We are beyond excited and honored to be named one of America’s Best Fertility Clinics for 2023 by Newsweek! None of this would have been possible without the hard work, dedication, and passion of our amazing #FIRMFamily doctors, nurses, and staff. A huge thank you to all the people who put their trust in us during their fertility journey – you are why we strive for excellence.
Category Archives: What’s New
In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”1 alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”2 The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.
From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.
The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.3
In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”
4. Prescribing clomiphene citrate without IUI
Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.4
Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta2-glycoprotein I assays.5 ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.
A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.
PGT-A for all
As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.8 In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.
ICSI for nonmale factor infertility; assisted hatching
In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.9 During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.10
Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.11
Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.12
Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.13 Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.13
To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.
2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.
3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.
4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.
5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.
6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.
7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.
8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.
9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.
10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.
11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.
12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.
13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.
Zika virus exposure and its complications continue to be an evolving area of patient care and clinical practice. Given this situation, we highly recommend going to the CDC website directly http://www.cdc.gov/zika/ and checking it periodically for the most up to date recommendations and travel restrictions.
Avoiding exposure is best. Since Zika virus can also be transmitted through sexual contact, it is important that both you and your partner protect yourselves from mosquito bites. Thus if you are presently trying to conceive, it is best to avoid traveling to areas of active mosquito-born Zika transmission. If you live in an area of active mosquito-born Zika transmission or are traveling to these areas, then we recommend taking all precautions to avoid mosquito bites. The following protective measures should be practiced, both day and night, including:
- The use of EPA-approved bug spray with at least 25% DEET*, can apply every 8 hours
- Covering exposed skin
- Staying in air-conditioned or screened-in areas
- Treating clothing with permethrin*
* When used as directed on the product label, these products can be used safely during pregnancy. Reapplication of insect repellant should be practiced as directed on the product label.
More information about preventing mosquito bites can be found at the CDC website: http://www.cdc.gov/zika/prevention/prevent-mosquito-bites.html
More information about areas with active mosquito-born Zika transmission can be found at the CDC website: http://www.cdc.gov/zika/geo/index.html
Over the last three years IVIGen Corporation, a reproductive medicine laboratory headquarterd in Valencia, Spain has been researching endometrial receptivity. Their work has led to a major breakthrough in the area of reproductive medicine, i.e., dispelling the notion that all women’s uterine lining respond to hormone replacement therapy the same way. The IVIGen physicians and scientists have studied patients who have had at least three failed IVF transfers of good quality embryos, i.e., individuals who you would expect to have a very high chance of pregnancy. These investigators have identified over 300 genes that are involved in making the uterus receptive. Their data indicate that approximately 26% of these failed patients have endometrial linings that are out of phase, meaning they are either resistant or hyperresponsive to progesterone. When these out of phase individuals are treated with additional or fewer days of progesterone they get pregnant at expected high rates. The status of being resistant or hyperresponsive seems to be consistent for periods up to two years. At the Florida Institute for Reproductive Medicine we are offering endometrial receptivity assay assessment. A mock cycle of estrogen preparation followed by progesterone is given at which time an endometrial biopsy is performed. Results of the biopsy are available approximately ten days later. Biopsies are interpreted as either receptive, meaning no problem with the standard preparation of the lining or non-receptive either resistant or hyperresponsive. Following correction of a non-receptive lining another mock cycle documenting a corrected window is recommended. Cost to perform the endometrial biopsy including IVIGen Lab interpretation and shipment is approximately $1,200. If there are other causes for an abnormal uterine lining, i.e., fluid in the cavity, a thin lining, polyps, fibroids or adhesions these factors need to be corrected prior to performing the assay. At the Florida Institute for Reproductive Medicine we believe an endometrial receptivity assay should be performed on any individual who has had two or more failed transfers of good quality embryos. We believe the endometrial assay is a major step forward in explaining why at least 26% of individuals may not be getting pregnant. If you feel you may be a candidate for endometrial receptivity assessment, please contact one of our physicians to discuss this in detail.
Kevin L. Winslow, M.D.
Florida Institute for Reproductive Medicine In Vitro Fertilization Program – 176 Consecutive Patient Reviews — Kevin L. Winslow, M.D.
In an effort to continually improve our IVF program, patients going through IVF were asked following their embryo transfer (prior to their pregnancy test) to grade on a scale of 1-4 (1 strongly disagree, 2 disagree, 3 agree and 4 strongly agree) ten different aspects of their IVF experience. In addition patients were encouraged to make recommendations to improve the program as well as any other comments they wished. Patients were given the choice to participate or not, to sign their name or not and to post their survey on the internet. Patients were left alone in the transfer room to either fill out their survey or to leave. No patient declined to fill out their survey. Nine patients chose not to sign their surveys. One hundred and eleven (63%) patients agreed to post their survey on the internet. Forty-seven (27%) patients did not indicate a preference to post and were not uploaded. Eighteen (10%) patients indicated they preferred their reviews not to be posted. Of the 111 patients who agreed to post their surveys, the average score was 3.9. Of the 47 patients who did not indicate a preference to post, the average score was 3.9. Of the 18 patients who indicated they did not want their survey posted, the average score was 3.8. Actual copies of the surveys are included so that you may review the actual questions as well as all recommendations and comments.
We thank all of our patients for participating in this survey we will continue to make every effort to improve our IVF experience.
Click thumbnails below to enlarge the reviews
The Florida Institute for Reproductive Medicine – One of the largest Donor Embryo Programs in the Country – Kevin Winslow, M.D.
Couples going through in vitro fertilization frequently have additional embryos that are cryopreserved. The majority of couples end up using these embryos for a second or third pregnancy. Approximately 10% of couples will not use their cryopreserved embryos. At the Florida Institute for Reproductive Medicine we strongly encourage these couples to consider embryo donation. For many infertile patients embryo donation is the ideal answer to their dreams of becoming parents. It is a relatively simple and inexpensive option. With embryos from over 50 couples the Florida Institute for Reproductive Medicine has one of the largest donor embryo programs in the country. We have embryos from Caucasian, African American and Hispanic couples. Couples interested in embryo donation can make an initial phone consultation with one of our board certified reproductive medicine specialists (904-399-5620 or www.firmjax.com).
The purpose of this consult is to determine whether embryo donation is an appropriate treatment option. Following this consultation couples will have a follow up consultation with our donor embryo IVF nurse coordinator to review donor embryos. The program is totally anonymous, i.e., the donating couple does not know who the adopting couple are and vice versa. The adopting couple may ask anything they wish regarding medical history, age, infectious disease screening of the donating couple to help make their decision. The female partner prior to undergoing embryo transfer will be asked to have a sonohysterosalpingogram to rule out any significant uterine pathology. This study can be done by the patient’s local ob/gyn or a reproductive medicine specialist.
Preparation for donor embryo transfer is relatively simple – the female is treated initially with estrogen either orally or by patch, on day 13 of estrogen she will have an ultrasound to assess uterine thickness (this can be performed by the patient’s local physician). As long as her lining has thickened appropriately she will begin progesterone. Progesterone can be given either vaginally or IM. Transfer will occur 3-5 days later depending on the age of the embryos. The female partner will travel to the Florida Institute for Reproductive Medicine in Jacksonville for embryo transfer (a relatively pain free procedure). Once the transfer is performed the patient can travel back to her home that same day.
A pregnancy test will be checked 11-13 days later. If the patient is pregnant she will continue on estrogen and progesterone through eleven weeks. She will have a pregnancy ultrasound two weeks after her pregnancy test. If the patient is not pregnant she will stop hormone therapy and can expect a period within 3-5 days. Pregnancy rates with the donor embryo program are primarily determined by the age of the mother producing the embryos, as well as the number and quality of day three and day five embryos transferred. With embryos from a female less than 35 years of age with two, day five embryos pregnancy rates of 50-60% are typical. Of those individuals who are pregnant 30-40% will have a twin pregnancy. In general no more than two, day five embryos or three, day three embryos are transferred at any time to minimize the risk of triplets and high order multiples.
The cost for the embryo donation program is typically around $4,000.00. If the adopting couple or treating physician feel additional screening of the donating couple or adopting couple are indicated additional costs may be incurred.
FREEZING EGGS NO LONGER EXPERIMENTAL
63 Babies Born – Florida Institute for Reproductive Medicine
The American Society of Reproductive Medicine recently removed the label “experimental” in describing egg freezing. To date over 4000 babies have been born from frozen eggs, health data on these babies has been extremely reassuring. Pregnancy rates using cryo eggs have continued to improve now approaching those from frozen embryos. Egg freezing offers tremendous advantages to at least three groups of women: those faced with losing their fertility due to cancer treatment or surgery, women who for whatever reason must postpone childbearing late into their 30s or beyond, and patients requiring in vitro fertilization who are ethically opposed to freezing embryos. While ASRM has not endorsed the use of egg freezing for delayed childbearing, we at the Florida Institute for Reproductive Medicine feel it is an appropriate option for those who otherwise would have little chance of having their own genetic children later in life. At the Florida Institute for Reproductive Medicine, Dr. Yang has pioneered the technology of oocyte cryopreservation, we have had one of the largest experiences in the United States with sixty-three babies born, including the first baby born in the world to a cancer patient who froze her eggs. Again our follow up health data on these babies has been reassuring. I do advise couples that the ultimate health testament will be when children born from frozen eggs have had their own healthy children. We hope by lifting the label of experimental, insurance companies will consider covering egg preservation for at least those women faced with sterilizing. The technique of egg freezing involves going through an IVF cycle, costs are almost identical, approximately $10,000.00 to $12,000.00 depending on the amount of medicine used. The Florida Institute for Reproductive Medicine has participated with a national group, Fertile Hope, in providing significantly discounted costs for egg freezing for cancer patients. Ferring pharmaceuticals has been extremely generous in donating medications saving patients as much as $3,500.00. We welcome ASRM’s recent opinion on egg freezing and hope many other women will be able to avail themselves of this remarkable technology.
Don’t be misled by statements reporting we have the largest IVF, donor egg IVF or gestational surrogate IVF program. The truth is that what is often being represented is far from what you’re probably interested in. Ask specific pointed questions, i.e. how many IVF pregnancies have come from your current lab, not another lab or program that you may have participated in the past. Ask what the take-home pregnancy rate is, be careful to also ask how many total IVF cycles have been performed to get an idea of the programs experience. Ask for official CDC pregnancy results in writing (http://www.cdc.gov/art/). Ask who the lab director is, is the director a doctoral level embryologist? Has the director obtained the certification of highly complex lab director? Has the director been involved in any original reproductive medicine research? At the Florida Institute for Reproductive Medicine we have had over 4,000 babies born from our IVF program over the last twenty years. Our pregnancy rates have consistently been in the top ten percentile nationwide. We have accounted for 87% of all IVF pregnancies, 83% of all donor egg IVF pregnancies and 99% of all pregnancies from cryo eggs over the last ten years in the North Florida/South Georgia area. Our embryology team consists of three doctoral and one master’s level embryologists, headed by Dr. Yang. Dr. Yang has over twenty years of embryology experience; he holds the certification of highly complex lab director. Dr. Yang is world renowned for his original research regarding intracytoplasmic sperm injection/IVF, as well as his work on egg freezing.
We are pleased to announce Florida Institute for Reproductive Medicine is now one of a select group of IVF programs in the nation now offering Day 5 Laser Embryo Biopsy. This technology allows for the laser extraction of multiple cells from a day 5 embryo to test for genetic normalcy prior to transfer. Prior day 3 embryo biopsies where only one or two cells were available for testing has been shown not only to be inaccurate, but to compromise implantation rates. Day 5 embryo biopsy has tremendous implications in terms of avoiding multiple births, i.e. with accurate pre-embryo genetic screening ongoing pregnancy rates of 60-70% have been reported with a transfer of a single chromosomally normal embryo. Because the majority of pregnancy losses are due to chromosomally abnormal embryos, this technology is expected to significantly reduce miscarriage rates. The cost for this service will range from $2,500.00 to $3,000.00 depending on the number of embryos biopsied. We expect these costs to be recouped by avoiding freezing and transfer of abnormal embryos. By avoiding multiple births with their inherent risks and costs, we have eliminated the greatest problem associated with IVF. If you are interested in learning more about this technology, please make a consult appointment with one of our physicians.