Essure Multicenter Off-Label Treatment for Hydrosalpinx Before In Vitro Fertilization

Original Article
Essure Multicenter Off-Label Treatment for Hydrosalpinx Before
In Vitro Fertilization
Donald I. Galen, MD*, Naveed Khan, MD, and Kevin S. Richter, PhD
From the Reproductive Science Center of the San Francisco Bay Area, San Ramon, California (Dr. Galen) and Shady Grove Fertility Reproductive Science
Center, Rockville, Maryland (Drs. Khan and Richter).
ABSTRACT Study Objective: To estimate the safety and efficacy of Essure placement for proximal tubal occlusion in women with hydrosalpinx before in vitro fertilization (IVF).
Design: Prospective 2-center clinical study of women with hydrosalpinx who were recruited for off-label unilateral or bilateral placement of Essure before IVF (Canadian Task Force classification II-2).
Setting: Tertiary office-based infertility and IVF practice settings.
Patients: Twenty women with bilateral or unilateral hydrosalpinx desiring IVF.
Interventions: Office-based Essure placement and subsequent hysterosalpingography confirmation of proximal tubal
occlusion.
Measurements and Main Results: Placement success, and proximal tubal occlusion and birth rate after IVF. Eight women
with unilateral hydrosalpinx received unilateral Essure placement, and 12 women with bilateral hydrosalpinx received bilateral placement. One unsuccessful placement occurred. Hysterosalpingography confirmed proximal tubal occlusion in 19 of 20
women (95%) and of 31 of 32 tubes (97%) with Essure placement. Subsequent IVF resulted in 12 live births, for a birth rate per
transfer of 57% (12 of 21) and a birth rate per patient of 67% (12 of 20). Four obstetric complications were reported including
placenta previa, hypertension, maternal diabetes with premature rupture of membranes, and preeclampsia. All infants are
well.
Conclusion: Placement of Essure microinserts is an effective method of nonincisional proximal tubal occlusion of hydrosalpinx. Success rates achieved through subsequent IVF are typical of outcomes of good-prognosis in similarly aged patients
without hydrosalpinx in our same programs, based on 2008 Society for Assisted Reproductive Technologies data. Journal
of Minimally Invasive Gynecology (2011) 18, 338–342 Ó 2011 AAGL. All rights reserved.
Keywords:
Essure; Hydrosalpinx; Hysteroscopic tubal occlusion; In vitro fertilization; Microinsert; Outpatient; Tubal factor
A hydrosalpinx is a distally blocked, dilated, fluid-filled
fallopian tube often a consequence of previous pelvic infection, and may be unilateral or bilateral. Tubal factor accounts
for 25% to 35% of female infertility [1], and hydrosalpinx is
present in 10% to 30% of all patients undergoing in vitro fertilization (IVF) [2]. Both retrospective and prospective studies have demonstrated that women with hydrosalpinx have
up to a 50% reduction in implantation and pregnancy rates
The authors have no commercial, proprietary, or financial interest in the
products or companies described in this article.
Corresponding author: Donald I. Galen, MD, Reproductive Science Center
of the San Francisco Bay Area, 3160 Crow Canyon Rd, Ste 150, San Ramon,
CA 94583.
E-mail: [email protected]
Submitted October 25, 2010. Accepted for publication January 26, 2011.
Available at www.sciencedirect.com and www.jmig.org
1553-4650/$ - see front matter Ó 2011 AAGL. All rights reserved.
doi:10.1016/j.jmig.2011.01.016
after IVF compared with women with tubal factor infertility
without hydrosalpinx [1–7].
Exactly what mechanisms negatively affect implantation
rates in women with hydrosalpinx are not known; some
possibilities include the effects of bacterial toxins in the
hydrosalpingeal fluid on the gamete or embryo, reduced expression of cytokines and integrins, decreased endometrial
blood flow, and possible mechanical flushing of the embryo
from the endometrium [3,8–11]. Spontaneous abortion and
ectopic pregnancy rates have been reported to be as much
as 2- to 3-fold higher in patients with hydrosalpinx [3,4].
Also reported are spontaneous abortions in patients with
unilateral hydrosalpinx when other causes of abortion have
been excluded [12].
Essure (Conceptus Inc, San Carlos, CA) is a nonincisional
procedure that involves hysteroscopic insertion of a small
flexible device called a microinsert into each fallopian
Galen et al.
Essure Tubal Occlusion Before IVF
tube to permanently occlude the proximal tube for permanent female sterilization. In addition to the ‘‘space-filling’’
aspect of the microinsert, the primary method of action is
an inflammatory benign tissue ingrowth that occurs after
placement. The Essure system comprises the microinsert
and a disposable delivery system, and has undergone clinical
investigation since 1996. Essure received US Food and Drug
Administration approval in 2002 for use in permanent
female sterilization. By occluding the proximal tube, the
Essure microinsert also prevents hydrosalpingeal fluid
from entering the endometrial cavity. Consequently, the
procedure has been proposed as a nonincisional treatment
for hydrosalpinx before IVF. The effects of Essure on the
success of IVF have been uncertain. If pregnancy is
achieved, the risks of the microinsert to the patient, the fetus,
and continuation of the pregnancy have been unclear. Thus,
the need for off-label clinical studies to measure the safety
and efficacy of Essure during IVF cycles was identified.
339
Fig. 2
Hysterosalpingogram shows proximal bilateral placement of Essure microinserts.
Materials and Methods
This was a prospective, 2-center, off-label, sequential,
nonrandomized Investigational Device Exemption– and institutional review board–approved observational study of
Essure microinsert proximal tubal occlusion in women
with hydrosalpinx and of their subsequent pregnancy rate after IVF using fresh embryo transfer or frozen embryo transfer cycles. Twenty-one women with either unilateral or
bilateral hydrosalpinx were identified via laparoscopy or ultrasound (Fig. 1) from existing patients in the 2 study practices. Patients were offered off-label hysteroscopic
placement of Essure rather than incisional surgery to achieve
proximal tubal occlusion (Fig. 2). Enrollment began on April
14, 2009; enrollment is complete, and follow-up is ongoing.
Primary inclusion criteria were age 21 through 38 years;
Fig. 1
Transvaginal ultrasonogram shows a left-sided hydrosalpinx post Essure placement.
normal ovarian reserve (day 3 serum follicle-stimulating
hormone ,10 mIU/mL and day 3 estradiol ,80 mIU/mL,
and combined antral follicle count R10 for both ovaries)
or use of an eligible egg donor; attempt to achieve pregnancy
for at least 1 year; and unilateral or bilateral hydrosalpinx as
demonstrated at laparoscopy, hysterosalpingography (HSG),
or ultrasound. Primary exclusion criteria were active or recent upper or lower pelvic infection, hypersensitivity to
nickel or allergy to HSG contrast media, pregnancy or suspected pregnancy, delivery or termination of pregnancy
less than 6 weeks before Essure placement, body mass index
greater than 35, abnormal Papanicolaou smear (cervical intraepithelial neoplasia grade 2 or greater) within past year,
and evidence of intrauterine abnormalities.
Typical insertion time for the Essure device, whether unilateral or bilateral, was 10 to 20 minutes. Patients were given
an oral dose of doxycycline 100 mg 1 to 3 hours before the
procedure and then brought to the office procedure room.
The patient was placed with her legs in padded Allen stirrups, and cervical preparation was with povidone-iodine.
Nine patients received paracervical block anesthesia using
15 to 30 mL of 1% lidocaine with epinephrine 1:200 000,
and 11 patients received intravenous sedation using midazolam 2 mg, fentanyl 25 to 100 mg, and propofol 200 to 400
mg, titrated to patient needs. A tenaculum was placed on
the cervix, and if necessary, cervical dilation proceeded sufficient to admit a 5-mm operative hysteroscope. With prewarmed normal saline solution, each proximal tubal ostia
was noted hysteroscopically, and Essure microinserts were
placed specifically with the goal of limiting the number of
340
intrauterine coils to 2 to 4 after placement. Patients were
then taken to the recovery room, and were discharged to
home within 30 to 60 minutes. Each patient was followed
up at HSG 3 months after Essure placement to confirm proximal tubal occlusion, and then proceeded with IVF or frozen
embryo transfer cycles.
Results
One patient was excluded because of an extremely retroverted uterus not accessible at hysteroscopy; thus, 20 patients were included in the study. Eight patients underwent
unilateral Essure placement, and 12 patients underwent bilateral Essure placement. Four intended to undergo subsequent IVF with donor eggs, and the remaining 16 intended
to undergo IVF using their own eggs. To date, 18 women
have undergone either a fresh cycle of IVF–embryo transfer
(n 5 16) or a frozen embryo transfer cycle (n 5 2). Three
women attempted a second transfer (frozen embryo) after
an unsuccessful cycle of fresh IVF–embryo transfer, for a total of 21 embryo transfer procedures. One woman is currently waiting for an egg donor for her first IVF cycle, and
another woman was lost to follow-up (could not be located).
The 16 patients using their own eggs ranged in age from 24
to 38 years (median, 34 years), and had day 3 folliclestimulating hormone concentrations ranging from 4.1 to 9.8
IU/L (median, 6.6 IU/L) and antral follicle counts ranging
from 10 to 38 (median, 15.5). The 4 patients using donor
eggs ranged in age from 24 to 44 years (median, 38.5 years).
One patient using donor eggs had previously undergone 2 attempts at IVF attempts. Two patients using their own eggs had,
respectively, 1 and 2 previous unsuccessful attempts at IVF.
All Essure devices were intentionally placed with a reduced number of intrauterine coils visible (range, 1–5;
median, 2). Follow-up HSG confirmed proximal tubal
occlusion in 19 women (95%) (95% confidence interval
[CI], 75%–100%). In 1 patient with bilateral Essure placement, only 1 of 2 tubes were occluded at follow-up HSG,
and laparoscopic tubal occlusion of the remaining patent
tube was required before IVF. Thus, after placement of 32
Essure devices, 31 tubes were successfully occluded (97%)
(95% CI, 83%–100%).
In vitro fertilization was generally initiated approximately
4 months after confirmation of tubal occlusion. In each of
these cycles, either 1 embryo (n 5 6) or 2 embryos (n 5
15) were transferred. As a result of the 21 embryo transfer
procedures performed to date, there have been 12 live births,
for a birth rate per transfer of 57% (95% CI, 36%–76%) and
a birth rate per patient of 67% (95% CI, 44%–84%).
Birth outcomes were not noticeably changed by factors
such as use of donor eggs, fresh vs cryopreserved embryo
transfer, or unilateral vs bilateral Essure placement, although
the small sample size greatly limited the ability to assess the
potentially confounding effects of these variables. There was
1 birth after 3 embryo transfers in 3 donor egg recipients, and
11 births after 18 embryo transfers in 16 women using their
Journal of Minimally Invasive Gynecology, Vol 18, No 3, May/June 2011
own eggs (p 5 .55). Two of 5 transfers of cryopreserved embryos resulted in births, compared with 10 of 16 fresh embryo transfers (p 5 .61). Birth rates per transfer did not
differ significantly between those study patients who had
unilateral hydrosalpinx (n 5 8) and those who had bilateral
hydrosalpinx (n 5 13): 63% (5 of 8) and 54% (7 of 13),
respectively (p 5 .99).
The median (range) gestational age at birth was 37 (33–
40) weeks, with 3 pairs of full-term twins, 1 preterm pair
of twins at 33 weeks, 6 full-term singleton births, and 2 preterm singleton births at 33 and 35 weeks. All preterm infants
are now home and doing well. One of the term singletons resulted from a twin pregnancy that spontaneously reduced
during early pregnancy. In 1 additional pregnancy, nonviable
twins were lost during the first trimester. Six deliveries
were via caesarean section, which occurs more frequently
in IVF pregnancies. Reported complications, which resulted
in cesarean section deliveries, included placenta previa, hypertension, preeclampsia, and maternal diabetes with premature rupture of membranes (n 5 1 each). Pregnancies and
births were otherwise uncomplicated and healthy.
Discussion
The observed live birth rates per embryo transfer and
per patient of 57% and 67%, respectively, are typical of
IVF in patients with good prognosis without hydrosalpinx
(https://www.sartcorsonline.com/rptCSR_PublicMultYear.
aspx?ClinicPKID52351 and https://www.sartcorsonline.
com/rptCSR_PublicMultYear.aspx?ClinicPKID, Society for
Reproductive Technology. Clinic Data Summary. Accessed
January 20, 2011). The high rate (6 of 12; 50%) of cesarean
deliveries reported in the present study was associated with
twin births: 4 of the twin births were via cesarean section.
Overall cesarean delivery rates in the United States
(31.8%) [13] (more than the approximate 20% [14] in other
developed countries that has been reported by the World
Health Organization) have become notoriously commonplace regardless of patient history. In addition, obstetric
complications such as preeclampsia, diabetes, preterm
labor, preterm rupture of membranes, and placental abnormalities have been reported in women who conceive using
donated oocytes compared with IVF patients using autologous eggs [15].
Conventional treatment options for hydrosalpinx include
salpingectomy, salpingostomy, proximal tubal occlusion,
and drainage of the hydrosalpingeal fluid at either laparoscopy, laparotomy, and transvaginal ultrasound needle aspiration. Incisional treatment of hydrosalpinx before IVF
improves implantation and pregnancy rates [5,6,10,16–19].
Numerous studies have measured pregnancy outcome
after proximal tubal occlusion as an alternative to
salpingectomy [5,17,19–21]. There are not, however, so
many large randomized controlled studies [8,20].
Laparoscopic proximal tubal occlusion may be achieved
using monopolar or bipolar coagulation, applying rings or
Galen et al.
Essure Tubal Occlusion Before IVF
clips, or by removing a section of the tube. Other studies
reporting treatment by either proximal tubal occlusion or
salpingectomy restored pregnancy rates to those expected
for patient age and tubal factor infertility in women without
hydrosalpinx. The American Society for Reproductive
Medicine in collaboration with The Society of Reproductive
Surgeons concluded that ‘‘For every six women with
hydrosalpinges, one more ongoing pregnancy will be
achieved if salpingectomy or tubal occlusion is performed
before IVF’’ [22]. Although generally safe and effective, these
incisional procedures carry increased risk of operative
complications and are typically performed with the patient
under general anesthesia. Moreover, women with diagnosed
hydrosalpinx are more likely to have associated pelvic adhesions, which can make a laparoscopic or open surgical procedure more technically difficult, increase the risk of surgical
complications, or not feasible.
Office-based hysteroscopic Essure placement has recently
been described as part of a pain and satisfaction study in a cohort of 209 women with an average (SD) age of 35.1 (5.2)
years who received paracervical block anesthesia [23]. Pain
was assessed at the time of the procedure using a visual analog scale (grade 0–10) as 2.6 (2.1). A hysteroscopic approach
to tubal occlusion is also less invasive and may be a safer option than traditional incisional surgical treatments for hydrosalpinx in women who plan to undergo IVF [11,20]. The first
reported case using Essure to treat hydrosalpinx was by
Rosenfield et al [24], who treated 1 woman with unilateral
hydrosalpinx by performing hysteroscopic placement of
Essure before proceeding with IVF. The patient’s history included morbid obesity, infertility, pelvic adhesive disease,
and previous intraoperative complications related to general
anesthesia. In vitro fertilization was successful, resulting in
a twin gestation. Those authors concluded that proximal
tubal occlusion with the Essure device may be an alternative
to a laparoscopic procedure to occlude hydrosalpinx in
women who are not good surgical candidates.
In 2007, Galen and McWatters [16] reported results of an
off-label pilot study using Essure for proximal tubal occlusion in women with hydrosalpinx before IVF. Eight women
aged 32 to 44 years with unilateral or bilateral hydrosalpinx
were evaluated. Bilateral Essure placement was performed
in 6 women with bilateral hydrosalpinx; unilateral Essure
placement was performed in 1 woman with unilateral hydrosalpinx; and 1 Essure placement attempt was unsuccessful.
The devices were intentionally placed with only 2 to 4
intrauterine coils visible after the procedure. Follow-up confirmatory HSG was performed in 6 patients, and all demonstrated bilateral proximal tubal occlusion related to the
device. One woman elected not to undergo HSG. In vitro fertilization was initiated in 5 women at 3 to 4 months after confirmation of tubal occlusion. Four women became pregnant
in their first IVF cycle, and delivered at term. One woman
did not achieve pregnancy. All women used their own eggs
for the IVF cycles. Results of this pilot study demonstrated
an 80% term delivery rate per embryo transfer. Although
341
none of these patients underwent second-look hysteroscopy
to assess the status of the trailing ends of the Essure microinserts before IVF, Kerin et al [25] and Mijatovic et al [21]
demonstrated almost complete tissue encapsulation of the
intrauterine portion of the coils by performing second-look
hysteroscopy before IVF.
Mijatovic et al [21] reported a series of 10 patients who
received the Essure device for treatment of hydrosalpinx before IVF, all of whom had contraindications for laparoscopy.
The live birth and ongoing pregnancy rates reported for these
10 patients were 20% and 40%, respectively [21].
Hitkari et al [17] described a series of 5 patients with
hydrosalpinx who underwent the Essure procedure. Four
of these women underwent hysteroscopic placement of the
Essure device, and 1 underwent fluoroscopic-guided placement of the Essure device. Successful bilateral Essure placement occurred in only 2 of 5 patients, and no pregnancies
after IVF were reported.
Conclusion
Based on our research of published literature (PubMed/
Medline and Cochrane databases; search terms, Essure,
Essure hydrosalpinx, Essure in vitro fertilization, Microinsert hydrosalpinx, Tubal occlusion, and Essure IVF), the
present study is the largest case series reported to date on
the use of Essure for proximal tubal occlusion of hydrosalpinx before IVF. This prospective clinical trial adds support
to earlier reports of cases and smaller series, including our
previous pilot study, that suggested that placement of Essure
microinserts is an effective method of inducing proximal
tubal occlusion in infertile patients with hydrosalpinx.
Observed outcomes of subsequent IVF were typical of those
in patients with good prognosis without hydrosalpinx. Essure may offer an equally effective, yet easier, office-based
and less costly alternative to traditional incisional methods
of hydrosalpinx treatment before IVF. Ideally, these potential benefits should be confirmed in a large randomized clinical trial comparing Essure with incisional methods of
proximal tubal occlusion.
Acknowledgment
We thank research coordinators Jennifer McWatters and
Tasha Newsome, our clinical research coordinators, without
whose valuable assistance this study would not have been
possible.
References
1. Murray DL, Sagoskin AW, Widra EA, Levy MJ. The adverse effect of
hydrosalpinges on in vitro fertilization pregnancy rate and the benefit of
surgical correction. Fertil Steril. 1998;69:41–45.
2. Barmat LI, Rauch E, Spandorfer S, et al. The effect of hydrosalpinges
on IVF-ET. J Assist Reprod Genet. 1999;16:350–354.
3. Camus E, Poncelet C, Goffinet F, et al. Pregnancy rates after IVF in
cases of tubal infertility with and without hydrosalpinx: meta-analysis
of published comparative studies. Hum Reprod. 1999;14:1243–1249.
342
4. Galen D. Examining the evidence: clinical implications of key trials.
OBG Manage. 2003;15:10–12.
5. Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BWJ. Surgical
treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev. 2004;(3):CD002125.
6. Soares RS, Vesasco JAG, Fernandez M, et al. Clinical factors affecting
endometrial receptiveness in oocyte donation cycles. Fertil Steril. 2008;
89:491–501.
7. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on
pregnancy rates after in vitro fertilization–embryo transfer. Fertil Steril.
1998;70:492–499.
8. Strandell A, Lindhard A, Waldenstr€om U, Thoburn J, Janson PO,
Hamberger L. Hydrosalpinx and IVF outcome: a prospective randomized multicentre trial in Scandinavia on salpingectomy prior to IVF.
Human Reprod. 1999;14:2762–2769.
9. Strandell A, Lindhard A, Waldenstr€om U, Thorburn J. Hydrosalpinx
and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod. 2001;16:2403–2410.
10. Nackley AC, Muasher SJ. The significance of hydrosalpinx in in vitro
fertilization. Fertil Steril. 1998;69:373–384.
11. Granot I, Dekel N, Segal I, Fieldust S, Shoham Z, Barash A. Is hydrosalpinx fluid cytotoxic? Hum Reprod. 1998;13:1620–1624.
12. Zolghadri J, Momtahan M, Alborzi S, Mohammadinejad A,
Khosravi D. Pregnancy outcome in patients with early recurrent abortion following laparoscopic tubal corneal interruption of a fallopian
tube with hydrosalpinx. Fertil Steril. 2006;86:149–151.
13. Hamilton BE, Martin JA, Ventura SJ. Births: preliminary data for 2007.
Natl Vital Stat Rep. 2009;57:1–23.
14. Lauer JA, Betran AP, Merialdi M, Wojdyla D. Determinants of caesarean section rates in developed countries: supply, demand and opportunities for control. World Health Report. 2010. Background Paper 29.
15. Krieg SA, Henne MB, Westphal LM. Obstetric outcomes in donor
oocyte pregnancies compared with advanced maternal age in in vitro
fertilization pregnancies. Fertil Steril. 2007;90:65–70.
Journal of Minimally Invasive Gynecology, Vol 18, No 3, May/June 2011
16. Galen D, McWatters J. Utilization of the Essure microinsert for the
treatment of hydrosalpinx prior to in vitro fertilization. Fertil Steril.
2007;88:O–42.
17. Hitkari JA, Sukhbir SS, Shapiro HM, Leyland N. Essure treatment of
hydrosalpinges. Fertil Steril. 2007;88:1663–1666.
18. Sagoskin AW, Lessey BA, Mottla GL, et al. Salpingectomy or proximal
tubal occlusion of unilateral hydrosalpinx increases the potential for
spontaneous pregnancy. Human Reprod. 2003;18:2634–2637.
19. Surrey E, Schoolcraft W. Laparoscopic management of hydrosalpinges
before in vitro fertilization–embryo transfer: salpingectomy versus
proximal tubal occlusion. Fertil Steril. 2001;75:612–617.
20. Kontoravdis A, Makrakis E, Pantos K, Botsis D, Deligeoroglou E,
Creatsas G. Proximal tubal occlusion and salpingectomy result in
similar improvement in in vitro outcome in patients with hydrosalpinx.
Fertil Steril. 2006;86:1642–1649.
21. Mijatovic V, Veersema S, Emanuel MH, Schats R, Hompes PGA.
Essure hysteroscopic tubal occlusion device for the treatment of
hydrosalpinx prior to in vitro fertilization–embryo transfer in patients
with a contraindication for laparoscopy. Fertil Steril. 2010;93:
1338–1341.
22. Practice Committee of the American Society for Reproductive Medicine in collaboration with The Society of Reproductive Surgeons. Salpingectomy for hydrosalpinx prior to in vitro fertilization. Fertil Steril.
2008;90:S66–S68.
23. Levie M, Weiss G, Kaiser B, Daif J, Chufnoff SG. Analysis of pain and
satisfaction with office-based hysteroscopic sterilization. Fertil Steril.
2010;94:1189–1194.
24. Rosenfield RB, Stones RE, Coates A, Matteri RK, Hesla JS. Proximal
occlusion of hydrosalpinx by hysteroscopic placement of microinsert
before in vitro fertilization–embryo transfer. Fertil Steril. 2005;83.
1547.e11–1547.e14.
25. Kerin JF, Munday D, Ritossa M, Rosen D. Tissue encapsulation of the
proximal Essure micro-insert from the uterine cavity following hysteroscopic sterilization. J Minim Invasive Gynecol. 2007;14:202–204.