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Robert L. Barbieri, MD

 

Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

  • The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
  • Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.3 However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.8

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

 

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.9 Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.9

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.10 In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).11

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.14 The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

 

 

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.28 In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.28

 

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,30 including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.29

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.31 In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

 

 

Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.26 Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.26

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.27 In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.27

 

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.32TABLES 1,1, 26, 33–362,37 and 337 summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)1 recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.38 ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.38 Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.9 See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.39 The patient’s partner often reports feeling unacknowledged as a grieving parent.40 Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

  1. reduce stigma
  2. provide respectful care
  3. involve patients in care planning
  4. attempt to provide an explanation for the demise1
  5. acknowledge the depth of the grief response and provide emotional support
  6. offer information about ongoing psychological support
  7. provide information about future pregnancy planning
  8. provide opportunities for specialized training and support for care providers.41

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

References
  1. American College of Obstetricians and Gynecologists. Management of stillbirth. ACOG Obstetric Care Consensus. No. 10. Obstet Gynecol. 2020;135:e110-132.
  2. Tsakiridis I, Giouleka S, Mamopoulos A, et al. Investigation and management of stillbirths: a descriptive review of major guidelines. J Perinat Med. 2022;50:796-813.
  3. Spingler T, Sonek J, Hoopman M, et al. Complication rate after termination of pregnancy due to fetal defects. Ultrasound Obstet Gynecol. 2023;Epub January 7.
  4. Goldberg AB, Drey EA, Whitaker AK, et al. Misoprostol compared with laminaria before early second-trimester surgical abortion: a randomized trial. Obstet Gynecol. 2005;106:234-241.
  5. Meirik O, My Huong NT, Piaggio G, et al. WHOR-GoP-MoF Regulation. Complications of first trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial. Lancet. 2012;379(9829):1817-1824.
  6. Bartz D, Maurer R, Allen RH, et al. Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial. Obstet Gynecol. 2013;122:57-63.
  7. Ngo LL, Mokashi M, Janiak E, et al. Acute complications with same-day versus overnight cervical preparation before dilation and evacuation at 14 to 16 weeks. Contraception. 2023;117:61-66.
  8. Kim CS, Dragoman M, Prosch L, et al. Same-day compared with overnight cervical preparation before dilation and evacuation between 16 and 19 6/7 weeks of gestation: a randomized controlled trial. Obstet Gynecol. 2022;139:1141-1144.
  9. Drunecky T, Reidingerova M, Plisova M, et al. Experimental comparison of properties of natural and synthetic osmotic dilators. Arch Gynecol Obstet. 2015;292:349-354.
  10. 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;171:1324-1328.
  11. Berthold C, Gomes David M, Gabriel P, et al. Effect of the addition of osmotic dilators to medical induction of labor abortion: a before-and-after study. Eur J Obstet Gynecol. 2020;244:185-189.
  12. Kemper JI, Li W, Goni S, et al. Foley catheter vs oral misoprostol for induction of labor: individual participant data meta-analysis. Ultrasound Obstet Gynecol. 2021;57:215-223.
  13. Attalli E, Kern Guy, Fouks Y, et al. Labor induction in third trimester non-viable fetus. J Matern Fetal Neonatal Med. 2022;Epub October 1.
  14. Fessehaye Sium A, Prager S, Wolderufael M, et al. Foley catheter for cervical preparation prior to second trimester dilation and evacuation: a supply-based alternative for surgical abortion: a case series. Contracept X. 2022;4:100085.
  15. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol. 1997;90:88-92.
  16. Gemzell-Danilesson K, Marions L, Rodriguez A, et al. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol. 1999;93:275-280.
  17. Aronsson A, Bygdeman M, Gemzell-Danielsson K. Effects of misoprostol on uterine contractility following different routes of administration. Hum Reprod. 2004;19:81-84.
  18. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by epithelial routes. Drug absorption and uterine response. Obstet Gynecol. 2006;108:582-590.
  19. Barbieri RL. Misoprostol: clinical pharmacology in obstetrics and gynecology. OBG Manag. 2022;34:8-10, 12.
  20. Andersen J, Grine E, Eng L, et al. Expression of connexin-43 in human myometrium and leiomyoma. Am J Obstet Gynecol. 1993;169:1266-1276.
  21. Ou CW, Orsino A, Lye SJ. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology. 1997;138:5398-5407.
  22. Petrocelli T, Lye SJ. Regulation of transcripts encoding the myometrial gap junction protein, connexin-43, by estrogen and progesterone. Endocrinology. 1993;133:284-290.
  23. Barbieri RL. Mifepristone for the treatment of miscarriage and fetal demise. OBG Manag. 2022;34:811, 15.
  24. Kapp N, Borgatta L, Stubblefield P, et al. Mifepristone in second-trimester medical abortion. Obstet Gynecol. 2007;110:1304-1310.
  25. Ngoc NTN, Shochet T, Raghavan S, et al. Mifepristone and misoprostol compared with misoprostol alone for second trimester abortion: a randomized controlled trial. Obstet Gynecol. 2011;118:601608.
  26. Allanson ER, Copson S, Spilsbury K, et al. Pretreatment with mifepristone compared with misoprostol alone for delivery after fetal death between 14 and 28 weeks of gestation. Obstet Gynecol. 2021;137:801-809.
  27. Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: a randomized trial. J Obstet Gynaecol Res. 2015;41:1884-1890.
  28. Prodan N, Breisch J, Hoopman M, et al. Dosing interval between mifepristone and misoprostol in second and third trimester termination. Arch Gynecol Obstet. 2019;299:675-679.
  29. Edlow AG, Hou MY, Maurer R, et al. Uterine evacuation for second trimester fetal death and maternal morbidity. Obstet Gynecol. 2011;117:1-10.
  30. Bryan AG, Grimes DA, Garrett JM, et al. Second-trimester abortion for fetal anomalies or fetal death. Obstet Gynecol. 2011;117:788-792.
  31. Goldberg AB, Fortin JA, Drey EA, et al. Cervical preparation before dilation and evacuation using adjunctive misoprostol or mifepristone compared with overnight osmotic dilators alone. Obstet Gynecol. 2015;126:599-609.
  32. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  33. Schreiber C, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
  34. Chu JJ, Devall AJ, Beeson LE, et al. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396:770-778.
  35. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  36. American College of Obstetricians and Gynecologists. Second-trimester abortion. Practice Bulletin No. 135. Obstet Gynecol. 2013;121:1394-1406.
  37. Wingo E, Raifman S, Landau C, et al. Mifepristone-misoprostol versus misoprostol-alone regimen for medication abortion at ≥ 24 weeks gestation. Contraception. Appendix 1. 2020;102:99-103.
  38. American College of Obstetricians and Gynecologists. Vaginal birth after cesarean delivery. ACOG Practice Bulletin No. 205. Obstet Gynecol. 2019;133:e110-e127.
  39. Atkins B, Blencowe H, Boyle FM, et al. Is care of stillborn babies and their parents respectful? Results from an international online survey. BJOG. 2022;129:1731-1739.
  40. Haezell AEP, Siassakos D, Blencowe H, et al. Stillbirths: economic and psychosocial consequences. Lancet. 2016;387(10018):604-616.
  41. Shakespeare C, Merriel A, Bakhbakhi D, et al. The RESPECT Study for consensus on global bereavement care after stillbirth. Int J Gynaecol Obstet. 2020;149:137-147.
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Brigham and Women’s Hospital
Kate Macy Ladd Distinguished Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts

The author reports no conflict of interest related to this article.

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Brigham and Women’s Hospital
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Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts

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Editor in Chief, OBG Management
Chair Emeritus, Department of Obstetrics and Gynecology
Brigham and Women’s Hospital
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Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts

The author reports no conflict of interest related to this article.

Article PDF
obgm03503005_editorial_0323.pdf
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obgm03503005_editorial_0323.pdf

 

Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

  • The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
  • Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.3 However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.8

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

 

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.9 Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.9

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.10 In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).11

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.14 The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

 

 

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.28 In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.28

 

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,30 including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.29

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.31 In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

 

 

Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.26 Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.26

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.27 In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.27

 

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.32TABLES 1,1, 26, 33–362,37 and 337 summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)1 recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.38 ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.38 Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.9 See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.39 The patient’s partner often reports feeling unacknowledged as a grieving parent.40 Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

  1. reduce stigma
  2. provide respectful care
  3. involve patients in care planning
  4. attempt to provide an explanation for the demise1
  5. acknowledge the depth of the grief response and provide emotional support
  6. offer information about ongoing psychological support
  7. provide information about future pregnancy planning
  8. provide opportunities for specialized training and support for care providers.41

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

 

Clinical care for fetal demise is complex and multidimensional, including empathic emotional support for the patient and family members who are experiencing a tragedy, investigation of the cause of the demise, and a plan for emptying the uterus. This editorial narrowly focuses on the options for treatment of fetal demise with the goal of emptying the uterus while minimizing complications.

When planning treatment of fetal demise, focus on fetal size and gestational age

Most guidelines for the treatment of fetal demise use gestational age to guide selection of a treatment.1,2 I believe that fetal size is as important as gestational age for selecting a treatment plan. When considering treatment, there are 2 reasons why fetal size is as important as gestational age:

  • The physiologic processes that caused fetal demise may have caused fetal growth restriction, resulting in a fetal size that is 2 or more weeks below expected fetal size for gestational age.
  • Fetal demise may have occurred weeks before the diagnosis was made, resulting in gestational age being greater than fetal size. This editorial will use ultrasonography estimate of fetal size in gestational weeks to guide treatment recommendations. When discussing fetal size, we will use the convention of weeks-days (w-d). Twenty-five weeks and zero days gestation is represented as 25w0d.

Treatment in the second and third trimester is a 2-step process

Step 1: Cervical preparation

In most cases of first trimester fetal demise, no cervical preparation is necessary. Cervical dilation with metal dilators followed by uterine evacuation with an appropriately sized vacuum catheter is a highly successful treatment.3 However for second and third trimester fetal demise, it is best to use a 2-step process, beginning with cervical preparation followed by emptying the uterus. For example, at a fetal size of 13w0d to 16w0d, cervical preparation can be achieved by administering a single buccal dose of misoprostol 400 µg 3 to 4 hours prior to uterine evacuation or by inserting a Dilapan-S (Medicem Inc) osmotic cervical dilator 3 to 6 hours prior to uterine evacuation.4-7 At a fetal size of 16w0d to 19w6d, cervical preparation can be achieved by placing osmotic cervical dilators 4 to 6 hours before surgical evacuation and administering buccal misoprostol 400 µg 3 hours before surgical evacuation.8

Alternatively, from 16w0d to 25w0d osmotic cervical dilators can be placed on day 1 of a 2-day process, and the patient can return on day 2 to have the cervical dilators removed followed by surgical evacuation of the uterus. Mifepristone 200 mg oral dose can be administered on day 1 to facilitate cervical preparation. In my practice, I use mifepristone 200 mg on day 1 when the fetal size is ≥20w0d gestation. Options for cervical preparation include use of osmotic dilators, cervical balloons, misoprostol, and/or mifepristone. These options are discussed below. With fetal demise, natural physiologic processes often have caused sufficient cervical softening and dilation that no cervical preparation is necessary and immediate uterine surgical evacuation or induction of labor can be initiated.

 

Step 2: Emptying the uterus

In the second and third trimesters, the approach to uterine evacuation is based on fetal size. At fetal sizes <25w0d, options for emptying the uterus include surgical evacuation with a vacuum catheter and grasping forceps or induction of labor with misoprostol followed by vaginal birth and expulsion of the placenta. At fetal sizes ˃25w0d gestation, following completion of cervical preparation, the most common approaches to uterine evacuation are induction of labor with misoprostol or oxytocin. Rarely, with a stillbirth at term, some clinicians will select hysterotomy to empty the uterus, avoiding uterine rupture during labor induction for patients at the highest risk, including those with a prior classical cesarean birth or more than 2 prior cesarean births with a low-transverse uterine incision.

Osmotic cervical dilators

The 2 most used cervical dilators are Dilapan-S, a polyacrylate-based hydrogel rod, and laminaria, dried compressed seaweed stipe (stalk) from Laminaria japonica or Laminaria digitata. Dilapan-S rods are available in diameters of 3 mm and 4 mm and rod lengths of 55 mm and 65 mm. Laminaria dilators are available in diameters of 2, 3, 4, 5, 6, 8 and 10 mm and rod length of 60 and 70 mm. Dilapan-S dilators reach near-maximal dilation in approximately 4 to 6 hours but continue to expand over the following 18 hours to achieve a maximum dilation of 3.3 to 3.6 times their dry diameter.9 Laminaria dilators expand to 2.7 to 2.9 times their dry diameter over 24 hours.9

A general rule is that as many dilators as possible should be placed until significant resistance to the placement of additional dilators is encountered.10 In my practice, for fetal size ≥20 weeks’ gestation, I place 2 Dilapan-S rods, 4 mm in diameter, 55 mm in length, and then encircle the Dilapan-S with laminaria rods that are 4 mm in diameter and 60 mm in length. Once cervical resistance to the placement of the 4 mm laminaria rods is observed, I encircle those laminaria with laminaria 2 mm in diameter, filling in the interstices between the 4 mm laminaria. The next day, cervical dilation is routinely ≥3 cm.

In a retrospective study of 491 patients undergoing pregnancy termination after 14 weeks’ gestation, with a mean gestational age of 24 weeks, compared with no osmotic cervical dilators, inserting osmotic cervical dilators the day before initiating misoprostol for induction of labor resulted in a decrease in time to delivery (428 min vs 640 min; P<.001) and a decrease in total misoprostol dose (990 µg vs 1,449 µg; P<.0001).11

Cervical balloons

All clinicians know that a Foley catheter or a Cook cervical ripening balloon can be used for cervical preparation in the third trimester.12,13 The Foley catheter also has been reported to be useful for cervical preparation in the second trimester. In one study of 43 patients 17 to 24 weeks’ gestation scheduled for a second-trimester dilation and evacuation, an intracervical Foley catheter was placed the evening before evacuation, and the balloon was inflated with 30 mL to 50 mL of saline. At the same time, mifepristone 200 mg was administered to the patients.14 The following day, dilation and evacuation was performed. In 72% of cases no additional cervical dilation was required on the day of evacuation. The investigators concluded that if osmotic cervical dilators are not available, the placement of an intracervical Foley catheter plus administration of mifepristone facilitates performance of an evacuation on the following day. If the patient prefers a 1-day procedure, the Foley can be inserted in the morning to facilitate cervical preparation, and the uterus can be evacuated in the afternoon.

Continue to: Misoprostol...

 

 

Misoprostol

Misoprostol, a derivative of prostaglandin E1, is useful for both cervical preparation and induction of labor. The dose of misoprostol and the route of administration are major determinants of uterine response.15-19 When administered by an oral route, misoprostol has fast onset and offset of action and often does not cause sustained uterine contractions. Hence, oral misoprostol, at a low dose is useful for cervical ripening, but not as useful for stimulation of sustained uterine contractions for induction of labor. When administered by a buccal or vaginal route, misoprostol has prolonged activity and often results in sustained uterine contractions. At any given dose of misoprostol, buccal and vaginal misoprostol administration are more effective than oral administration in inducing sustained uterine contractions sufficient to empty the uterus.15-19

Mifepristone

Mifepristone, an anti-progestin, is useful for cervical preparation and sensitizing myocytes to the action of uterotonics. Progesterone reduces cell-to-cell communication among uterine myocytes, facilitating uterine quiescence by suppressing connexin 43 and other proteins. Mifepristone blocks the effect of progesterone, inducing the production of myocyte connexin 43, enhancing efficient cell-to-cell communication, permitting uterine myoctes to contract in unison, creating the potential for powerful and sustained contractions.20-23 Randomized clinical trials report that administration of mifepristone 200 mg prior to misoprostol induced labor results in more rapid emptying of the uterus.24-27

It takes time for mifepristone to have its full effect on uterine myocytes. Hence, most protocols recommend waiting 24 hours following mifepristone administration before initiating treatment with an agent to stimulate uterine contractions such as misoprostol or oxytocin. However, preliminary data suggest that partial benefit of mifepristone can be obtained when initiating misoprostol 3 to 5 hours after mifepristone administration.28 In a study of 481 patients undergoing induction of labor in the second or third trimester, the time from initiation of misoprostol to vaginal birth was 15 hours with no mifepristone pretreatment, 13.2 hours if mifepristone was administered 3 to 5 hours before initiating misoprostol, 9.3 hours if mifepristone was administered 24 hours before initiating misoprostol, and 10.5 hours if mifepristone was administered 48 hours before initiating misoprostol.28

 

Fetal size <25w0d gestation: Cervical preparation and surgical evacuation

For fetal demise at a fetal size less than 25w0d, if clinical experts are available, the best treatment option is cervical preparation followed by surgical evacuation of the uterus using a vacuum catheter and grasping forceps to empty the uterus.29,30 A disadvantage of surgical evacuation of the uterus is that an intact fetus is not available for the patient to hold and mourn, and pathologic examination of an intact fetus is not possible. An alternative approach is cervical preparation followed by induction of labor using misoprostol with the goal of delivering an intact fetus. Although no prospective clinical trials are available comparing these 2 options, retrospective studies have reported that, at fetal size <25w0d gestation, compared with induction of labor, surgical evacuation of the uterus results in fewer complications,30 including fewer cases of retained placenta requiring an unplanned procedure and fewer presumed uterine infections.29

For surgical evacuation of fetal demise with a fetal size of <25w0d gestation, the first step on day 1 is placement of osmotic cervical dilators. In addition to osmotic cervical dilators, if the gestational age or fetal size is ≥19 weeks’ gestation an oral dose of mifepristone 200 mg to facilitate cervical preparation may be considered. On day 2, the osmotic dilators are removed and surgical evacuation is performed. In one randomized study, for pregnancies at 19 to 24 weeks’ gestation, compared with osmotic dilators alone, administration of mifepristone 200 mg at the time of placement of osmotic dilators resulted in fewer procedures that were difficult to complete.31 In some cases, 2 consecutive days of cervical preparation with osmotic dilators may be needed to properly prepare the cervix for uterine evacuation. For example, the cervix of a nulliparous teenage patient may require 2 days of cervical preparation with osmotic dilators to facilitate uterine evacuation. In some cases of fetal demise, the cervix is already dilated to ≥3 cm and surgical evacuation of the uterus or induction of labor can be initiated without the need for cervical preparation.

Continue to: Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor...

 

 

Fetal size 14w0d to 28w6d gestation: Cervical preparation and induction of labor

Treatment of fetal demise at 14w0d to 28w6d gestation with the goal of the vaginal birth of an intact fetus is optimized by the administration of mifepristone for cervical preparation followed by induction of labor with misoprostol.26,27

In one clinical trial, 66 patients with fetal demise between 14w0d and 28w6d gestation were randomly assigned to receive mifepristone 200 mg or placebo followed 24 to 48 hours later with initiation of misoprostol induction of labor.26 Among the patients from 14w0d to 24 weeks’ gestation, the misoprostol dose was 400 µg vaginally every 6 hours. For patients from 24w0d to 28 weeks’ gestation, the misoprostol dose was 200 µg vaginally every 4 hours. At 24 hours, a consultant obstetrician determined if additional misoprostol should be given. The median time from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups was 6.8 hours and 10.5 hours (P=.002).

Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required fewer doses of misoprostol (2.1 vs 3.4; P= .002) and a lower total dose of misoprostol (768 µg vs 1,182 µg; P=.003). All patients in the mifepristone group delivered within 24 hours. By contrast, 13% of the patients in the placebo group delivered more than 24 hours after the initiation of misoprostol treatment. Five patients were readmitted with retained products of conception needing suction curettage, 4 in the placebo group and 1 in the mifepristone group.26

In a second clinical trial, 105 patients with fetal demise after 20 weeks of gestation were randomly assigned to receive mifepristone 200 mg or placebo.27 In this study, 86% of the patients were ≥26w0d gestation, with a mean gestational age of approximately 32w2d. Thirty-six to 48 hours later, misoprostol induction of labor was initiated. Among the patients from 20 to 25 completed weeks of gestation, the misoprostoldose was 100 µg vaginally every 6 hours for a maximum of 4 doses. For patients from ≥26 weeks’ gestation, the misoprostol dose was 50 µg vaginally every 4 hours for a maximum of 6 doses. The median times from initiation of misoprostol to birth for the patients in the mifepristone and placebo groups were 9.8 hours and 16.3 hours, respectively (P=.001). Compared with the patients in the placebo-misoprostol group, the patients in the mifepristone-misoprostol group required a lower total dose of misoprostol (110 µg vs 198 µg; P<.001). Delivery within 24 hours following initiation of misoprostol occurred in 93% and 73% of the patients in the mifepristone and placebo groups, respectively (P<.001). Compared with patients in the mifepristone group, shivering occurred more frequently among patients in the placebo group (7.5% vs 19.2%; P=.09), likely because they received greater doses of misoprostol.27

 

Fetal size ≥29w0d gestation

At a fetal size ≥29w0d gestation, if the cervix is ripe with a Bishop score of ≥7, oxytocin induction of labor is often used as a first-line treatment. If the cervix is not ripe, misoprostol induction of labor may be considered at doses less than those used in the second trimester of pregnancy.32TABLES 1,1, 26, 33–362,37 and 337 summarize regimens proposed for fetal size ≥29w0d. One regimen begins with an initial misoprostol dose of 50 µg. If adequate uterine contractions occur, the 50 µg dose is repeated every 4 hours up to 6 total doses. If contractions are inadequate, the dose can be increased to 100 µg every 4 hours for 5 additional doses.

For fetal demise after 28w0d gestation, the American College of Obstetricians and Gynecologists (ACOG)1 recommends standard obstetric protocols for induction of labor, including standard protocols for induction of labor following a previous cesarean birth. For a patient with a history of a prior cesarean birth or major uterine surgery, ACOG recommends that management of fetal demise should prioritize the use of mechanical cervical ripening, for example with a balloon catheter, and induction of uterine contractions with oxytocin.38 ACOG recommends against the use of misoprostol for cervical ripening or labor induction for patients with a stillbirth at term with a history of a cesarean birth.38 Preliminary experience suggests that stillbirth protocols using misoprostol doses modestly greater than those used in the management of a pregnancy with a viable fetus may be safe.9 See TABLES 2 and 3.

A multidisciplinary approach can optimize compassionate care

There are many gaps in the holistic care of patients and partners experiencing fetal demise. Patients with fetal demise often report that they did not receive sufficient information about the cause of the demise and wanted more opportunity to be involved in decision making about their care.39 The patient’s partner often reports feeling unacknowledged as a grieving parent.40 Fetal demise is experienced by many patients as a tragedy, triggering feelings of grief, anger, denial, anxiety and depression, sometimes resulting in isolation and substance misuse.

Using a 5-round Delphi process, experts identified 8 core goals in the care of patients with fetal demise:

  1. reduce stigma
  2. provide respectful care
  3. involve patients in care planning
  4. attempt to provide an explanation for the demise1
  5. acknowledge the depth of the grief response and provide emotional support
  6. offer information about ongoing psychological support
  7. provide information about future pregnancy planning
  8. provide opportunities for specialized training and support for care providers.41

Management of stillbirth is optimized by a multidisciplinary approach that includes the expert care of obstetrician-gynecologists, obstetric nurses, anesthesiologists, and expert consultation from social work, chaplaincy, and pathology. A heart-to-heart connection between clinician and patient is a key component of stillbirth care. ●

References
  1. American College of Obstetricians and Gynecologists. Management of stillbirth. ACOG Obstetric Care Consensus. No. 10. Obstet Gynecol. 2020;135:e110-132.
  2. Tsakiridis I, Giouleka S, Mamopoulos A, et al. Investigation and management of stillbirths: a descriptive review of major guidelines. J Perinat Med. 2022;50:796-813.
  3. Spingler T, Sonek J, Hoopman M, et al. Complication rate after termination of pregnancy due to fetal defects. Ultrasound Obstet Gynecol. 2023;Epub January 7.
  4. Goldberg AB, Drey EA, Whitaker AK, et al. Misoprostol compared with laminaria before early second-trimester surgical abortion: a randomized trial. Obstet Gynecol. 2005;106:234-241.
  5. Meirik O, My Huong NT, Piaggio G, et al. WHOR-GoP-MoF Regulation. Complications of first trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial. Lancet. 2012;379(9829):1817-1824.
  6. Bartz D, Maurer R, Allen RH, et al. Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial. Obstet Gynecol. 2013;122:57-63.
  7. Ngo LL, Mokashi M, Janiak E, et al. Acute complications with same-day versus overnight cervical preparation before dilation and evacuation at 14 to 16 weeks. Contraception. 2023;117:61-66.
  8. Kim CS, Dragoman M, Prosch L, et al. Same-day compared with overnight cervical preparation before dilation and evacuation between 16 and 19 6/7 weeks of gestation: a randomized controlled trial. Obstet Gynecol. 2022;139:1141-1144.
  9. Drunecky T, Reidingerova M, Plisova M, et al. Experimental comparison of properties of natural and synthetic osmotic dilators. Arch Gynecol Obstet. 2015;292:349-354.
  10. 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;171:1324-1328.
  11. Berthold C, Gomes David M, Gabriel P, et al. Effect of the addition of osmotic dilators to medical induction of labor abortion: a before-and-after study. Eur J Obstet Gynecol. 2020;244:185-189.
  12. Kemper JI, Li W, Goni S, et al. Foley catheter vs oral misoprostol for induction of labor: individual participant data meta-analysis. Ultrasound Obstet Gynecol. 2021;57:215-223.
  13. Attalli E, Kern Guy, Fouks Y, et al. Labor induction in third trimester non-viable fetus. J Matern Fetal Neonatal Med. 2022;Epub October 1.
  14. Fessehaye Sium A, Prager S, Wolderufael M, et al. Foley catheter for cervical preparation prior to second trimester dilation and evacuation: a supply-based alternative for surgical abortion: a case series. Contracept X. 2022;4:100085.
  15. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol. 1997;90:88-92.
  16. Gemzell-Danilesson K, Marions L, Rodriguez A, et al. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol. 1999;93:275-280.
  17. Aronsson A, Bygdeman M, Gemzell-Danielsson K. Effects of misoprostol on uterine contractility following different routes of administration. Hum Reprod. 2004;19:81-84.
  18. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by epithelial routes. Drug absorption and uterine response. Obstet Gynecol. 2006;108:582-590.
  19. Barbieri RL. Misoprostol: clinical pharmacology in obstetrics and gynecology. OBG Manag. 2022;34:8-10, 12.
  20. Andersen J, Grine E, Eng L, et al. Expression of connexin-43 in human myometrium and leiomyoma. Am J Obstet Gynecol. 1993;169:1266-1276.
  21. Ou CW, Orsino A, Lye SJ. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology. 1997;138:5398-5407.
  22. Petrocelli T, Lye SJ. Regulation of transcripts encoding the myometrial gap junction protein, connexin-43, by estrogen and progesterone. Endocrinology. 1993;133:284-290.
  23. Barbieri RL. Mifepristone for the treatment of miscarriage and fetal demise. OBG Manag. 2022;34:811, 15.
  24. Kapp N, Borgatta L, Stubblefield P, et al. Mifepristone in second-trimester medical abortion. Obstet Gynecol. 2007;110:1304-1310.
  25. Ngoc NTN, Shochet T, Raghavan S, et al. Mifepristone and misoprostol compared with misoprostol alone for second trimester abortion: a randomized controlled trial. Obstet Gynecol. 2011;118:601608.
  26. Allanson ER, Copson S, Spilsbury K, et al. Pretreatment with mifepristone compared with misoprostol alone for delivery after fetal death between 14 and 28 weeks of gestation. Obstet Gynecol. 2021;137:801-809.
  27. Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: a randomized trial. J Obstet Gynaecol Res. 2015;41:1884-1890.
  28. Prodan N, Breisch J, Hoopman M, et al. Dosing interval between mifepristone and misoprostol in second and third trimester termination. Arch Gynecol Obstet. 2019;299:675-679.
  29. Edlow AG, Hou MY, Maurer R, et al. Uterine evacuation for second trimester fetal death and maternal morbidity. Obstet Gynecol. 2011;117:1-10.
  30. Bryan AG, Grimes DA, Garrett JM, et al. Second-trimester abortion for fetal anomalies or fetal death. Obstet Gynecol. 2011;117:788-792.
  31. Goldberg AB, Fortin JA, Drey EA, et al. Cervical preparation before dilation and evacuation using adjunctive misoprostol or mifepristone compared with overnight osmotic dilators alone. Obstet Gynecol. 2015;126:599-609.
  32. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  33. Schreiber C, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
  34. Chu JJ, Devall AJ, Beeson LE, et al. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396:770-778.
  35. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  36. American College of Obstetricians and Gynecologists. Second-trimester abortion. Practice Bulletin No. 135. Obstet Gynecol. 2013;121:1394-1406.
  37. Wingo E, Raifman S, Landau C, et al. Mifepristone-misoprostol versus misoprostol-alone regimen for medication abortion at ≥ 24 weeks gestation. Contraception. Appendix 1. 2020;102:99-103.
  38. American College of Obstetricians and Gynecologists. Vaginal birth after cesarean delivery. ACOG Practice Bulletin No. 205. Obstet Gynecol. 2019;133:e110-e127.
  39. Atkins B, Blencowe H, Boyle FM, et al. Is care of stillborn babies and their parents respectful? Results from an international online survey. BJOG. 2022;129:1731-1739.
  40. Haezell AEP, Siassakos D, Blencowe H, et al. Stillbirths: economic and psychosocial consequences. Lancet. 2016;387(10018):604-616.
  41. Shakespeare C, Merriel A, Bakhbakhi D, et al. The RESPECT Study for consensus on global bereavement care after stillbirth. Int J Gynaecol Obstet. 2020;149:137-147.
References
  1. American College of Obstetricians and Gynecologists. Management of stillbirth. ACOG Obstetric Care Consensus. No. 10. Obstet Gynecol. 2020;135:e110-132.
  2. Tsakiridis I, Giouleka S, Mamopoulos A, et al. Investigation and management of stillbirths: a descriptive review of major guidelines. J Perinat Med. 2022;50:796-813.
  3. Spingler T, Sonek J, Hoopman M, et al. Complication rate after termination of pregnancy due to fetal defects. Ultrasound Obstet Gynecol. 2023;Epub January 7.
  4. Goldberg AB, Drey EA, Whitaker AK, et al. Misoprostol compared with laminaria before early second-trimester surgical abortion: a randomized trial. Obstet Gynecol. 2005;106:234-241.
  5. Meirik O, My Huong NT, Piaggio G, et al. WHOR-GoP-MoF Regulation. Complications of first trimester abortion by vacuum aspiration after cervical preparation with and without misoprostol: a multicentre randomised trial. Lancet. 2012;379(9829):1817-1824.
  6. Bartz D, Maurer R, Allen RH, et al. Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial. Obstet Gynecol. 2013;122:57-63.
  7. Ngo LL, Mokashi M, Janiak E, et al. Acute complications with same-day versus overnight cervical preparation before dilation and evacuation at 14 to 16 weeks. Contraception. 2023;117:61-66.
  8. Kim CS, Dragoman M, Prosch L, et al. Same-day compared with overnight cervical preparation before dilation and evacuation between 16 and 19 6/7 weeks of gestation: a randomized controlled trial. Obstet Gynecol. 2022;139:1141-1144.
  9. Drunecky T, Reidingerova M, Plisova M, et al. Experimental comparison of properties of natural and synthetic osmotic dilators. Arch Gynecol Obstet. 2015;292:349-354.
  10. 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;171:1324-1328.
  11. Berthold C, Gomes David M, Gabriel P, et al. Effect of the addition of osmotic dilators to medical induction of labor abortion: a before-and-after study. Eur J Obstet Gynecol. 2020;244:185-189.
  12. Kemper JI, Li W, Goni S, et al. Foley catheter vs oral misoprostol for induction of labor: individual participant data meta-analysis. Ultrasound Obstet Gynecol. 2021;57:215-223.
  13. Attalli E, Kern Guy, Fouks Y, et al. Labor induction in third trimester non-viable fetus. J Matern Fetal Neonatal Med. 2022;Epub October 1.
  14. Fessehaye Sium A, Prager S, Wolderufael M, et al. Foley catheter for cervical preparation prior to second trimester dilation and evacuation: a supply-based alternative for surgical abortion: a case series. Contracept X. 2022;4:100085.
  15. Zieman M, Fong SK, Benowitz NL, et al. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol. 1997;90:88-92.
  16. Gemzell-Danilesson K, Marions L, Rodriguez A, et al. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol. 1999;93:275-280.
  17. Aronsson A, Bygdeman M, Gemzell-Danielsson K. Effects of misoprostol on uterine contractility following different routes of administration. Hum Reprod. 2004;19:81-84.
  18. Meckstroth KR, Whitaker AK, Bertisch S, et al. Misoprostol administered by epithelial routes. Drug absorption and uterine response. Obstet Gynecol. 2006;108:582-590.
  19. Barbieri RL. Misoprostol: clinical pharmacology in obstetrics and gynecology. OBG Manag. 2022;34:8-10, 12.
  20. Andersen J, Grine E, Eng L, et al. Expression of connexin-43 in human myometrium and leiomyoma. Am J Obstet Gynecol. 1993;169:1266-1276.
  21. Ou CW, Orsino A, Lye SJ. Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology. 1997;138:5398-5407.
  22. Petrocelli T, Lye SJ. Regulation of transcripts encoding the myometrial gap junction protein, connexin-43, by estrogen and progesterone. Endocrinology. 1993;133:284-290.
  23. Barbieri RL. Mifepristone for the treatment of miscarriage and fetal demise. OBG Manag. 2022;34:811, 15.
  24. Kapp N, Borgatta L, Stubblefield P, et al. Mifepristone in second-trimester medical abortion. Obstet Gynecol. 2007;110:1304-1310.
  25. Ngoc NTN, Shochet T, Raghavan S, et al. Mifepristone and misoprostol compared with misoprostol alone for second trimester abortion: a randomized controlled trial. Obstet Gynecol. 2011;118:601608.
  26. Allanson ER, Copson S, Spilsbury K, et al. Pretreatment with mifepristone compared with misoprostol alone for delivery after fetal death between 14 and 28 weeks of gestation. Obstet Gynecol. 2021;137:801-809.
  27. Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol alone for induction of labor in intrauterine fetal death: a randomized trial. J Obstet Gynaecol Res. 2015;41:1884-1890.
  28. Prodan N, Breisch J, Hoopman M, et al. Dosing interval between mifepristone and misoprostol in second and third trimester termination. Arch Gynecol Obstet. 2019;299:675-679.
  29. Edlow AG, Hou MY, Maurer R, et al. Uterine evacuation for second trimester fetal death and maternal morbidity. Obstet Gynecol. 2011;117:1-10.
  30. Bryan AG, Grimes DA, Garrett JM, et al. Second-trimester abortion for fetal anomalies or fetal death. Obstet Gynecol. 2011;117:788-792.
  31. Goldberg AB, Fortin JA, Drey EA, et al. Cervical preparation before dilation and evacuation using adjunctive misoprostol or mifepristone compared with overnight osmotic dilators alone. Obstet Gynecol. 2015;126:599-609.
  32. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  33. Schreiber C, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
  34. Chu JJ, Devall AJ, Beeson LE, et al. Mifepristone and misoprostol versus misoprostol alone for the management of missed miscarriage (MifeMiso): a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396:770-778.
  35. Gomez-Ponce de Leon R, Wing D, Fiala C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet. 2007;99(suppl 2):S190-S193.
  36. American College of Obstetricians and Gynecologists. Second-trimester abortion. Practice Bulletin No. 135. Obstet Gynecol. 2013;121:1394-1406.
  37. Wingo E, Raifman S, Landau C, et al. Mifepristone-misoprostol versus misoprostol-alone regimen for medication abortion at ≥ 24 weeks gestation. Contraception. Appendix 1. 2020;102:99-103.
  38. American College of Obstetricians and Gynecologists. Vaginal birth after cesarean delivery. ACOG Practice Bulletin No. 205. Obstet Gynecol. 2019;133:e110-e127.
  39. Atkins B, Blencowe H, Boyle FM, et al. Is care of stillborn babies and their parents respectful? Results from an international online survey. BJOG. 2022;129:1731-1739.
  40. Haezell AEP, Siassakos D, Blencowe H, et al. Stillbirths: economic and psychosocial consequences. Lancet. 2016;387(10018):604-616.
  41. Shakespeare C, Merriel A, Bakhbakhi D, et al. The RESPECT Study for consensus on global bereavement care after stillbirth. Int J Gynaecol Obstet. 2020;149:137-147.
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