spontaneous abortion was defined as passage of the fetus outside or inside of the center before misoprostol administration. Hospital admission included admission to an emergency room or hospital occurring between osmotic dilator insertion on Day 1 and scheduled return for D&E. This variable did not include hospital transfers after D&E. Secondary outcomes included antiemetic use, failure to return for D&E, hemorrhage requiring transfusion after D&E, cervical lacerations requiring repair, uterine perforations, mean heart rate after digoxin and fetal heart motion by ultrasound on Day 2 after preoperative digoxin. Data were analyzed using SPSS 15.0 statistical software. We followed STROBE guidelines in the preparation of this manuscript [4]. We compared demographic, baseline and procedural characteristics by cohort using χ2 test and Fisher's Exact Test for all categorical variables, and t test for continuous variables. We generated odds ratios (ORs), confidence intervals (CIs) and p values using binomial logistic regression to test the likelihood of most complications by cohort. We used log-linear logic models to test the likelihood of spontaneous abortion, hospitalization and return on Day 2 by cohort because these contingency tables had zero observed occurrences in one cohort; this model provides empirical estimates of the population frequency despite the absence of empirical estimates in the sample [5]. No covariates were modeled because all measured characteristics that may have confounded the relationships between cohort
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and complications were equivalent between groups. Secondarily, we performed subgroup analyses of the digoxin cohort only using χ2 test and Fisher's Exact Test for differences in complication rates by physician and by month of procedure. In addition, we examined the impact of age, parity and gestational age on spontaneous abortion and infection.
3. Results Five hundred eight-three women received digoxin during the study period. Data were obtained from 566 records (97%); 17 records were unavailable for review at the time of request. We identified 532 patients with viable pregnancies at 18 to 24 weeks' gestation who presented for D&E during the control period. Of these, 513 (97%) records were reviewed; 19 records were unavailable. Three subjects in the digoxin cohort and none in the control cohort were lost to follow-up between Day 1 and Day 2 (Fig. 1). The cohorts did not differ significantly in any important respects. Overall, the sample was racially and ethnically diverse and relatively young (Table 1). Compared to the control group, patients in the digoxin cohort were slightly older, fewer identified their ethnicity as Hispanic and more identified their race as “other.” The mean number of osmotic dilators placed was similar (mean ± SD 6.6 ± 2.0 in digoxin subjects vs. 6.4 ± 2.1 in controls, p=.33). The variables of interest had no missing values with the exception of Day 2
preoperative temperature that was missing from 15 digoxin records and 24 controls. Overall, 40 (7%) digoxin patients experienced some form of complication compared to 11 (2%) control patients (OR 3.47; 95% CI 1.76–6.84). Fifteen digoxin patients did not return on Day 2, compared to zero controls (OR 6.93; 95% CI 4.16–9.71) (Fig. 1). Of nonreturning digoxin patients, eight experienced spontaneous abortions, four underwent hospital D&E and three were lost to follow-up. All three primary outcomes were more likely to occur in the digoxin cohort (Table 2). First, spontaneous abortions occurred in 11 digoxin patients and in no control patients (OR 6.93; 95% CI 4.16–9.71). Of these, five occurred in a hospital setting, three outside a medical facility and three at the center prior to misoprostol administration. Second, after routine discharge from the center following the preoperative visit, 11 digoxin patients were admitted to a hospital; no control patients were admitted (OR 6.93; 95% CI 4.61– 9.71). Third, the digoxin cohort had a greater likelihood of any sign of infection (19 digoxin subjects vs. 3 controls; OR 5.91; 95% CI 1.74–20.07), even after adjusting for misoprostol use (OR 4.33; 95% CI 1.24–15.13). Of note, 36 digoxin subjects and 10 controls received no misoprostol; data on misoprostol dose was missing from 17 subjects. On separate infection indicators, the digoxin cohort was more likely to be prescribed therapeutic antibiotics, and the proportion with temperature N38°C approached significance. Secondary complications, including hemorrhage requiring transfusion, uterine perforation and cervical lacerations,
All DIGOXIN records N=583 Records not available N=17
Records selected for CONTROL N=532 Records not available N=19
Digoxin records reviewed N=566
Returned to Center on Day 2 N=551
Control records reviewed N=513
Did not return to Center on Day 2 N=15
Spontaneous abortion at Center N=3
D&E at Center N=548 (one admitted to hospital overnight prior to return for D&E)
Spontaneous abortion: N=5 in hospital N=3 home (one presented to hospital after for retained placenta)
Return to Center on Day 2 N=513
D&E N=513
Hospital D&E N=4
Lost to follow-up N=3
Fig. 1. Flow diagram of digoxin and control records selected for analysis, number of subjects experiencing spontaneous abortions and hospital admissions, and number lost to follow-up.
G. Dean et al. / Contraception 85 (2012) 144–149 Table 1 Characteristics of patients in the digoxin and control groups
Demographics Patient age (years) Ethnicity Hispanic Non-Hispanic Declined or not recorded Race White Black Other Declined or not recorded Insurance typea Medicaid Commercial or MMC Self pay or sliding scale Other Body mass indexb Obstetrical Gravidity Parity Cesarean deliveries Vaginal births None 1–4 ≥5 Prior abortions Current pregnancy Gestational duration Twin gestations
Digoxin N=566
Control N=513
p
22.3±5.6
21.6±5.4
.04
287 (51) 172 (30) 107(19)
297 (58) 126 (25) 90 (17)
.05
45 (8) 265 (47) 65 (11) 191 (34)
46 (9) 250 (49) 32 (6) 185 (36)
.03
290 (52) 157 (28) 101 (18) 14 (3)
292 (57) 121 (24) 78 (15) 18 (4)
25.6±5.2
25.7±5.8
.78
2.9±2.1 0.9±1.2 46 (8)
2.9±2.1 0.3±1.2 52 (10)
.49 .78 .25
319 (56) 243 (43) 4 (0.7) 288 (51)
311 (61) 200 (39) 2 (.4) 251 (49)
.31 .52
20.5+1.7 5 (1)
20.7+1.6 11 (2)
.12 .13
14
Data presented as mean ± standard deviation (analyzed with Student's t test) or n (%) analyzed with χ2 test or Fisher's Exact Test where appropriate. MMC indicates Medicaid managed care. a Digoxin N=562, control N=509. b Digoxin N=565, control N=509.
occurred infrequently and did not differ significantly by cohort (Table 2). Delay of the D&E procedure to Day 3 due to inadequate dilation occurred as often in digoxin patients as in controls (2% of each group). Digoxin was generally well tolerated. Only one digoxin patient received an antiemetic. Mean heart rate in the digoxin group was 79 (range 50–118); only 22 patients had heart rates
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60 or lower, and no patient required medication for bradycardia. No complications occurred during preoperative procedures or recovery. All attempted digoxin injections were completed. Forty-four digoxin patients had positive fetal heart motion on ultrasound on Day 2. Nine (1.6% of the total digoxin cohort) of these patients received an additional digoxin dose before D&E; efficacy of second injections was not recorded. In the digoxin cohort, physicians administered digoxin as an intraamniotic injection in 90 subjects and as an intrafetal injection in 450 (there were an additional 5 subjects with twin pregnancies and 21 subjects with injection location not recorded). Location of digoxin injection was associated with spontaneous abortion; a significantly higher rate of spontaneous abortions occurred in the intraamniotic group (5.6%) compared to the intrafetal group (1.3%) (OR 4.35; 95% CI 1.30–14.59). The intraamniotic group also had higher rates of any sign of infection that approached significance (6.7% intraamniotic vs. 2.7% intrafetal; OR 2.61; 95% CI .95– 7.14). We found no association between the physicians performing the digoxin injection and the risk of infection or spontaneous abortion. Eight physicians performed the preoperative and D&E procedures during the study period. Six performed cases in both cohorts; the remaining two performed cases in one or the other cohort only. The number of cases performed by individual physicians was not equally distributed between cohorts (pb.001); therefore, we looked at the digoxin cohort only to examine whether any individual physician performing the digoxin injection was associated with a higher risk of complications. We found no differences in any sign of infection (p=.97) or spontaneous abortion (p=.72) by physician. Infections and spontaneous abortions were randomly distributed across the 11 months of digoxin use (p=.78 and p=.22, respectively), so we found no evidence for a learning curve effect on complication rates (i.e., complications did not lessen over time).
4. Discussion In this large retrospective cohort study, injection of digoxin prior to D&E was associated with an increased risk
Table 2 Primary and secondary complications by cohort
Spontaneous abortiona Hospital admissiona Any sign of infectionb Temperature N38°C Antibiotics Hemorrhage requiring transfusion Uterine perforation Cervical laceration requiring suture
Digoxin N=566
Control N=513
OR
CI
p
11 (1.9) 11 (1.9) 19 (3.4) 7 (1.2) 17 (3.0) 3 (0.5) 2 (0.4) 8 (1.4)
0 0 3 (0.6) 1 (0.2) 2 (0.4) 3 (0.6) 1 (0.2) 6 (1.2)
6.93 6.93 5.91 6.41 7.91 0.10 1.82 1.21
4.16–9.71 4.16–9.71 1.74–20.07 0.79–52.29 1.82–34.41 0.51–1.70 0.16–20.08 0.42–3.52
b.001 b.001 b.001 .08 .01 .90 .63 .72
Data presented as n (%) analyzed with χ2 test or Fisher's Exact Test where appropriate and binomial logistic regression except where indicated with footnotes. a Analyzed using log-linear logic models. b Unadjusted OR.
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G. Dean et al. / Contraception 85 (2012) 144–149
of spontaneous abortion and infection compared to D&E without preoperative digoxin. The number needed to harm (NNH), calculated as the inverse of the absolute risk difference, is a statistic that serves as a clinically useful indicator of the impact of an intervention [6]. The NNH for spontaneous abortion is 53, meaning that if 53 women receive digoxin, one will have a spontaneous abortion that would not have occurred otherwise. The NNH for infection is 36. Moreover, rates of failure to return for scheduled D&E and of emergency room and hospital admissions were significantly higher among patients who received digoxin. We found no evidence for a physician “learning curve” during the study period to explain our results. Published studies that examine complications in patients who received digoxin before D&E are few. In a small safety study, Drey et al. [7] found no cardiac or coagulation abnormalities in eight women who received digoxin 24 h prior to D&E at 18–23 weeks' gestation. Jackson et al. [3] randomized 126 women to receive digoxin or placebo 24 h prior to D&E at 20–23 weeks' gestation. The primary outcome, procedure time, did not differ significantly between the two groups. Vomiting was the only side effect that occurred more frequently in the digoxin cohort, and rates of complications were comparable. Molaei et al. [8] reported a large case series of 1795 women who received digoxin before D&E at 17 to 24 weeks' gestation. Although this study was not designed to track adverse events, the authors reported that nine women (0.5%) who did not return for D&E were known to have had spontaneous contractions or extramural deliveries. In two series by Hern [9,10] of patients undergoing surgical and induction abortions from 18 through 24 weeks' gestation in which digoxin and other feticidal agents were used, complication rates were low; in the larger series, infection was recorded in only 0.3% of patients. In a small pilot study of 52 women who received digoxin, Nucatola et al. [11] found no infections or spontaneous abortions. The D&E procedure has been shown to be a safe method of second-trimester abortion with a low rate of serious adverse events, including an infection rate of approximately 0.8%–0.9% [12–14], consistent with the rate we found in patients not receiving digoxin. The risk of spontaneous abortion associated with preoperative osmotic dilator placement is unknown. The 1.9% rate of spontaneous abortion among digoxin patients in our study is at least double the rate of fetal loss reported with amniocentesis (0.6% to 1%) [15,16]. The difference may be due to patient factors (including higher rates of sexually transmitted infections among abortion patients [17] and relatively more advanced gestational age [18]), the injection of medication (as opposed to the withdrawal of amniotic fluid), properties of digoxin itself, technique or the concomitant use of osmotic cervical dilators. Our results suggest that intraamniotic digoxin injection may carry a higher risk for spontaneous abortion than intrafetal injection; however, we had comparatively few intraamniotic cases.
Strengths of this study include the large cohort of over 1000 records, reference to multiple data sources, and rigorous tracking and follow-up of complications at the clinical site. Although we relied on retrospective data, errors or omissions in documentation of complications are unlikely given the stringent reporting requirements for serious adverse events mandated by the center's Quality Management Program. On the other hand, a single-institution observational study limits the ability to generalize our findings to other facilities or to draw definitive conclusions about digoxin safety. In addition, a key limitation of this study is the use of historical controls: the control group received care in 2006 and part of 2007, while the digoxin cohort received care during the remainder of 2007 and 2008. However, the patient populations varied little between the two periods, and except for the addition of preoperative digoxin, no notable changes occurred in protocols for the D&E service. Although the distribution of physicians performing procedures in the two cohorts was uneven, subgroup analyses show that the complications recorded were not due to physician variation. In conclusion, we found that digoxin before D&E is associated with increased rates of spontaneous abortion and infection and greater use of hospital facilities. The benefit of using digoxin to cause fetal demise for legal reasons, in particular to comply with Gonzales v. Carhart, must be weighed against its risks. Indeed, in recent Clinical Guidelines, the Society of Family Planning called for further study on the safety of digoxin before second-trimester abortion, noting that current data are not sufficient to recommend its use [1]. Based on the findings from this study, we do not recommend digoxin injection before D&E. Acknowledgments Funding for this study was provided by the Society of Family Planning. References [1] Diedrich J, Drey E, Society of Family Planning. Induction of fetal demise before abortion. Contraception 2010;81:462–73. [2] Gonzales v. Carhart, 550 U.S. 124 (2007). [3] Jackson RA, Teplin VL, Drey EA, Thomas LJ, Darney PD. Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial. Obstet Gynecol 2001;97:471–6. [4] Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Prev Med 2007;45:247–51. [5] Knoke D, Burke PJ. Log-linear models. Thousand Oaks (CA): Sage; 1980. [6] McAlister FA, Straus SE, Guyatt GH, Haynes RB. Evidence-Based Medicine Working Group. Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. JAMA 2000;283:2829–36. [7] Drey EA, Thomas LJ, Benowitz NL, Goldschlager N, Darney PD. Safety of intra-amniotic digoxin administration before late second-
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[8]
[9] [10]
[11]
[12]
trimester abortion by dilation and evacuation. Am J Obstet Gynecol 2000;182:1063–6. Molaei M, Jones HE, Weiselberg T, McManama M, Bassell J, Westhoff C. Effectiveness and safety of digoxin to induce fetal demise prior to second trimester abortion. Contraception 2008;77: 223–5. Hern WH. Laminaria, induced fetal demise and misoprostol in late abortion. Int J Gynaecol Obstet 2001;75:279–86. Hern WH, Zen C, Ferguson KA, et al. Outpatient abortion for fetal anomaly and fetal death from 15–34 menstrual weeks' gestation: techniques and clinical management. Obstet Gynecol 1993;81: 301–6. Nucatola D, Roth N, Gatter M. A randomized pilot study on the effectiveness and side effect profiles of two doses of digoxin as fetocide when administered intraamniotically or intrafetally prior to second-trimester surgical abortion. Contraception 2010;81:67–74. Grimes DA, Schulz KF, Cates Jr W, Tyler CA. Midtrimester abortion by dilatation and evacuation: a safe and practical alternative. N Engl J Med 1977;296:1141–5.
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[13] Peterson WF, Berry FN, Grace MR, Gulbranson CL. Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. Obstet Gynecol 1983;62:185–90. [14] Hern WM. Laminaria versus Dilapan osmotic cervical dilators for outpatient dilation and evacuation abortion: randomized cohort comparison of 1001 patients. Am J Obstet Gynecol 1994;171:1324–8. [15] Eddleman KA, Malone FD, Sullivan L, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 2006;108:1067–72. [16] Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007;110:687–94. [17] Patel A, Rashid S, Godfrey EM, Panchal H. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae genital infections in a publicly funded pregnancy termination clinic: empiric vs. indicated treatment? Contraception 2008;78:328–31. [18] Roper EC, Konje JC, De Chazel RC, Duckett DP, Oppenhimer CA, Tayler DJ. Genetic amniocentesis: gestation-specific pregnancy outcome and comparison of outcome following early and traditional amniocentesis. Prenat Diagn 1999;19:803–7.
Original research article
Safety of digoxin for fetal demise before second-trimester abortion by dilation and evacuation Gillian Deana,⁎, Lisa Colarossia, Britt Lundeb, Adam R. Jacobsc, Lauren M. Porscha, Maureen E. Paula a Planned Parenthood of New York City, New York, NY 10012, USA Department of Obstetrics and Gynecology, University of Illinois, Chicago, IL, USA c Department of Obstetrics, Gynecology, and Reproductive Sciences, The Mount Sinai Medical Center, New York, NY 10029, USA Received 1 February 2011; revised 19 May 2011; accepted 21 May 2011 b
Abstract Background: Digoxin is used to induce fetal demise before dilation and evacuation (D&E) abortion. Published data on the safety of digoxin in abortion care are limited. Study Design: We conducted a retrospective cohort study with historical controls at a large family planning center. We reviewed the records of patients at 18 to 24 weeks' gestation who received digoxin before D&E from May 15, 2007 (date the center initiated digoxin use), through March 31, 2008. We also reviewed the records of patients who presented for D&E without digoxin from February 22, 2006, through May 12, 2007. We compared the rates of immediate complications. Results: We included 566 digoxin patients and 513 controls. Eleven spontaneous abortions occurred in the digoxin cohort; none occurred among controls (pb.001). We found 19 cases of infection in the digoxin cohort and three among controls (odds ratio 5.91; 95% confidence interval 1.74–20.07). Eleven digoxin patients were admitted to a hospital after the preoperative visit; no controls were admitted (pb.001). Conclusions: Patients who received digoxin before D&E were more likely to experience spontaneous abortion, infection and hospital admission than controls who underwent D&E without digoxin. © 2012 Elsevier Inc. All rights reserved. Keywords: Digoxin; Abortion; Safety; Dilation and evacuation; Feticide
1. Introduction Since the 1980s, physicians have used digoxin to induce fetal demise before dilation and evacuation (D&E) abortion for a variety of reasons. Following the 2007 Supreme Court decision Gonzales v. Carhart upholding the Partial Birth Abortion Act of 2003, routine use of digoxin before later second-trimester D&E increased. Gonzales v. Carhart outlaws abortion procedures in which the physician intentionally removes a “living fetus” to or past the point of various anatomic landmarks [1,2]. Feticide prior to abortion is one means of ensuring compliance with the ban. Research to date has not shown medical benefits of digoxin before abortion, although one study found patient preference for preoperative fetal demise [3]. Despite widespread use, published data on the safety of digoxin in abortion care are limited. We conducted a ⁎ Corresponding author. Tel.: +1 212 274 7324; fax: +1 212 274 7218. E-mail address: [email protected] (G. Dean). 0010-7824/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2011.05.016
retrospective cohort study with historical controls to compare complication rates in patients who received digoxin before late second-trimester D&E to complication rates in patients who underwent D&E without digoxin. We hypothesized that patients who received digoxin would have higher rates of certain complications, particularly spontaneous abortion and infection, but not other surgical complications, such as hemorrhage and perforation.
2. Materials and methods We conducted this study at a large urban family planning center. The center instituted routine use of digoxin for abortion patients with viable pregnancies at 18 to 24 weeks' gestation on May 15, 2007, and discontinued digoxin on March 31, 2008. After discontinuing digoxin use, physicians at the center relied on surgical techniques to comply with Gonzales v. Carhart. Patients who received digoxin (the digoxin cohort) were compared with all patients with viable
G. Dean et al. / Contraception 85 (2012) 144–149
pregnancies at a similar gestational age range who had D&E without digoxin from February 22, 2006, through May 12, 2007 (the control cohort). We limited our control period to the 15 months immediately prior to the initiation of digoxin use in order to limit the number of physicians included in the analysis; physician movement into and out of employment by the facility was at its lowest during the period included in the analysis. The Institutional Review Board of the Mount Sinai School of Medicine approved the study. All patients who received digoxin were eligible for inclusion. We identified the digoxin cohort using the digoxin log maintained by the charge nurse. All patients with viable pregnancies at 18 to 24 weeks' gestation who presented for D&E in the control period were eligible for inclusion; we used computerized billing records to identify control patients. We also reviewed the Office of Quality Management's Occurrence Log that listed all serious adverse events associated with D&E, including hospitalizations, spontaneous abortions and failures to return for D&E. All patients had osmotic dilators inserted on the preoperative day, Day 1. The standard procedure included applying povidone-iodine to the cervix, injecting 10–20 cc of 1% lidocaine paracervically and inserting laminaria or Dilapan® tents. All patients received doxycycline 200 mg after osmotic dilator placement in recovery (or azithromycin 1 g if doxycycline allergic or if lactating) and were observed for at least 30 min before being discharged home. Patients in the digoxin cohort received digoxin injection using an 18- or 20gauge spinal needle on Day 1 immediately before osmotic dilator insertion. Physicians administered digoxin according to a standard protocol under ultrasound guidance. Physicians used 1 mg of digoxin (4 mL of undiluted digoxin at a concentration of 250 mcg/mL) per fetus if the injection was intrafetal or 1 mg per sac if intraamniotic. Other than paracervical block prior to osmotic dilator placement, patients were not routinely administered analgesia for the preoperative visit. Patients with contraindications to digoxin were referred elsewhere. Digoxin patients underwent ultrasound on Day 2; digoxin injection was repeated at the physician's discretion before D&E for persistent fetal cardiac activity. On Day 2, patients routinely received buccal misoprostol 600–800 mcg 90 min before D&E. In rare cases of inadequate dilation, the patient received additional misoprostol or osmotic dilators; for markedly poor cervical dilation, the patient returned for D&E on Day 3. The center staff recorded preoperative body temperatures routinely before misoprostol administration and per physician discretion after D&E. If a patient experienced a complication outside the center between dilator placement and D&E, the staff obtained details from the patient or treating physician and requested records from the hospital where she received care. Failure of a patient to return for D&E prompted rigorous attempts to contact her by phone. Attending physicians were all experienced providers of D&E in high-volume settings. The Medical Director observed all physicians performing digoxin injections before granting
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privileges to provide this service. All but one, a general surgeon, were obstetricians/gynecologists with prior training in amniocentesis; the general surgeon was trained in digoxin administration by the Medical Director. Attending physicians performed over 90% of digoxin injections, osmotic dilator placements and D&E procedures; in the remainder, resident physicians in obstetrics and gynecology provided care under the direct supervision of the attending physician. We reviewed the medical records for all study subjects and the occurrence reports and available hospital records for patients with adverse events. We collected data on patient demographic and background characteristics, the preoperative visit, the D&E procedure and any complications that occurred during the period from osmotic dilator placement through the recovery room stay after D&E. We did not collect data on delayed complications. Double data abstractions were conducted on a subsample of 10 charts from each cohort to assess the interrater reliability of data abstraction; no major discrepancies in data abstraction were identified. Our primary outcomes were infection, spontaneous abortion and hospitalization. The diagnosis of infection was not standardized in the medical record. Therefore, we created two variables to measure infection and one variable that was a composite of these two as follows: (a) temperature N38°C on Day 2 or 3 and (b) antibiotics administered at the center on Day 2 or 3 other than those used for routine prophylaxis or treatment of vaginal or cervical infections, or administration of parenteral antibiotics at a hospital and (c) any sign of infection, from presence of either of the first two indicators. Spontaneous abortion was defined as passage of the fetus outside or inside of the center before misoprostol administration. Hospital admission included admission to an emergency room or hospital occurring between osmotic dilator insertion on Day 1 and scheduled return for D&E. This variable did not include hospital transfers after D&E. Secondary outcomes included antiemetic use, failure to return for D&E, hemorrhage requiring transfusion after D&E, cervical lacerations requiring repair, uterine perforations, mean heart rate after digoxin and fetal heart motion by ultrasound on Day 2 after preoperative digoxin. Data were analyzed using SPSS 15.0 statistical software. We followed STROBE guidelines in the preparation of this manuscript [4]. We compared demographic, baseline and procedural characteristics by cohort using χ2 test and Fisher's Exact Test for all categorical variables, and t test for continuous variables. We generated odds ratios (ORs), confidence intervals (CIs) and p values using binomial logistic regression to test the likelihood of most complications by cohort. We used log-linear logic models to test the likelihood of spontaneous abortion, hospitalization and return on Day 2 by cohort because these contingency tables had zero observed occurrences in one cohort; this model provides empirical estimates of the population frequency despite the absence of empirical estimates in the sample [5]. No covariates were modeled because all measured characteristics that may have confounded the relationships between cohort
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and complications were equivalent between groups. Secondarily, we performed subgroup analyses of the digoxin cohort only using χ2 test and Fisher's Exact Test for differences in complication rates by physician and by month of procedure. In addition, we examined the impact of age, parity and gestational age on spontaneous abortion and infection.
3. Results Five hundred eight-three women received digoxin during the study period. Data were obtained from 566 records (97%); 17 records were unavailable for review at the time of request. We identified 532 patients with viable pregnancies at 18 to 24 weeks' gestation who presented for D&E during the control period. Of these, 513 (97%) records were reviewed; 19 records were unavailable. Three subjects in the digoxin cohort and none in the control cohort were lost to follow-up between Day 1 and Day 2 (Fig. 1). The cohorts did not differ significantly in any important respects. Overall, the sample was racially and ethnically diverse and relatively young (Table 1). Compared to the control group, patients in the digoxin cohort were slightly older, fewer identified their ethnicity as Hispanic and more identified their race as “other.” The mean number of osmotic dilators placed was similar (mean ± SD 6.6 ± 2.0 in digoxin subjects vs. 6.4 ± 2.1 in controls, p=.33). The variables of interest had no missing values with the exception of Day 2
preoperative temperature that was missing from 15 digoxin records and 24 controls. Overall, 40 (7%) digoxin patients experienced some form of complication compared to 11 (2%) control patients (OR 3.47; 95% CI 1.76–6.84). Fifteen digoxin patients did not return on Day 2, compared to zero controls (OR 6.93; 95% CI 4.16–9.71) (Fig. 1). Of nonreturning digoxin patients, eight experienced spontaneous abortions, four underwent hospital D&E and three were lost to follow-up. All three primary outcomes were more likely to occur in the digoxin cohort (Table 2). First, spontaneous abortions occurred in 11 digoxin patients and in no control patients (OR 6.93; 95% CI 4.16–9.71). Of these, five occurred in a hospital setting, three outside a medical facility and three at the center prior to misoprostol administration. Second, after routine discharge from the center following the preoperative visit, 11 digoxin patients were admitted to a hospital; no control patients were admitted (OR 6.93; 95% CI 4.61– 9.71). Third, the digoxin cohort had a greater likelihood of any sign of infection (19 digoxin subjects vs. 3 controls; OR 5.91; 95% CI 1.74–20.07), even after adjusting for misoprostol use (OR 4.33; 95% CI 1.24–15.13). Of note, 36 digoxin subjects and 10 controls received no misoprostol; data on misoprostol dose was missing from 17 subjects. On separate infection indicators, the digoxin cohort was more likely to be prescribed therapeutic antibiotics, and the proportion with temperature N38°C approached significance. Secondary complications, including hemorrhage requiring transfusion, uterine perforation and cervical lacerations,
All DIGOXIN records N=583 Records not available N=17
Records selected for CONTROL N=532 Records not available N=19
Digoxin records reviewed N=566
Returned to Center on Day 2 N=551
Control records reviewed N=513
Did not return to Center on Day 2 N=15
Spontaneous abortion at Center N=3
D&E at Center N=548 (one admitted to hospital overnight prior to return for D&E)
Spontaneous abortion: N=5 in hospital N=3 home (one presented to hospital after for retained placenta)
Return to Center on Day 2 N=513
D&E N=513
Hospital D&E N=4
Lost to follow-up N=3
Fig. 1. Flow diagram of digoxin and control records selected for analysis, number of subjects experiencing spontaneous abortions and hospital admissions, and number lost to follow-up.
G. Dean et al. / Contraception 85 (2012) 144–149 Table 1 Characteristics of patients in the digoxin and control groups
Demographics Patient age (years) Ethnicity Hispanic Non-Hispanic Declined or not recorded Race White Black Other Declined or not recorded Insurance typea Medicaid Commercial or MMC Self pay or sliding scale Other Body mass indexb Obstetrical Gravidity Parity Cesarean deliveries Vaginal births None 1–4 ≥5 Prior abortions Current pregnancy Gestational duration Twin gestations
Digoxin N=566
Control N=513
p
22.3±5.6
21.6±5.4
.04
287 (51) 172 (30) 107(19)
297 (58) 126 (25) 90 (17)
.05
45 (8) 265 (47) 65 (11) 191 (34)
46 (9) 250 (49) 32 (6) 185 (36)
.03
290 (52) 157 (28) 101 (18) 14 (3)
292 (57) 121 (24) 78 (15) 18 (4)
25.6±5.2
25.7±5.8
.78
2.9±2.1 0.9±1.2 46 (8)
2.9±2.1 0.3±1.2 52 (10)
.49 .78 .25
319 (56) 243 (43) 4 (0.7) 288 (51)
311 (61) 200 (39) 2 (.4) 251 (49)
.31 .52
20.5+1.7 5 (1)
20.7+1.6 11 (2)
.12 .13
14
Data presented as mean ± standard deviation (analyzed with Student's t test) or n (%) analyzed with χ2 test or Fisher's Exact Test where appropriate. MMC indicates Medicaid managed care. a Digoxin N=562, control N=509. b Digoxin N=565, control N=509.
occurred infrequently and did not differ significantly by cohort (Table 2). Delay of the D&E procedure to Day 3 due to inadequate dilation occurred as often in digoxin patients as in controls (2% of each group). Digoxin was generally well tolerated. Only one digoxin patient received an antiemetic. Mean heart rate in the digoxin group was 79 (range 50–118); only 22 patients had heart rates
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60 or lower, and no patient required medication for bradycardia. No complications occurred during preoperative procedures or recovery. All attempted digoxin injections were completed. Forty-four digoxin patients had positive fetal heart motion on ultrasound on Day 2. Nine (1.6% of the total digoxin cohort) of these patients received an additional digoxin dose before D&E; efficacy of second injections was not recorded. In the digoxin cohort, physicians administered digoxin as an intraamniotic injection in 90 subjects and as an intrafetal injection in 450 (there were an additional 5 subjects with twin pregnancies and 21 subjects with injection location not recorded). Location of digoxin injection was associated with spontaneous abortion; a significantly higher rate of spontaneous abortions occurred in the intraamniotic group (5.6%) compared to the intrafetal group (1.3%) (OR 4.35; 95% CI 1.30–14.59). The intraamniotic group also had higher rates of any sign of infection that approached significance (6.7% intraamniotic vs. 2.7% intrafetal; OR 2.61; 95% CI .95– 7.14). We found no association between the physicians performing the digoxin injection and the risk of infection or spontaneous abortion. Eight physicians performed the preoperative and D&E procedures during the study period. Six performed cases in both cohorts; the remaining two performed cases in one or the other cohort only. The number of cases performed by individual physicians was not equally distributed between cohorts (pb.001); therefore, we looked at the digoxin cohort only to examine whether any individual physician performing the digoxin injection was associated with a higher risk of complications. We found no differences in any sign of infection (p=.97) or spontaneous abortion (p=.72) by physician. Infections and spontaneous abortions were randomly distributed across the 11 months of digoxin use (p=.78 and p=.22, respectively), so we found no evidence for a learning curve effect on complication rates (i.e., complications did not lessen over time).
4. Discussion In this large retrospective cohort study, injection of digoxin prior to D&E was associated with an increased risk
Table 2 Primary and secondary complications by cohort
Spontaneous abortiona Hospital admissiona Any sign of infectionb Temperature N38°C Antibiotics Hemorrhage requiring transfusion Uterine perforation Cervical laceration requiring suture
Digoxin N=566
Control N=513
OR
CI
p
11 (1.9) 11 (1.9) 19 (3.4) 7 (1.2) 17 (3.0) 3 (0.5) 2 (0.4) 8 (1.4)
0 0 3 (0.6) 1 (0.2) 2 (0.4) 3 (0.6) 1 (0.2) 6 (1.2)
6.93 6.93 5.91 6.41 7.91 0.10 1.82 1.21
4.16–9.71 4.16–9.71 1.74–20.07 0.79–52.29 1.82–34.41 0.51–1.70 0.16–20.08 0.42–3.52
b.001 b.001 b.001 .08 .01 .90 .63 .72
Data presented as n (%) analyzed with χ2 test or Fisher's Exact Test where appropriate and binomial logistic regression except where indicated with footnotes. a Analyzed using log-linear logic models. b Unadjusted OR.
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of spontaneous abortion and infection compared to D&E without preoperative digoxin. The number needed to harm (NNH), calculated as the inverse of the absolute risk difference, is a statistic that serves as a clinically useful indicator of the impact of an intervention [6]. The NNH for spontaneous abortion is 53, meaning that if 53 women receive digoxin, one will have a spontaneous abortion that would not have occurred otherwise. The NNH for infection is 36. Moreover, rates of failure to return for scheduled D&E and of emergency room and hospital admissions were significantly higher among patients who received digoxin. We found no evidence for a physician “learning curve” during the study period to explain our results. Published studies that examine complications in patients who received digoxin before D&E are few. In a small safety study, Drey et al. [7] found no cardiac or coagulation abnormalities in eight women who received digoxin 24 h prior to D&E at 18–23 weeks' gestation. Jackson et al. [3] randomized 126 women to receive digoxin or placebo 24 h prior to D&E at 20–23 weeks' gestation. The primary outcome, procedure time, did not differ significantly between the two groups. Vomiting was the only side effect that occurred more frequently in the digoxin cohort, and rates of complications were comparable. Molaei et al. [8] reported a large case series of 1795 women who received digoxin before D&E at 17 to 24 weeks' gestation. Although this study was not designed to track adverse events, the authors reported that nine women (0.5%) who did not return for D&E were known to have had spontaneous contractions or extramural deliveries. In two series by Hern [9,10] of patients undergoing surgical and induction abortions from 18 through 24 weeks' gestation in which digoxin and other feticidal agents were used, complication rates were low; in the larger series, infection was recorded in only 0.3% of patients. In a small pilot study of 52 women who received digoxin, Nucatola et al. [11] found no infections or spontaneous abortions. The D&E procedure has been shown to be a safe method of second-trimester abortion with a low rate of serious adverse events, including an infection rate of approximately 0.8%–0.9% [12–14], consistent with the rate we found in patients not receiving digoxin. The risk of spontaneous abortion associated with preoperative osmotic dilator placement is unknown. The 1.9% rate of spontaneous abortion among digoxin patients in our study is at least double the rate of fetal loss reported with amniocentesis (0.6% to 1%) [15,16]. The difference may be due to patient factors (including higher rates of sexually transmitted infections among abortion patients [17] and relatively more advanced gestational age [18]), the injection of medication (as opposed to the withdrawal of amniotic fluid), properties of digoxin itself, technique or the concomitant use of osmotic cervical dilators. Our results suggest that intraamniotic digoxin injection may carry a higher risk for spontaneous abortion than intrafetal injection; however, we had comparatively few intraamniotic cases.
Strengths of this study include the large cohort of over 1000 records, reference to multiple data sources, and rigorous tracking and follow-up of complications at the clinical site. Although we relied on retrospective data, errors or omissions in documentation of complications are unlikely given the stringent reporting requirements for serious adverse events mandated by the center's Quality Management Program. On the other hand, a single-institution observational study limits the ability to generalize our findings to other facilities or to draw definitive conclusions about digoxin safety. In addition, a key limitation of this study is the use of historical controls: the control group received care in 2006 and part of 2007, while the digoxin cohort received care during the remainder of 2007 and 2008. However, the patient populations varied little between the two periods, and except for the addition of preoperative digoxin, no notable changes occurred in protocols for the D&E service. Although the distribution of physicians performing procedures in the two cohorts was uneven, subgroup analyses show that the complications recorded were not due to physician variation. In conclusion, we found that digoxin before D&E is associated with increased rates of spontaneous abortion and infection and greater use of hospital facilities. The benefit of using digoxin to cause fetal demise for legal reasons, in particular to comply with Gonzales v. Carhart, must be weighed against its risks. Indeed, in recent Clinical Guidelines, the Society of Family Planning called for further study on the safety of digoxin before second-trimester abortion, noting that current data are not sufficient to recommend its use [1]. Based on the findings from this study, we do not recommend digoxin injection before D&E. Acknowledgments Funding for this study was provided by the Society of Family Planning. References [1] Diedrich J, Drey E, Society of Family Planning. Induction of fetal demise before abortion. Contraception 2010;81:462–73. [2] Gonzales v. Carhart, 550 U.S. 124 (2007). [3] Jackson RA, Teplin VL, Drey EA, Thomas LJ, Darney PD. Digoxin to facilitate late second-trimester abortion: a randomized, masked, placebo-controlled trial. Obstet Gynecol 2001;97:471–6. [4] Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Prev Med 2007;45:247–51. [5] Knoke D, Burke PJ. Log-linear models. Thousand Oaks (CA): Sage; 1980. [6] McAlister FA, Straus SE, Guyatt GH, Haynes RB. Evidence-Based Medicine Working Group. Users' guides to the medical literature: XX. Integrating research evidence with the care of the individual patient. JAMA 2000;283:2829–36. [7] Drey EA, Thomas LJ, Benowitz NL, Goldschlager N, Darney PD. Safety of intra-amniotic digoxin administration before late second-
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[13] Peterson WF, Berry FN, Grace MR, Gulbranson CL. Second-trimester abortion by dilatation and evacuation: an analysis of 11,747 cases. Obstet Gynecol 1983;62:185–90. [14] Hern WM. Laminaria versus Dilapan osmotic cervical dilators for outpatient dilation and evacuation abortion: randomized cohort comparison of 1001 patients. Am J Obstet Gynecol 1994;171:1324–8. [15] Eddleman KA, Malone FD, Sullivan L, et al. Pregnancy loss rates after midtrimester amniocentesis. Obstet Gynecol 2006;108:1067–72. [16] Mujezinovic F, Alfirevic Z. Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstet Gynecol 2007;110:687–94. [17] Patel A, Rashid S, Godfrey EM, Panchal H. Prevalence of Chlamydia trachomatis and Neisseria gonorrhoeae genital infections in a publicly funded pregnancy termination clinic: empiric vs. indicated treatment? Contraception 2008;78:328–31. [18] Roper EC, Konje JC, De Chazel RC, Duckett DP, Oppenhimer CA, Tayler DJ. Genetic amniocentesis: gestation-specific pregnancy outcome and comparison of outcome following early and traditional amniocentesis. Prenat Diagn 1999;19:803–7.