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Laser assisted hatching in good prognosis patients

undergoing in vitro fertilization-embryo transfer: a


randomized controlled trial
Arthur W. Sagoskin, M.D.,a Michael J. Levy, M.D.,a Michael J. Tucker, Ph.D.,a
Kevin S. Richter, Ph.D.,a and Eric A. Widra, M.D.a,b
a b
Shady Grove Fertility Reproductive Science Center, Rockville, Maryland, and Georgetown University Department of
Obstetrics and Gynecology, Washington, D.C.

Objective: To evaluate whether assisted hatching improves clinical outcomes of embryo transfers to good prognosis
patients, defined as patients ⱕ39 years with normal follicle-stimulating hormone (FSH) and E2 levels, no more than
one previous unsuccessful cycle of in vitro fertilization (IVF)– embryo transfer, and good embryo quality.
Design: Prospective randomized controlled trial.
Setting: Private assisted reproductive technology (ART) center.
Patient(s): One hundred ninety-nine good prognosis patients undergoing IVF– embryo transfer.
Intervention(s): In vitro fertilization followed by embryo transfer on day 3 after oocyte retrieval with or without
assisted hatching using a 1,480-nm wavelength infrared laser.
Main Outcome Measure(s): Clinical intrauterine pregnancy, spontaneous pregnancy loss, and live birth.
Result(s): Rates of clinical intrauterine pregnancy with fetal cardiac activity (53% vs. 54% per cycle), sponta-
neous pregnancy loss (13% vs. 16% per pregnancy), and live birth (47% vs. 46% per cycle) were very similar
between treatment cycles with laser-assisted hatching and control cycles in which embryos were transferred
without assisted hatching. There were no significant differences between treatment and control groups in any
measured clinical outcome parameters.
Conclusion(s): Assisted hatching does not improve clinical outcomes among good prognosis patients. (Fertil
Steril威 2007;87:283–7. ©2007 by American Society for Reproductive Medicine.)
Key Words: In vitro fertilization, embryo transfer, assisted hatching, laser micromanipulation, good prognosis,
implantation, pregnancy, live birth

The ability of a blastocyst to hatch, or escape, from the zona assisted reproduction protocols may also contribute to the
pellucida (ZP) that surrounds and protects the embryo during inability of some blastocysts to successfully hatch.
its first few days of development is one of many critical
events that must occur for successful reproduction. Implan- Assisted hatching (AH), in which the ZP is artificially
tation of the embryo in the uterine lining is impossible unless breached or thinned to facilitate hatching, has been proposed
hatching occurs. It has been suggested that impaired hatch- as a way of overcoming these intrinsic or assisted reproduc-
ing of embryos resulting from IVF contributes to low im- tive technology (ART)-induced barriers to hatching of oth-
plantation rates (1). erwise viable embryos (1). Studies using animal models have
demonstrated that AH can significantly increase rates of
Intrinsic factors such as age (2), basal FSH and diagnosis embryo hatching (9 –12). Assisted hatching has also been
(3), the altered hormonal environment to which maturing shown to significantly increase hatching rates of human
oocytes are exposed during ovarian stimulation (3, 4), or the embryos (13–16). Studies using animal models have also
artificial conditions of the in vitro culture environment (5–7), found that AH results in earlier hatching than occurs in
may induce abnormal thickening or hardening of the ZP, unmanipulated embryos (8, 9). Data from patients undergo-
making hatching more difficult. In vitro culture conditions ing IVF demonstrated that hCG is detectable in maternal
may also adversely effect quantitative or qualitative serum earlier when AH is performed than when it is not (17),
trophectoderm-produced zona lysin secretion that has been suggesting that human embryos also hatch earlier when
proposed as the primary mechanism of blastocyst hatching assisted. Facilitation of earlier embryonic hatching may be
(8). Intrinsic variation in lysin secretion independent of particularly important given that the short window of endo-
metrial receptivity appears to be shifted 1–2 days earlier in
Received March 8, 2006; revised and accepted July 5, 2006. cycles with ovarian stimulation for ART compared to natural
Presented in part at the 59th Annual Meeting of the Society for Repro- cycles (18 –20).
ductive Medicine, San Antonio, TX, October 11–15, 2003.
Reprint requests: Kevin S. Richter, Ph.D., Shady Grove Fertility Repro-
A variety of different micromanipulation techniques, in-
ductive Science Center, 15001 Shady Grove Road, Suite 400, Rock-
ville, MD 20850 (FAX: 301-340-0623; E-mail: kevin.richter@integramed. cluding mechanical partial zona dissection (1, 21, 22), zona
com. drilling using acidic Tyrode’s solution (23, 24), laser drilling

0015-0282/07/$32.00 Fertility and Sterility姞 Vol. 87, No. 2, February 2007 283
doi:10.1016/j.fertnstert.2006.07.1498 Copyright ©2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
(12, 25–27), and piezo-micromanipulation (28) have been Assisted embryo hatching was performed using a
reported to improve ART outcomes among select groups of 1,480-nm wavelength infrared laser (Zilos Laser System,
patients. Two recent meta-analyses of studies evaluating Hamilton Thorne Research, Beverly, MA). An approxi-
potential benefits of AH reported significant heterogeneity mately 20 ␮m defect was created in the ZP before transfer in
among study results (29, 30), suggesting that effects of AH the treatment group, whereas those in the control group were
may differ depending on patient characteristics. Both con- transferred with no laser-AH. The laser was set to deliver a
cluded that there is strong evidence that AH increases preg- 500-␮sec pulse of energy at 100% power, such that by
nancy rates (PR) among patients with a history of previous targeting a suitable area of the ZP with an area of periv-
IVF failures. However, it remains uncertain whether AH is itelline space beneath, a suitable 20-␮m hole could be drilled
beneficial to other patients. Other patient populations that with 6 –10 bursts of the laser. Embryo transfer was under-
have been reported to benefit from AH include patients taken with either of two soft compound catheters (Tucker
whose embryos have thick zonae and patients with elevated
Embryo Catheter, Fertility Technology Resource Inc, Mari-
FSH (23), older patients (21, 24, 31–33), and patients using
etta, GA; Wallace Embryo Replacement Catheter, Irvine
cryopreserved embryos (34 –37).
Scientific, Santa Ana, CA) under ultrasound guidance.
Based on this evidence, our program routinely offers AH
to patients with a history of two or more previous IVF– Implantation and pregnancy outcomes were determined
embryo transfer failures, patients aged 39 years or greater, based on ultrasound identification of fetal cardiac activity
and patients with a basal serum FSH concentration greater 4 – 6 weeks after embryo transfer.
than 10 mIU/mL. However, there are indications that im-
Cycle characteristics and clinical outcomes were com-
paired hatching may be a direct result of ART treatment
pared between treatment and control groups by t-test (nu-
(4 – 6, 8), and thus a potentially pervasive limitation of
IVF– embryo transfer implantation rates. If so, AH may also merical variables) or ␹2 (categorical variables). The sample
benefit patients with a better prognosis. We therefore de- size was calculated based on a ␤ ⫽ 0.08 and an ␣ ⫽ 0.05
signed this trial to test the hypothesis that AH of good quality with a predicted difference in implantation rate of 8% be-
embryos in good prognosis patients would improve PR and tween treatments and controls.
implantation rate.
RESULTS
MATERIALS AND METHODS A total of 203 patients were consented and enrolled in the
Patients undergoing IVF with cleavage stage (day 3) embryo study. Three patients were excluded from subsequent anal-
transfer at Shady Grove Fertility Reproductive Science Cen- ysis due to violations of inclusion criteria: elevated FSH
ter between August 2001 and March 2005 were enrolled (n ⫽ 1); advanced maternal age (n ⫽ 1); or poor embryo
after discussion of the study and informed written consent. quality (n ⫽ 1). One patient was lost to follow-up and had no
Western Institutional Review Board (WIRB) approved the pregnancy outcome data available and was therefore ex-
study protocol. This study has been registered with Clinical- cluded from analysis. Patient and cycle characteristics are
Trials.gov [NCT00120549]. compared among the 199 remaining patients in Table 1.
Inclusion criteria included first or second autologous IVF– Mean patient age was 34 years. Mean FSH was 6.6
embryo transfer cycles, maximum female age 39 years, mIU/mL, and mean E2 was 34.7 pg/mL. On day 3 after
maximum baseline FSH 10 mIU/mL, maximum baseline E2 oocyte retrieval, before embryo transfer, mean cell number
75 pg/mL, ovulatory menstrual cycles, no uterine abnormal- among transferred embryos was 7.6, with 2.9% fragmenta-
ity or communicating hydrosalpinx, and good embryo qual- tion. A mean of 2.1 embryos were transferred per cycle.
ity. Good embryo quality was defined by the presence of six
Treatment and control groups were comparable in terms of
to eight cells, and a maximum of 20% fragmentation on day
age, baseline FSH and E2, proportion of cycles with intra-
3. Eligible diagnoses included tubal disease (excluding com-
cytoplasmic sperm injection (ICSI), cell number and frag-
municating hydrosalpinx), endometriosis, male factor in-
mentation on day 3, and the number of embryos transferred.
fertlity, or unexplained infertility. Patients diagnosed with
diminished ovarian reserve, polycystic ovarian syndrome Pregnancies with fetal cardiac activity occurred in 53.8%
(PCOS), uterine or egg factor infertility were not eligible. of all treatment cycles, with an overall implantation rate of
Patients with more than one previous unsuccessful IVF cycle
34.0% of transferred embryos. Fifteen pregnancies (14.0%)
were also excluded.
ended in spontaneous pregnancy loss, and 92 ended in live
Enrolled patients were randomly assigned to either the birth (46.2% per cycle). Rates of pregnancy, implantation,
treatment group (laser-assisted hatching [laser-AH]) or the spontaneous pregnancy loss, and live birth were all very
control group (no laser-AH). Treatment assignments were similar between treatment and control cycles. There were no
determined by a computer-generated randomized series in a statistically significant differences between the treatment and
2:1 ratio of treatments to controls. control groups in any of the examined variables.

284 Sagoskin et al. Assisted hatching in good prognosis patients Vol. 87, No. 2, February 2007
TABLE 1
Cycle characteristics and clinical outcomes compared between cycles with assisted hatching
(treatment) and those without assisted hatching (control).

Treatment (hatched) Control (unhatched) P value

Number enrolled 121 82


Number analyzed 118 81
Patient agea 34.0 ⫾ 3.3 34.0 ⫾ 3.2 .89
Baseline FSHa 6.6 ⫾ 1.5 6.6 ⫾ 1.6 .92
Baseline E2a 35.3 ⫾ 15.6 33.7 ⫾ 14.1 .51
ICSI 57/118 (48.3%) 38/81 (46.9%) .85
Day 3 cell numbera 7.6 ⫾ 0.6 7.7 ⫾ 0.8 .44
Day 3 fragmentation (%)a 3.3 ⫾ 3.6 2.5 ⫾ 3.0 .15
Number of embryos 254 170
Embryos per cyclea 2.2 ⫾ 0.4 2.1 ⫾ 0.3 .30
Positive hCG 73/118 (61.9%) 52/81 (64.2%) .75
Gestational sac 64/118 (54.2%) 45/81 (55.6%) .87
Fetal cardiac activity 63/118 (53.4%) 44/81 (54.3%) .92
Implantation (fca/embryo) 84/254 (33.1%) 60/170 (35.3%) .74
Multiple fca 21/63 (33.3%) 16/44 (36.4%) .91
Spontaneous abortion 8/63 (12.7%) 7/44 (15.9) .64
Live birth per cycle 55/118 (46.6%) 37/81 (45.7%) .90
Note: fca ⫽ fetal cardiac activity.
a
Values are means plus or minus one standard deviation.
Sagoskin. Assisted hatching in good prognosis patients. Fertil Steril 2007.

DISCUSSION have reported significantly improved implantation rate and


Many studies have evaluated the effects of AH on implan- PR (21, 24, 31, 33), but other investigators have found no
tation rates of embryos transferred after IVF. However, more benefit (40 – 43). One study reported no benefit for AH
than 15 years after the introduction of AH into the practice among patients older than 36 years, but increased implanta-
of assisted reproduction, the indications for its use still tion and pregnancy with AH among patient 36 years or
remain poorly defined. younger (27).

Some studies have reported significant improvements in An early randomized trial found that AH significantly
implantation rate and PR with the application of AH to improved implantation rate and PR among patients with a
treatment cycles by “poor prognosis” patients, defined by a day 3 basal FSH ⬎15 mIU/mL (23). No study since has
history of repeated IVF– embryo transfer failures, elevated investigated AH among patients designated as poor progno-
FSH, or advanced age (32, 38). However, pooled analysis of sis specifically because of elevated FSH level alone. Several
such heterogeneous populations leaves ambiguity regarding studies have investigated AH among cycles in which cryo-
whether all of these different reasons for a poor prognosis are preserved embryos were transferred. Some of these studies
responsive to AH. A more recent randomized study reported have suggested that AH increases implantation and preg-
no benefit for AH among patients classified as poor progno- nancy among this patient population (34 –37). However,
sis because of either advanced age or elevated FSH (39). other studies have reported that there is no benefit from AH
of cryopreserved embryos (39, 44). Embryos with thick ZP
The population for whom the benefits of AH are best reportedly benefit from AH (23), although this claim has
documented are patients with a history of repeated IVF– been refuted (27, 42). There is also evidence that AH im-
embryo transfer without successful implantation. Many stud- proves outcomes of transfers of later-developing blastocysts
ies have reported significantly improved implantation rate (45), and of embryos with zonas that were difficult to pen-
and PR for these patients (21, 22, 24 –26, 28). Two recent etrate during ICSI (46).
meta-analyses found that there was conclusive evidence for
improved success with AH among patients with repeat IVF Few studies have investigated AH among patients with a
failures (29, 30), but uncertainty regarding other patient relatively good prognosis. Studies of unselected populations
populations. One of these meta-analyses reported a nearly suggest that the benefits of AH may not be universal. An-
significant trend toward improved outcomes among older tinori et al. (25) reported significant improvement in implan-
women (29). Several studies of AH among older patients tation and pregnancy among patients undergoing their first

Fertility and Sterility姞 285


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