Implantation & IVF Success

Mark R. Bush, MD, FACOG, FACS

Medical Director

www.ConceptionsRepro.com

Mark R. Bush, MD, FACOG, FACSTiffany Von Wald, MD, MPH, FACOGMichael S. Swanson, MD, FACOG

Implantation efficiency and sustenanceMyomectomy

• Distortion or disruption of the endometrium and implantation due to atrophy or venous ectasia over a myoma

• Impaired endometrial blood flow

• Endometrial inflammation and/or secretion of vasoactive substances

• Uterine artery embolization, myolysis, and MRI-guided ultrasonic treatment is not recommended for women seeking to maintain or improve their fertility because the safety and efficacy has not been established

ASRM Practice Committee, Myomas and reproductive function 2008: 90(3) S125-30.

Implantation efficiency and sustenanceMyomectomy

• Size and location

• Prospective cohort unexplained infertility, 11% conceived with myomas v. 25% without myomas v. 42% laparoscopic myomectomy (1)

• IVF rates lower with intramural myomas (2), with mean diameter 2.4 cm (3), when larger than 5 cm (4)

• 23 studies examined, fibroids with a submucosal component led to decreased clinical pregnancy and implantation rates with removal likely to improve pregnancy rates (5)

1) Donnez et al, Hum Reprod 2002; 17: 1424-30.

2) Somigliana et al, Hum Reprod Update 2007; 13: 465-76.

3) Eldar-Geva et al, Fertil Steril 1998; 70(4): 687-691.

4) Kolankaya et al, Obstet Gynecol Clin North Am 2006;33: 145-52.

5) Pritts et al, Fertil Steril 2009; 91(4): 1215-23.

Implantation efficiency and sustenanceMyomectomy

Implantation efficiency and sustenanceSeptolysis

Letterie, Structural Abnormalities and Reproductive Failure, Blackwell Science, 1998.

Implantation efficiency and sustenanceSeptolysis

Implantation efficiency and sustenanceSeptolysis

Implantation efficiency and sustenanceSeptolysis

Implantation efficiency and sustenanceSeptolysis

Implantation efficiency and sustenanceSeptolysis

• Hysteroscopic resection with laparoscopic follow

• 5mL intrauterine stent x10 days with doxy 50mg BID

• Estrace 2mg BID for 21 days followed by Prometrium 200 qHS x 7d (2 courses) starting day after surgery

• Office hysteroscopy test of cure

• 15% fundal coaptation rate requiring H/S resection

Implantation efficiency and sustenanceImportance of TOC office hysteroscopy

Implantation efficiency and sustenanceChallenging

Implantation efficiency and sustenanceSalpingectomy for hydrosalpinx

• 116 randomized to salpingectomy before IVF, 88 control

• Delivery rates 28.6% v. 16.3% (p < .05) (1)

• Subgroup of hydros visable on ultrasound: 40% v. 17.5% (1)

• Direct embryotoxic effect (2), decreased endometrial receptivity, mechanical disruption of implantation by fluid

• Based on the results from 3 trials, ongoing pregnancy rate after salpingectomy or proximal occlusion is two-fold higher than controls, 34% v. 17% (3)

1) Strandell et al, Hum Reprod 1994; 9: 2762-9.

2) Mukherjee et al, Fertil Steril 1996; 66: 851-3.

3) ASRM Practice Committee, Salpingectomy for hydrosalpinx 2008; 90(3) S66-8.

Implantation efficiency and sustenanceSalpingectomy for hydrosalpinx

Preimplantation Genetic Testing

• Indications

1. > 35 y/o

2. RPL

3. Past history of chromosomal abnormality

4. Concern of chromosomal abnormality

5. Previous IVF with implantation failure

6. Balanced translocation or inversion

7. Couple at risk for genetic disease

Blastocyst

• American Society for Reproductive Medicine, September, 2010

• Pacific Coast Reproductive Society, March, 2011

Criterion FISH CGH aCGH PS (GSN)

Accuracy 85-90% unknown unknown Typically 99%

24 chromosome aneuploidy detection X

Fresh transfer possible X

Partial Aneuploidy (de novo large deletions & additions)

X

Corrects for „noisy‟ DNA X X X

Simultaneous single gene testing and 24 chromosome PGS on a single cell

X X X(IRB study)

Parental origin of aneuploidy X X X

Haploidy and Polyploidy detection Incomplete X X

Uniparental Disomy (UPD) detection X X X

DNA contamination detection, parentage confirmation

X X X

Individual confidences for accuracy of each call

X X X

Summary of Technical Capabilities of Existing PGS Technologies

Published study in Human Reproductionvalidates GSN approach

Description:

• Comparison of GSN‟s Parental SupportTM

performance to metaphase karyotype

• One of the largest and most comprehensive studies of human cleavage stage embryos availableKey Findings:

• Overall accuracy comparable to metaphase karyotype

• Calls made using Parental data have lower error rate than calls made using signal intensity alone

Determination of whether the extra or missing chromosome came from the egg or sperm is extremely powerful in determining future therapies

In house biopsy with freeze and then sending tissue samples to high-throughput lab with daily QA is advantageous

Collaboration with GSN allows for full genetic counseling pre-and post-biopsy

"We are so grateful to have found Dr. Bush and Conceptions. At age 40, we are finally holding

our beautiful daughter (and suffering the late-night feedings) just as we had always wanted.

My husband and I underwent a six-year long journey, involving multiple IVF cycles performed in two states, no fewer than five doctors (by circumstances and not by choice) and a king’s

ransom worth of medical costs. We were exhausted and devastated after the last failed cycle at

another “well-known” clinic. Looking back on it, I am not sure how we had the strength to pick

up the phone and call Conceptions. Then, immediately, the Conceptions nurse who answered

the phone, Melanie, made us glad we did. We later found not only Melanie, but practically

everyone at the Conceptions is truly wonderful -- throughout each step of the process. Infertility is difficult enough. I strongly believe that having nurses and other staff members

who are not only knowledgeable and professional, but who show genuine kindness and

patience, contributed to the eventual success. Of course, Dr. Bush’s medical skills and

intuition, and his use of cutting-edge technology were essential. Dr. Bush was thorough in his

review of our records, straight forward in sharing his thoughts and thoughtful in designing the treatment protocol. He made us feel comfortable with proceeding one more time in his good

hands. Looking at our daughter’s beautiful eyes, we are so grateful of the dream that the

Conceptions team helped us realize." J&T (2010)

• Surgical case yesterday

• 26 year old G2P1S1

• Uterine septum with h/o 26 wk PPROM as well as first trimester loss

• Balanced translocation between 14 and 21

• IVF retrieval 22 days ago

• Two blastocysts biopsied and assayed for 23 pair disomy and consequences of balanced translocation

• She will have her FET after TOC O-HSC demonstrating optimal new endometrial growth over her resected septal regions

Bringing it all together

• $175. flat rate for all New Infertility MD consults

• We accept all insurance plans as payment (including BC/BS and Cigna). We do not bill the patient cash to our center and then assist them in recouping that payment from their insurance.

• If no surgical coverage, flat fee for operative laparoscopy/hysteroscopy at 6,000 which includes all hospital charges, anesthesia, pathology and surgical fees. Myomas, septums, hydrosalpinges.

• We accept all testing previously performed by the referring providers. We do not require a $3000.+ testing package to be performed at our facility prior to cycle start.

Costs

• 12,875. IVF

TET, SHG or O-HSC, complete cycle management & monitoring regardless of the number of visits, egg retrieval, ICSI, day 5 culture and embryo transfer. Repeat cycle 10,600. FET 4,750.

• 19, 125. IVF with CCS (complete chromosomal screening)

IVF cycle as above, TE biopsy (1500), GSN (3100), cryopreservation (N/C), FET cycle (1,650).

• 24, 957 Donor egg cycle – includes fee to donor of 5K

w/ICSI and D5 ET

• IVF Refund Program also available

IVF Cost

Implantation efficiency and sustenanceCoagulopathy and MTHFR defect

• Observational data suggests a relationship between elevated homocysteine levels and decreased folate levels with pregnancy loss as well as a benefit of folate, B6 and B12 supplementation (1).

• Folgard 2.2 BID (or equivalent) delivers 4.4 mg folic acid, 50mg B6 and 1mg B12. Water soluable B vitamins that can decrease intensity of N/V and be prophylactic with regard to NTD.

• Panel cost (Colorado LabCorp 3/3/10):

Factor V ($263.50), Factor II (263.50), AT III (134.50), ACA (342.75), LAC (379.25)

MTHFR (263.50), Protein C/S activity (143.50/146)

Nelen et al, Obstet Gynecol 2000, 95: p 519-24.

Coagulopathy and MTHFR defect

• RPL and single C677T

– Folgard 2.2 BID and 81 ASA QD

• RPL and C677T x2 or C677T/A129

– Lovenox 40 QD at +hCG

• History of VTE, RPL and thrombophilia : Hematology Consult

– Low risk (Factor V hetero, Factor II hetero, C/S deficiency)

• Lovenox 30 BID, anti-Xa level (0.1 – 0.2) after 2 weeks

– High risk (AT III, homozyg V or II, compound V/II, +APA)

• Lovenox 1mg/kg BID, anti Xa (0.6 – 1.0)

• Monitor for heparin induced thrombocytopenia

• Unfractionated heparin: prophylaxis 5000 BID; therapeutic 5–10K q 8-12h with aPTT midway between doses 1.5 – 2.5x

Implantation efficiency and sustenanceCoagulopathy and MTHFR defect

• While controversial, frame of reference is not second and third trimester obstetrical outcomes but first trimester failure of nidation and early maternal interaction and perfusion of placenta.

• Lovenox potentiates AT III to foster increased flow through placental intervillous spaces (delivery of 02 and nutrients) as well as a direct anti-inflammatory effect.

Anti-phospholipid syndrome

• Sydney criteria (1)

Clinical

- arterial or venous thrombosis

- > 3 unexplained miscarriages < 10 wks

- unexplained fetal death > 10 wks

- premature birth ( < 34 wks) complicated by severe pre-

eclampsia or placental insufficiency

Laboratory

- ACA IgG or IgM > 40 GPL or MPL

- Anti-B2 glycoprotein-1 IgG or IgM > 99th percentile

-LAC

• Treatment (2)

- Livebirth rates of 69-78% with lovenox and ASA

(1) Miyakis et al, J Thromb Haemost 2006. (2) RCT Farquharson et al 2002. (3) RCT Stephenson et al 2004.

ACOG Perspectives

Editorial

“The Truth About Inherited Thrombophilias and Pregnancy”

Branch, Vol 115, No. 1, January 2010

“Nothing is more trying for me as an obstetrician than cajoling a woman into discontinuing the low molecular weight heparin prescribed by another, nonobstetric physician”

“No improvement in live-birth rates using low molecular weight heparin in women with anti-phospholipid antibodies and recurrent miscarriage (1)”

(1) Farquarsen et al, Obstet Gynecol 2002, 100(3): p 408-13.

ACOG Perspectives

Regarding the 2002 study by Farquharsen et al:

“seriously flawed in inclusion criteria, design and analysis” (1)

“only 11 of 98 women (11%) met laboratory criteria that are generally accepted for the diagnosis of APS” (2)

“the lack of benefit of heparin reported are entirely expected as the majority of participants in this study did not have APS” (1)

“the authors describe a power analysis; however it did not achieve significance. Is there a B error?” (2)

(1) Rai et al, Obstet & Gynecol 2002: 100(3) 1354. (2) Kutteh, Obstet & Gynecol 2002: 100(3) 1354.

ACOG Perspectives

Practice Bulletin No. 111: Inherited Thrombophilias in Pregnancy, Obstet & Gynecol. 11(4): 877, April 2010. As of 5/25/2010: “This document has been withdrawn. Please contact ACOG Resource Center (resources@acog.org; 202-863-2518) for further information.”

No level A recommendations (good and consistent evidence)

Level B (based on limited or inconsistent evidence)

Thrombophilia testing in women with RPL is not recommended because it is unclear whether anticoagulation reduces recurrence

Level C (expert opinion)

Screening should include V, II, AT3, C & S with recommendations per Table 4

ACOG Perspectives

Solution: Lovenox 40 SQ QD from +hCG or in IVF cycles the day after ET through 12 weeks. Hematology consult for lifetime risk issues and recommendations for second & third trimester and post-partum.

Maternal immune acceptance of placenta

• Thyroid function and TPO/TG

• Prednisone

Thyroid function and TPO/TG

• Miscarriage rate in TPO positive women was significantly higher than in those with no antibody, 13.8 versus 2.4 %, (RR 4.95, CI 2.59-9.48) (1)

• Levothyroxine dose requirements can increase as much as 50% during pregnancy. With the importance in implantation, maintenance of pregnancy and fetal cognitive development, one group‟s approach is to increase levothyroxine dosing 30% at positive pregnancy test

(1) Negro R, et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91:2587.

(2) Alexander EK, et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351:241.

• Safety and efficacy of prednisone 10mg BID thru 12 weeks demonstrated with a livebirth rate of 77% in 80 women with therapy as opposed to a 35% pregnancy rate in 52 matched women without therapy. Concurrent use of 5mg folate QOD, 100mg ASA QD, 20mg PO progesterone QD; autoimmunity not tested (1).

• Reznikoff-Etievant et al, Human Reproduction 1999, Vol 14(8) p. 2106 also demonstrated safety of prednisone at 20mg/d in 277 women.

• Category B. Drugs in Pregnancy and Lactation, 5th ed, Briggs, Freeman, Yaffe. Williams & Wilkins, 1998, p. 884-5.

(1) Tempfer et al, Fertil & Steril 2006, Vol 86(1) p. 145.

Prednisone

• Women with recurrent loss had significantly more uNK than controls (p = 0.008).

• Prednisone treatment (20 mg/d for 21 days) significantly reduced the number of CD56 cells in the endometrium, from a median of 14% before to 9% after treament (p = 0.0004).

• Demonstrated that high numbers of uterine natural killer cells in preimplantation endometrium of women with recurrent miscarriage can be reduced with the administration of prednisone.

Quenby et al, Fertil & Steril 2005, 84: p 980-4.

Prednisone