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Intra-fetal Compared With Intra-amniotic Digoxin Before Dilation and Evacuation

A Randomized Controlled Trial

White, Katharine O'Connell MD, MPH; Nucatola, Deborah L. MD; Westhoff, Carolyn MD, MSc

doi: 10.1097/AOG.0000000000001671
Contents: Original Research
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OBJECTIVE: To compare the effectiveness of 1.0 mg intra-fetal or intra-amniotic digoxin to achieve fetal asystole before second-trimester surgical pregnancy termination.

METHODS: In a randomized trial, women received 1.0 mg transabdominal intra-fetal or intra-amniotic digoxin on the day of laminaria placement before dilation and evacuation between 20 and 24 weeks of gestation. The primary outcome was incidence of fetal asystole, documented immediately before dilation and evacuation. We planned to analyze the primary outcome by original group assignment as well as by as-treated and per-protocol populations. A sample size of 270 was needed to detect an 8% difference in failure rates between groups. Prespecified secondary outcomes included the incidence of adverse events, side effects, and procedural differences.

RESULTS: Between January 2012 and January 2013, we screened 381 women and randomized 270 women to receive intra-fetal (n=136) or intra-amniotic (n=134) digoxin. Characteristics were similar across groups; the mean gestational age was 21.6 weeks (standard deviation 1.2). The proportion of fetal asystole was higher in the intra-fetal group (128/135 [94.8%]) than the intra-amniotic group (107/130, 82.3%; relative risk of failure to achieve asystole 3.41, 95% confidence interval 1.52–7.68). Results were similar in the as-treated and per-protocol populations. There were no significant differences in adverse events or side effects and no differences in injection duration, operative time, or estimated blood loss.

CONCLUSION: Administration of intra-fetal injection of digoxin led to a higher proportion of participants achieving fetal asystole within 24 hours than intra-amniotic injection.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01047748.

Administration of intra-fetal digoxin leads to a higher proportion of participants achieving fetal asystole before dilation and evacuation compared with intra-amniotic digoxin.

Boston University School of Medicine, Boston, Massachusetts; and Planned Parenthood Federation of America and Columbia University, New York, New York.

Corresponding author: Katharine O'Connell White, MD, MPH, Department of Obstetrics and Gynecology, Boston Medical Center, 850 Harrison Avenue, YACC-5, Boston, MA 02118; e-mail: katharine.white@bmc.org.

Supported by a grant from the Society of Family Planning.

The sponsor had no role in the study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the report for publication. The findings and conclusions in this article are those of the authors and do not necessarily represent the views of Planned Parenthood Federation of America, Inc.

Financial Disclosure The authors did not report any potential conflicts of interest.

Presented in at the North American Forum on Family Planning, October 6–7, 2013, Seattle, Washington.

The authors thank Mayra Ferreira at Physicians for Reproductive Health for grant administration and Bonnie Smith, Amy Briggs, and Venus Oliva for their assistance with data collection.

Intrauterine digoxin is commonly used to achieve fetal asystole before dilation and evacuation (D&E) procedures.1 Adverse reactions to digoxin, when used to treat heart failure, are uncommon and include heart block, gastrointestinal disturbances, headache, dizziness, and visual disturbances.2 Risks of intrauterine digoxin include infection and spontaneous abortion.2–5

Limited data are available regarding the efficacy of digoxin use by dose or route of administration.6–9 One placebo-controlled study (n=126) found 92% effectiveness of 1.0 mg intra-amniotic digoxin with no confidence interval (CI) provided.6 A four-arm randomized trial (n=52) reported 92% effectiveness of 1.0 mg digoxin in both the intra-amniotic and intra-fetal groups (12/13, 95% CI 64–100) with no increased effectiveness with a 1.5-mg dose.7 A study of 1.0 mg transvaginal intra-amniotic digoxin (n=24) also reported 92% effectiveness at achieving asystole (95% CI 75–99%).8 A case series (n=1,596) from a single center examined effectiveness of intravaginal intra-amniotic and intra-fetal digoxin injection at multiple doses (92% were 1.0 mg but ranged from 0.5 to 3.0 mg).9 Fetal demise was documented in 99.4% of cases, including 99.6% of women who received intra-fetal injections. Doses at or above 1 mg were equally effective regardless of site of injection (intra-amniotic, intra-fetal, or both); no CIs were provided.

We performed a randomized trial to compare effectiveness between two frequently used locations of transabdominal digoxin injection, intra-amniotic and intra-fetal, before a second-trimester surgical abortion. Our hypothesis was that intra-fetal injection would have higher efficacy at achieving fetal asystole than intra-amniotic injection.7,10

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MATERIALS AND METHODS

The study was conducted at a single freestanding health center in California after receiving approval by the Western Institutional Review Board. Women eligible to participate were those scheduled for D&E between 20 0/7 weeks and 23 6/7 weeks of gestation on the day of the procedure. Women were approached about study involvement after completion of all decision-making about the abortion procedure. Participants were at least 18 years old, spoke English, had documented fetal cardiac activity, and were able to give informed consent. Exclusion criteria included significant medical illness or cardiovascular disease, current use of cardiac or antihypertensive medications, multiple gestation, morbid obesity (body mass index [BMI, calculated as weight (kg)/[height (m)]2] greater than 40), hemoglobin less than 9 mg/dL, and known digoxin allergy or intolerance.

After we obtained informed consent from eligible women, we conducted a brief interview to elicit demographic and reproductive history. We then randomized participants to intra-fetal or intra-amniotic digoxin injection. The randomization scheme was generated using a random number table with an allocation ratio of one to one in blocks of four. An investigator who had no contact with study participants prepared the randomization scheme using a random number table and placed the treatment assignments in sequentially numbered, sealed opaque envelopes. The research assistant opened the envelopes after consent and enrollment was complete.

Participants received routine care per health center protocols. Transabdominal digoxin injection was performed per group assignment after both ultrasound confirmation of gestational age and cardiac activity and placement of laminaria, generally under local anesthesia. Experienced health care providers performed all digoxin injections (1.0 mg) under ultrasound guidance (details in Appendix 1, available online at http://links.lww.com/AOG/A868). Intra-fetal injections were defined as those into any part of the fetus; exact location of the injection into the fetus was at the discretion of the performing clinician and was not recorded. Intra-amniotic injections were defined as those given into the amniotic fluid and not into any part of the fetus. Location of the injection was recorded as “both” when the needle moved in or out of the fetus leading to injection in both places. No antibiotic prophylaxis was given.

The next day, before the planned abortion, we administered a questionnaire to assess symptoms since the time of digoxin administration. Surgeons documented presence or absence of fetal cardiac activity by ultrasonography immediately preceding the D&E, 15–24 hours after the injection. The surgeon performing the D&E was not the same health care provider who had inserted the dilators and performed the digoxin injection; although surgeons were not formally blinded to study group, the digoxin injection location was recorded only in the study chart. If fetal asystole had not occurred, repeat digoxin injection was not performed. All participants received a combination of fentanyl and midazolam followed by propofol administered by a certified registered nurse anesthetist. We telephoned all participants who did not return to the center for the scheduled D&E to obtain details on the pregnancy disposition.

The primary study outcome was the proportion of participants with fetal asystole in each group based on intent-to-treat analysis. The secondary outcomes were adverse events (injection site reactions, adverse reaction to digoxin, chorioamnionitis, preprocedure expulsion of the pregnancy, and standard D&E complications such as hemorrhage and need for additional surgery) and procedural differences. We recorded any adverse events that occurred in the perioperative period, and participants completed a questionnaire that included questions about digoxin-related side effects. To assess the procedural differences, we recorded the amount of time required for each digoxin administration (from needle insertion to drug injection), number of laminaria placed, initial cervical dilation after laminaria removal (as assessed digitally and recorded by the surgeon), D&E operative time, and surgeon-estimated blood loss.

The expected failure rates in each group were based on previous results6,10 that reported failure to achieve asystole after intra-amniotic digoxin (0.5–1.0 mg) of 8% and after intra-fetal digoxin (1.0 mg) of 0%. To have 80% power to detect a difference of this magnitude or greater between groups, with a two-sided test and an α of 0.05, we required 121 participants in each arm. Assuming a 10% noncompletion rate, we needed to enroll 270 participants.

Success and failure rates were reported as counts and percentages. The relative effect was reported by relative risk of failure with corresponding 95% CIs, and the significance was assessed with Fisher exact test. We examined differences in secondary outcomes with descriptive statistics, t tests (for continuous measures), and Fisher exact tests (for categorical measures). We compared procedure characteristics using Fisher exact and Wilcoxon tests. In addition to intent-to-treat analysis, we examined the primary and secondary outcomes based on the actual digoxin injection location (as-treated analysis) rather than based on treatment assignment and comparing only those with injection location corresponding to treatment assignment (per-protocol analysis). We used IBM SPSS Statistics for Windows 19.0 for all analyses.

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RESULTS

We enrolled participants from January 2012 through January 2013. Participant flow through the trial is detailed in Figure 1. Two participants were excluded after informed consent was obtained but before randomization (one withdrew, one was inadvertently enrolled with a BMI higher than 40). Two participants were excluded after randomization (one withdrew, one was inadvertently enrolled with hemoglobin under 9 mg/dL), both in the group assigned to intra-amniotic group digoxin. Thus, 268 participants (99%) received a digoxin injection. Three health care providers performed almost two thirds (63%) of the injections; 12 health care providers performed the remaining injections. Intra-fetal injection was achieved in 82% of the participants assigned to intra-fetal injection and intra-amniotic injection was achieved in 91% of the participants assigned to intra-amniotic injection; this difference was significant (P=.049). Participants who did not receive the assigned treatment received the other treatment (or both).

Fig. 1.

Fig. 1.

Table 1 shows baseline characteristics of the study population. There were no differences between groups in demographic or pregnancy history.

Table 1.

Table 1.

In the primary analysis (Fig. 2), the group assigned to intra-fetal digoxin achieved asystole in 94.8% of cases (128/135) compared with 82.3% (107/130) in the group assigned to intra-amniotic digoxin (P=.002, relative risk of failure to achieve asystole 3.41, 95% CI 1.52–7.68). In the as-treated analysis, based on the actual digoxin injection location, participants who received intra-fetal injections achieved asystole 98.4% (120/122) of the time compared with 80.1% (113/141) who received intra-amniotic injections (P<.001, relative risk of failure to achieve asystole 12.1, 95% CI 2.95–49.8). The per-protocol analysis yielded similar results. The median time from digoxin injection to fetal heart rate assessment was 19 hours 3 minutes (interquartile range 17:58–20:29); there was no difference between participants with fetal asystole and those without. There were no differences in demographic characteristics, BMI, parity, abortion history, number of laminaria placed, or health care provider experience between women who received a successful or unsuccessful intra-amniotic injection.

Fig. 2.

Fig. 2.

Women in this study experienced a low incidence of adverse events (6.7%), which are detailed in Table 2. The as-treated analysis showed results similar to the intent-to-treat analysis with no difference between groups (P=.24). The treatment groups reported similar side effects in both the intent-to-treat analysis and the as-treated analysis (Table 3).

Table 2.

Table 2.

Table 3.

Table 3.

There were no operative differences between groups (details by group in Appendix 2, available online at http://links.lww.com/AOG/A868). Digoxin injection took an average of 1.3 minutes (standard deviation [SD] 1.2, range 0.5–13 minutes). Participants received an average of 1.7 sets of dilators (SD 0.6, range 1–3) with a mean of seven dilators in the final set (SD 1.7, range 1–12). Initial cervical dilation averaged 3.1 cm (SD 1.3, range 0–10 cm). The mean procedure time was 7.3 minutes (SD 3.9, range 2–24 minutes) and mean estimated blood loss was 44 mL (SD 15.6, range 20–100 mL).

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DISCUSSION

Use of intra-fetal digoxin injection led to a higher proportion of participants achieving fetal asystole than intra-amniotic injection with no differences in adverse events, side effects, or procedure time. The intra-fetal injection did not have a longer duration of administration.

The failure proportion of 18% for intra-amniotic injection is somewhat higher than previously reported. These studies7,8 had wide CIs that included our point estimate. The current investigation had a larger study population than the previous studies and as a result of the high number of health care providers may represent a more generalizable outcome; some previous studies had only one or two clinicians administering digoxin.8,11 The failure rate of 5% after intra-fetal injection is also higher than previously reported, although the effectiveness in the as-treated analysis (98%) is comparable with that in previous studies.7,10 Overall, previous studies are either noncomparative or lack the statistical power to assess even large differences in efficacy between the routes of digoxin injection. In our study, the median time between digoxin injection and fetal heart rate assessment was 19 hours. It is possible that digoxin, particularly when administered intra-amniotically, requires more time to achieve maximum efficacy. Only one previous study specified the time between injection and assessment, which was 24±3.8 hours.7

Health care providers' decision-making as to where to inject digoxin may be made based on several factors. Some may prefer intra-amniotic injection as a result of its perceived ease of administration, requiring less skill. Intra-fetal injection may not always be feasible by transvaginal administration. In fact, intra-fetal injection was more difficult in this study; a significant number of participants randomized to intra-fetal administration (23/136 [17%]) actually received an intra-amniotic injection, most often as a result of technical considerations such as placenta location, fetal position, large maternal habitus, or low amniotic fluid volume.

Women in this study experienced a low incidence of adverse events. The single cervical laceration and the two hospital transfers seem unlikely to be related to the digoxin injection. The number of preprocedure fetal expulsions (seven) is consistent with reports of the risk of labor and delivery after digoxin injection by any route.3,4 Side effects that may be attributable to digoxin injection such as headache, dizziness, and visual disturbances did not differ between groups.

Analysis of our other secondary outcomes yielded no differences between groups in procedure time, estimated blood loss, or complications. The mean cervical dilation (3 cm) was higher than expected given the average number of laminaria placed (seven). We speculate that digoxin may act as an irritant to the uterine lining, possibly inducing prostaglandin release, leading to cervical ripening; the same mechanism may be responsible for the incidence of preprocedure fetal expulsions. A recent analysis of the amniotic fluid of women undergoing second-trimester surgical abortion (n=22) demonstrated elevated inflammatory markers 24 hours after digoxin injection and dilator placement compared with preinjection marker levels.12 Digoxin injection may, in this way, facilitate the abortion itself by leading to greater initial dilation in the face of fewer laminaria.

Our study has several limitations. The study was performed in a single center, so results may not be generalizable to all clinical settings. The surgeons were not formally blinded to the route of digoxin injection, which may have affected their assessment of procedure ease or blood loss, although the measurement of digoxin efficacy should not have been affected. Because our study lacked an untreated control group, we cannot assess the risks and benefits of the present treatments to no digoxin use. Most abortion providers who use digoxin require it for all of their patients of a certain gestational age. Consequently, it may not be feasible to carry out a randomized controlled trial randomizing women to digoxin or placebo. Finally, our study lacked sufficient power to perform subanalyses to assess the reasons for the high rate of intra-amniotic injection failure or to detect differences in adverse events or side effects.

The clinical implications of our study are significant for health care providers who rely on the efficacy of digoxin before D&E. Our findings should be confirmed in additional studies; if validated, clinicians may want to consider a preference for intra-fetal digoxin injection when designing clinical protocols. Until then, health care providers should examine the results of their own practice in light of our findings. Future research also should address how the time interval between digoxin injection and D&E affects the rate of fetal asystole. Although underpowered to fully assess secondary outcomes, we did not find any differences in adverse events or side effects between the two locations of digoxin administration.

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REFERENCES

1. O'Connell K, Jones H, Lichtenberg ES, Paul M. Second trimester surgical abortion practices: a survey of National Abortion Federation members. Contraception 2008;78:492–9.
2. Lanoxin (digoxin) prescribing information. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009330s026lbl.pdf. Retrieved June 23, 2016.
3. Drey EA, Thomas LJ, Benowitz NL, Goldschlager N, Darney PD. Safety of intra-amniotic digoxin administration before late second-trimester abortion by dilation and evacuation. Am J Obstet Gynecol 2000;182:1063–6.
4. Dean G, Colarossi L, Lunde B, Jacobs AR, Porsch LM, Paul ME. Safety of digoxin for fetal demise before second-trimester abortion by dilation and evacuation. Contraception 2012;85:144–9.
5. Steward R, Melamed A, Kim R, Nucatola D, Gatter M. Infection and extramural delivery with use of digoxin as a feticidal agent. Contraception 2012;85:150–4.
6. Garg M, Markovchick N. Hyperkalemic paralysis: an elective abortion gone wrong. J Emerg Med 2013;45:190–3.
7. 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.
8. 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.
9. Gariepy AM, Chen BA, Hohhmann HL, Achilles SL, Russo JA, Creinin MD. Transvaginal administration of intraamniotic digoxin prior to dilation and evacuation. Contraception 2013;87:76–80.
10. Tocce K, Sheeder JL, Edwards LJ, Teal SB. Feasibility, effectiveness and safety of transvaginal digoxin administration prior to dilation and evacuation. Contraception 2013;88:706–11.
11. Molaei M, Jones HE, Weiselberg T, McManama M, Bassell J, Westhoff CL. Effectiveness and safety of digoxin to induce fetal demise prior to second-trimester abortion. Contraception 2008;77:223–5.
12. Roncari D, Politch JA, Sonalkar S, Finneseth M, Borgatta L. Inflammation or infection at the time of second trimester induced abortion. Contraception 2013;87:67–70.

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