Alternatives to In Vitro Fertilization (IVF) for Overcoming Infertility and Delivering a Healthy Baby

Co-authored by Craig Turczynski, Ph.D., Marguerite Duane, M.D., M.H.A. FAAFP, and Naomi Whittaker, M.D.

This is Issue 18 of CLI’s On Science Series.

Executive Summary:

• Infertility is often a symptom of multiple underlying health issues and chronic conditions impacting millions of reproductive-age couples. Unfortunately, too many wait until there is difficulty conceiving to begin investigating these issues and, when problems arise, most think IVF is the only solution.

• This paper reviews multiple alternatives for overcoming infertility. Some of these were once available but subsequently abandoned because of progress in IVF. Others are currently available but are not widely obtainable, and still others could be developed if scientific ingenuity and resources were directed to them.

• Emphasis and training should be focused on prerequisite diagnosis and treatment of the conditions causing infertility, both surgically and medically, before IVF is considered.

• An emphasis on surgical and restorative alternatives by re-allocating some of the NIH funding currently dedicated to IVF fellowships and contraceptive research would make a significant difference to the field.

• Patients with infertility deserve treatment and care that is not unreasonably financially burdensome, as well as options that do not present ethical concerns about the treatment of human embryos. Many of the methods discussed in this paper are less costly and more therapeutic for the patient than IVF, yet IVF is routinely offered as the first-line “treatment” without seriously investigating or attempting to address underlying causes of infertility.

Introduction and Background

Infertility, defined as the inability to achieve pregnancy within 12 months of non-contraceptive intercourse, is increasing in frequency, affecting 8-12% of reproductive-aged couples globally, which amounts to an estimated 186 million people.^[1] The current standard recommendations for couples trying to conceive includes 12 months of random acts of intercourse (six months if the woman is over 35) and then referral to a reproductive endocrinologist.^[2] Reproductive endocrinologists are OB-GYNs that have completed a fellowship in reproductive endocrinology, where they primarily learn how to apply in vitro fertilization (IVF). The Charlotte Lozier Institute (CLI) has covered what IVF is and how it is currently applied in a previous article.^[3] The purpose of this article is to present and explain alternatives to IVF, including both conventional and restorative approaches – attempting to describe each method, what underlying causes of infertility it treats, effectiveness, and financial considerations.

The impetus for discussing alternatives to IVF is the financial burden, increased peri- and neo-natal complications, rates of congenital and epigenetic abnormalities in the offspring,^[4] and ethical dilemmas often involved in IVF.  Couples experiencing infertility may be hesitant to pursue conventional IVF for these and other reasons, and this primer provides information on alternative methods that can be offered. Some of these methods need further development because they were abandoned for various reasons as discussed in this paper. Others are explored as potential solutions that need to be developed. As discussed in CLI’s IVF Primer, there can be negative health consequences of not fully diagnosing and correcting underlying health issues for both the pregnancy and the offspring.^[5] Therefore, we will present restorative and surgical treatments that seek to address the root causes of infertility, and explain the benefits that addressing this as a prerequisite can have on the success and long-term health of the parents and children.

The methods selected for inclusion in this primer encompass what is and could be offered in clinical practice, except for the use of herbal and Chinese medicine. Embryo adoption is also not covered. Both of these are more complex and require their own focus. Where relevant, ethical considerations – such as whether a method demands the creation of excess human embryos – are mentioned, though we do not explore in detailed religious views that have been more elegantly discussed elsewhere. The inclusion of a method in this primer should not be considered an endorsement.

Intrauterine Insemination (IUI)

IUI is often used in conventional fertility programs as a pre-requisite to IVF. The patient can try 3-6 attempts, and if unsuccessful, may then attempt IVF.

The process of IUI begins with procuring a semen sample from the man, typically encouraged to be collected by masturbation, and washing this with a gradient of culture medium so that it removes seminal plasma and concentrates the motile sperm.^[6] The sperm are then placed into a syringe and with the use of a catheter, deposited through the woman’s cervix into the uterus. The woman is typically prepared in some way so that the insemination is performed at the time of ovulation. This can be done by blood hormone and/or ultrasound monitoring of a natural cycle, or by combining the use of ovarian stimulation drugs to improve follicle development and trigger ovulation.

The benefit of IUI comes from bypassing the vagina and cervix and depositing the sperm closer to the site of fertilization. Vaginal and cervical factors are not often the cause of infertility, but mild male factor (male factor is when a man has a semen analysis below normal levels which is associated with a reduced ability to conceive) may be helped with IUI by transferring the sperm to be closer to the egg. Therefore, IUI would not be expected to be effective if uterine or tubal abnormalities or endometriosis exist because these problems are more related to egg health, egg/embryo transport, and embryo implantation. It also would not work if the man had severe male factor because the sperm are not sufficiently helped to cause fertilization, and IUI would not do anything to improve underlying health issues. IUI, however, would be especially useful for the following rare but specific reasons:

1. Retrograde ejaculation is when a neurological defect causes the sperm to be ejaculated into the bladder. This may be overcome by IUI because the man can collect his sperm-containing urine right after ejaculation and the sperm can be extracted, washed, and placed into the uterus.^[7]

2. Immune or inflammatory responses to sperm, called “antisperm antibodies,” can happen due to a prior testicular trauma, vasectomy/reversal, or other causes. With IUI, semen can be placed into a medium that immediately inactivates the antibodies before being washed and then placed into the uterus. The female partner can also have antibodies to her male partner’s sperm, and IUI could have a therapeutic benefit due to bypassing the cervix or shortening the time sperm are exposed to her immune system before fertilization can take place. Alternatively, either partner can have immune suppression therapy just prior to timed intercourse during the fertile period.^[8],[9]

3. Ovarian deficiencies may be helped with IUI, but effectiveness in such cases is more likely due to the ovarian stimulation procedure and not the intrauterine insemination itself. Prospective studies comparing the same ovarian stimulation procedures before both timed intercourse and IUI are needed to ascertain this.

4. Insufficient cervical mucus or dilation can in rare cases prevent sperm from making it past the cervix. This can be exacerbated by prior long-term use of hormonal contraception which has caused atrophy of the cervical cells.^[10]

Effectiveness of IUI will vary significantly based on the age of the woman and the reason for infertility, but on average, pregnancy rates are about 11% per attempt or just under 20% for patients using multiple attempts.^[11]

IUI does not present a threat to unborn human life unless it is done recklessly, leading to multiple pregnancy (twins, triplets, or more). For most religious patients, including (generally speaking) those of the Jewish or Islamic faith, IUI does not present a moral challenge, especially if it is the husband’s sperm that is used for the insemination and not donor sperm.^[12] IUI is considered in the Catholic Church to be under study and potentially licit under certain conditions,^[13] though some Catholic bioethicists and organizations object to its use on principle, considering it a replacement of the marital act.^[14],[15] The cost of IUI can range from $300 to $4,000 per cycle based on the amount of pre-testing performed and if stimulation drugs are employed.^[16]

Natural Cycle IVF

Natural Cycle IVF differs from conventional IVF by the lack of hormonal stimulation of ovarian follicle development prior to egg retrieval. Essentially, the woman’s cycle is tracked using serial ultrasound and/or blood hormone analysis, and just prior to her natural ovulation, she is brought in for aspiration of her follicle to retrieve an egg. A closely related procedure is called “minimal stimulation IVF,” where effort is made to limit the number of follicles prior to egg retrieval.^[17] The benefits of these procedures are savings on the cost of stimulation drugs, exerting less stress on the woman’s body, and minimizing the number of excess embryos and multiple pregnancies. Success rates for these procedures, however, are consistently below those of conventional IVF.^[18] Natural and minimal stimulation are more often proposed for women who have had multiple conventional IVF failures or have responded poorly to stimulation protocols.^[19] Since the higher doses of stimulatory gonadotropin drugs are not effective in this population, little or no stimulation seem to elicit an adequate response while being less costly and less invasive.^[20]

From an ethical perspective regarding threats to human life, natural cycle or minimal stimulation IVF reduces the creation of excess embryos leading to less embryo destruction. However, it is important to emphasize that effectiveness will be reduced. Conventional IVF became the gold standard in the fertility industry because it allows a greater probability of selecting viable or “higher quality” embryos, a result of having multiple embryos to choose from per cycle.

The cost of each natural cycle or minimal stimulation IVF attempt is less than conventional IVF because the patient saves money on stimulation drugs, but if multiple attempts are needed to achieve pregnancy and birth (as is likely), little or no cost savings will be realized.^[21] While more research is needed to prospectively compare the methods, current data indicate that on average, it takes 2-3 natural cycle IVF attempts to equal the effectiveness of one conventional IVF attempt.^[22] However, patient selection appears to be important, because women who respond to conventional IVF poorly may have improved embryo viability with a natural cycle, and natural cycle IVF can have reduced adverse perinatal outcomes.^[23]

Gamete Intrafallopian Transfer (GIFT)

During the early days of IVF in the U.S. in the mid to late 1990s, before we had the knowledge of how to adequately culture human embryos in vitro, an alternative procedure was available for women who had at least one healthy fallopian tube. The procedure, Gamete Intrafallopian Transfer (GIFT), involved ovarian stimulation and egg retrieval, similar to IVF, but on the day of egg retrieval, instead of fertilizing the eggs in vitro, 2-4 eggs were selected and transferred back into the fallopian tubes along with the husband’s sperm that had been prewashed. Both the retrieval and the transfer could be done during the same procedure with the woman able to go home the same day.

The American Society for Reproductive Medicine (ASRM) published statistics for 1996 showing that there were 2,879 GIFT procedures performed with a 29% live birth rate.^[24] That same year, there were 44,647 IVF retrievals reported with a live birth rate of 26%, so GIFT was more successful than IVF in this cohort, but the covariables were not controlled and patient selection could play a role. Success rates for IVF have since increased due to improved technical developments, but most of these improvements would also have applied to GIFT. Some improvements, however, are unique to the success of IVF—most importantly, the process of culturing the embryos for 5-6 days, causing them to prove their viability. This “survival of the fittest” process is thought to be a major reason for improvement in the success of IVF. Of course, once the embryos are formed, it also allows for pre-screening for undesired chromosomal and genetic traits, an additional purported benefit that would not be possible with GIFT. Additionally, if more severe male factor is involved in the infertility diagnosis, IVF allows for confirmation of fertilization and the application of intracytoplasmic sperm injection (ICSI) which will almost guarantee fertilization in even the worst cases. By contrast, when GIFT does not result in a positive pregnancy test, it is not known if failure was due to fertilization, embryo viability, or implantation.

From the perspective of respect for human life, the pre-screening and selection process of embryos usually involved in IVF are not considered ethical; therefore, GIFT would represent a more ethical solution, albeit at a lower chance of success at the present time. GIFT would also eliminate the creation of excess embryos and the subsequent problems with destruction or indefinite freezing, as long as the extra eggs were either frozen or discarded and not fertilized. Viability screening of the gametes instead of the embryos would also have fewer ethical challenges but improved development of technology and knowledge for this is needed.

Despite the strictest of critiques on the morality of assisted reproductive technology (ART) like IVF, the Catholic Church has allowed GIFT to be considered and discerned by individual couples as long as a few principles are applied.^[25] Though, as with IUI, some Catholic bioethicists believe it is always incompatible with the Church’s teaching, considering it a replacement of the marital act. Regardless, if used, sperm must be collected in a morally acceptable manner as outlined above for IUI, and the sperm and egg must not come in contact until they are placed into the body of the woman. This is accomplished by placing an air bubble between the sperm and egg inside the catheter and this barrier remains until the contents of the catheter are released into the fallopian tube. Development of better techniques for transferring the ovum into different sections of the fallopian tubes and bypassing the diseased or missing area is needed. This option would be considered moral and has been named “lower tubal ovum transfer.”^[26] Unfortunately, the challenge of finding a fertility center that does these procedures today is a significant reason they are not applied and, therefore, there are very few practitioners trained and experienced to conduct them.

The cost of GIFT is difficult to determine because of its lack of widespread use today. Preparation, stimulation, and retrieval would be similar to conventional IVF, but there would be no embryo culture and micromanipulation procedures, and freezing oocytes would be like the cost of freezing embryos. Therefore, overall, the cost of GIFT should be slightly less than IVF. Potentially, the GIFT surgical procedure could be done in tandem with diagnostic laparoscopy (surgery that is minimally invasive, using a tool which visualizes the abdominal cavity through a small incision, allowing inspection and diagnosis of anatomic disease), which ideally should be part of a pre-IVF work-up anyway.

In conclusion, the primary benefit of GIFT over conventional IVF is fewer ethical problems and a slightly lower cost, but at a potentially lower success rate unless the science of gamete health and selection are further developed.

Surgery for PCOS, Fallopian Tube Pathology, and Endometriosis

Polycystic ovary syndrome (PCOS, a form of ovulatory dysfunction), fallopian tube pathology, and endometriosis are three of the leading causes of female infertility. Couples seeking ART for infertility are found to have ovulatory dysfunction 13.9% of the time, tubal factor 10.2%, and endometriosis 6.3%.^[27] But this is not the whole picture of their prevalence in the female population, as ART, and specifically IVF, is not the only way to treat these causes. Surgery is another option that may help restore fertility, so these CDC statistics do not capture the true prevalence of the disease. Furthermore, PCOS for example, can be improved through lifestyle and medication. Costs and third-party reimbursement are other factors involved in treatment decisions. We will attempt to address these complicated issues in each section below.

Surgical and Medical Options for Polycystic Ovary Syndrome

PCOS is one of the most common endocrine (hormone-related) disorders in women of reproductive age, with an estimated prevalence of roughly 9–18%.^[28] It is a metabolic and hormonal condition related to insulin resistance or diabetes, characterized by other health issues such as sleep apnea, high cholesterol, endometrial cancer,^[29]  vitamin D and other nutrient deficiencies,^[30] easy weight gain,^[31] and hypothyroidism.^[32] It is most notorious for causing irregular cycles, excess hair growth due to elevated androgens, and infertility.^[33]

When a personalized approach is taken and underlying health issues are targeted with treatment, PCOS patients can experience improvements in fertility. Primary treatment should focus on lifestyle changes, including a healthy diet, exercise, weight loss, and supplementation (i.e., myoinositol, vitamins) to increase insulin sensitivity.^[34] Depending on the severity and subtype of PCOS, medications used for treating diabetes, such as pioglitazone and metformin, have been shown to be effective.^[35]  Newer drugs are also being evaluated.^[36]

When circumventing the medical issues of PCOS with IVF, complications are more likely to occur. According to one study, women with PCOS were 13.9 times more likely to experience Ovarian Hyperstimulation Syndrome (OHSS).^[37] OHSS causes vascular permeability and fluid build-up in the abdomen. It is painful, and more serious cases can lead to fluid in the lungs, kidney dysfunction, blood clots, and death.^[38] If pregnancy is achieved, women with PCOS are also more likely to experience complications like miscarriage and pre-term birth.^[39]

For women with PCOS who desire pregnancy, regardless of whether they eventually pursue IVF, letrozole or clomiphene is considered first line treatment for ovulation induction followed by natural conception or IUI.^[40] But if medications and lifestyle changes are not working, the patient can be offered surgery, and most studies suggest that this should be done before proceeding to IVF.^[41] Surgery for PCOS includes ovarian wedge resection and laparoscopic ovarian drilling.

Ovarian wedge resection was one of the first treatments used to induce ovulation in women with PCOS dating back to 1935.^[42] It is performed by cutting out a wedge-shaped segment of the ovary and then closing that with sutures. How this is done can impact the amount of ovarian and tubal adhesions that form which would be a subsequent cause of infertility. Laparoscopic ovarian drilling is an alternative to wedge resection which uses an insulated needle cautery or laser to create approximately 5-10 perforations in each ovary, depending on the size.^[43] These treatments can lead to reduced androgen levels, normalization of the menstrual cycle, and ovulation, thus also leading to improved fertility. The mechanism for how this works is not fully understood but the trauma and subsequent wound healing that occurs appears to reset local cellular mechanisms and restore normal pituitary-ovarian endocrine feedback.^[44]

Of particular interest is that we were unable to find any studies directly comparing ovarian drilling to IVF for fertility outcomes. Despite the recommendations that surgery should be done before proceeding to IVF, it is not clear that this is what routinely happens in practice.^[45] More recent studies are comparing ovarian drilling plus IVF to IVF without ovarian drilling, and they have found that adding ovarian drilling before IVF improves outcomes.^[46]

Fallopian Tube Surgery

There are generally two categories of tubal pathology, with disease either affecting the proximal or distal part of the fallopian tube. Proximal blockages, those that are closest to the uterus, are often quite straightforward to treat with selective hysterosalpingography (SHSG). Selective HSG with tubal cannulation is a quick, minimally invasive procedure that is both diagnostic and therapeutic. The procedure involves a device which is inserted through the uterus into the tube, measures the pressure to detect even mild obstructions, and, if occluded, a gentle wire can be used to open the tube through the device.^[47],[48]

Partial obstructions are not uncommon, and they are missed by regular HSGs. Studies report technical success rates of 70% to 100% for SHSG with tubal catheterization/cannulation, with pregnancy rates averaging around 30%, and ranging from 20% to 60% depending on the patient’s condition and procedure specifics.^{[49],[50],[51]} In addition, SHSG can be combined with other procedures with added fertility benefits (such as endometriosis excision).

Distal tubal surgery, including procedures like fimbrioplasty, addresses blockage or damage at the ends of the fallopian tubes, near the ovaries, where the tube needs to capture the egg via hairlike structures. Fimbrioplasty entails correcting damage of these hairlike structures called fimbria and unblocking these distal occlusions, such as by clearing out scar tissue closing off the end of the tube, typically with robotic assistance. Pregnancy success after distal tubal surgery varies widely based on severity of the damage: approximately 9% for severe tubal damage, and up to 60–70% for mild cases.^[52] Fimbrioplasty specifically reports pregnancy rates of about 50%.^[53] Of note, tubal reversal surgery, which is the repair of the fallopian tubes in women who have had prior tubal ligation (severing and suturing the tubes for purposes of sterilization), has been shown to achieve higher pregnancy rates than IVF for those women without a history of infertility other than after their sterilization procedure.^[54]

With the advent of IVF, tubal surgery to correct obstructed fallopian tubes became rarer.^[55] This occurred due to Reproductive Endocrinology and Infertility (REI) training programs focusing on IVF procedures over corrective surgical procedures.^[56] This is evidenced by the tubal surgery minimum training requirements in the fellowship program for board certification by the American Board of OBGYNs. Specifically, in the Accreditation Council for Graduate Medical Education procedural volume guidelines for OB-GYNs, there is no specific requirement for tubal surgery but there is a need to perform at least 100 IVF retrievals.^[57] As the skills to perform this surgery are rare and additional studies are not being performed, some are sounding the alarm that training the next generation in this surgery is imperative.^[58]

It is plausible that economic factors also favor IVF in many fertility clinics, influencing the recommended treatments. From the patient’s perspective, tubal surgery can offer a cheaper option with lower cost than repeat IVF cycles, and the ability to be used for subsequent pregnancies.

Surgery for Endometriosis

Endometriosis is a condition in which the cells that normally line the inside of the uterus grow outside the uterine cavity. It is a progressive disease because it can cause organ damage and adhesions over time which subsequently may cause tubal blockage or prevent release of an egg. Endometriosis grows and spreads like cancer and is related to immune system dysfunction. Women with this condition commonly report a history of cyclic pelvic pain, pain with their periods, and pain with sex. In the United States, it takes on average 0.3-12 years to make the diagnosis of endometriosis from onset of symptoms, which can result in disease progression before any treatment is even attempted.^[59]

In addition to the physical impairments and pain, endometriosis may initiate inflammation resulting in an impact on hormones and causing oxidative stress, leading to egg and sperm damage, impaired embryo quality, and decreased ability for the embryo to implant.^[60]

Surgery is necessary for the diagnosis and definitive treatment of endometriosis, which requires excision of the endometrial lesions.^[61] Burning the lesions with ablation sometimes results in recurrence and the need for repeat surgeries.^[62],[63] In contrast, complete excision, which seeks to remove all the endometrial lesions and prevent adhesions, results in a recurrence rate of only 2.5%.^[64]

The most current ASRM guidance document on endometriosis, published in 2012, recommends surgery for patients with late-stage endometriosis, but not for earlier stage disease, before proceeding to IVF.^[65]

Proper surgical treatment has been shown to improve not only pain but also fertility. Proper surgery includes detailed assessment and identification of all appearances by a trained expert, multidisciplinary care, and excising the disease in its entirety anywhere in the abdominal or pelvic cavity.^[66] This is very similar to oncological (cancer) surgery in its approach.

There is a lack of standardization^[67] for the diagnosis of endometriosis and an absence of procedural requirements of OB-GYN residents for endometriosis surgery.^[68] However, even with these limitations, excision surgery for endometriosis is continuing to develop, building on data published 20 years ago showing more success with pregnancy after failed IVF attempts.^[69]

Restorative Reproductive Medicine (RRM)

To address rising rates of infertility, it is critical for women and men, including medical professionals, to understand the way the reproductive system is designed to function so couples may learn to observe the narrow window of time when they may be fertile and identify factors that can affect their fertility. Physiologically, healthy men are almost always fertile, because they produce sperm on a daily basis. However, healthy women are not able to conceive at most times. Since women only ovulate one time each cycle and the ovum or the egg will only survive for up to 12 to 24 hours after it is released, fertilization can only occur during that 24-hour window of time if sperm are present. Although fertilization can only occur in that 24-hour period, the window of time when a couple may be fertile spans from 5-6 days prior to ovulation up to one day after ovulation, depending on the presence of estrogenic cervical mucus fluid secretions, one of three observable signs or biomarkers that women can learn to track to identify her fertile window. Cervical fluid or mucus produced under the influence of estradiol, indicating fertility, allows for the support and survival of sperm for up to 5-6 days prior to ovulation. Based on this science of reproductive physiology, modern natural or fertility awareness-based methods (FABMs) have been developed to teach women to observe, chart, and interpret specific biomarkers or algorithms to identify when she may be fertile or infertile.^[70]

These natural methods empower women by emphasizing the importance of understanding the female cycle as a part of their overall health. There are six general types of FABMs based on the biomarkers (cervical fluid, basal body temperature, and urinary hormones) and/or fertility indicators used to identify ovulation and the fertile window.^[71] These include: cervical fluid (mucus-only) methods, calendar-based (cycle length-based) methods, urinary hormone methods, basal body temperature methods,  symptothermal methods, and symptohormonal methods. While all can be used by couples seeking to prevent pregnancy, some are better suited for couples trying to achieve pregnancy, even those experiencing subfertility or suffering from infertility. When women learn to chart their biomarkers, this can aid them in monitoring their health and fertility, because, as ACOG affirms, the female cycle can serve as the fifth vital sign.^[72] And when medical professionals are trained to interpret FABM charts, they can use it as a tool to aid in the diagnosis and management of common reproductive health concerns, including infertility.

The first step in addressing infertility is to teach women to chart the signs of their cycle to identify possible ovulation, ideally using a cervical fluid or mucus-based method, including the Billings Ovulation Method, Creighton Model, symptothermal method, Marquette Model, FEMM (Fertility Education and Medical Management), or NeoFertility.

NaPro Technology, which was developed in conjunction with the Creighton Model, as well as FEMM and NeoFertility, are discussed more fully below as each has developed medical protocols designed to identify the root causes of reproductive and hormonal health issues and utilize treatments designed to restore these systems to the way they are biologically designed to function.

Natural Procreative Technology, or “NaPro,” was developed by the OB-GYN Dr. Thomas Hilgers and colleagues at Creighton University in the 1970s. Using NaPro, Creighton-trained medical consultants can use information ascertained from Creighton charts in conjunction with appropriate medications and surgical procedures to evaluate and treat infertility, endometriosis, and other reproductive problems.^[73] Although Creighton Model charting is very detailed and requires training for both the instructor and couple, its universal and standard recording system allows a Creighton-trained health professional to better understand what symptoms women are describing, so root causes of infertility and other underlying reproductive health issues can be identified. Since some patterns of mucus may suggest certain pathologies, NaPro Technology employs a set of evaluation and treatment protocols based on the woman’s chart used in conjunction with targeted hormonal laboratory testing, ultrasound imaging, and treatment.^[74],[75] There are two tracks of training with NaPro technology encompassing both medical management and surgical methodology.

There have been at least three large studies of NaPro Technology demonstrating its effectiveness in the treatment of infertility. The key outcome of these studies was not just pregnancies, which is often the measure of success for artificial or assisted reproductive technologies, but live births. Since pregnancies can result in miscarriages or other undesired outcomes, live births are important to measure, because having a baby is what matters most to patients struggling with infertility and seeking assistance.

A 2008 study of over 1,000 couples in Ireland by Stanford et al. reported that before undergoing NaPro evaluation, almost half of the couples (47.2%) had no explanation as to why they could not conceive and 11.6% had no clear explanation for why they were consistently miscarrying.^[76] After NaPro evaluation, many patients had a better understanding of the causes of their infertility or recurrent miscarriages.^[77] Patients received new diagnoses of conditions that were often treatable once the diagnoses were made. For example, over 86% of patients had suboptimal luteal progesterone and over 63% of patients had suboptimal luteal estrogen. Furthermore, in this study population, where the average woman was of advanced maternal age (35.8 years) and they had been trying to conceive for more than five years, there was a 25.5% crude percentage of live births following evaluation and two-year treatment with NaPro Technology. A follow-up study in 2012 by Tham et al. found a 38% crude percentage live birth rate with up to two years of treatment.^[78] This was with a population of older Canadian women who were trying to conceive for more than 3-5 years. In a 2021 study by Carpentier et al, the cumulative (crude) live birth rate at two years was 29% overall and higher in women with a normal BMI (40%) or who were less than 35 years old (34%).^[79]

Therefore, with training in medical and/or surgical NaPro Technology, family physicians or obstetricians may have the ability to treat infertility with live birth rates comparable to assisted reproductive technologies, without the ethical concerns associated with ART (and in particular, IVF).

Fertility Education and Medical Management, or “FEMM,” provides women with information about their bodies to help them manage their health and fertility from puberty to menopause. FEMM’s approach recognizes that ovulation is a sign of health, and women can learn to chart the signs of their cycle to monitor the ovarian cycle as a vital sign. FEMM collaborates with the Reproductive Health Research Institute (RHRI) to develop protocols, medical research, and training for healthcare workers. RHRI’s “research-based treatment can range from immunological support to pharmacological interventions, and includes emphasis on diet, exercise, and lifestyle changes.”^[80] FEMM medical professionals “offer comprehensive physical and lab workups to diagnose and treat the root cause of health conditions, rather than simply managing symptoms,” with a particular focus on addressing hormonal and metabolic health issues.^[81]

Through FEMM charting, women recognize the patterns of four major hormones: estrogen, progesterone, follicular stimulating hormone, and luteinizing hormone. Each hormone must reach certain levels at certain points of the female cycle to trigger ovulation and other cycle events necessary for achieving and maintaining pregnancy. FEMM enables women to monitor hormonal biomarkers and cycle patterns with a free, intuitive app, providing them and their FEMM medical professional with valuable information to guide the diagnosis and treatment of underlying causes of infertility like hyperprolactinemia, hypothyroidism, hypoestrogenic insulin insensitivity, and other reproductive health concerns.^[82] Authors affiliated with RHRI have also published on the topic of FEMM, including materials such as a set of medical guidelines for training purposes in addition to clinical case studies on the effectiveness of FEMM and FABM more generally.^[83]

NeoFertility is a groundbreaking approach within the field of RRM, offering a comprehensive, science-based alternative to conventional fertility treatments. Developed in 2016 by Dr. Phil Boyle, a family physician in Ireland, NeoFertility integrates advanced cycle charting with targeted medical diagnostics, hormonal support, and lifestyle interventions to uncover and address the root causes of infertility. Rather than bypassing the natural reproductive process, NeoFertility seeks to restore and optimize it, helping couples to achieve pregnancy through intercourse even after failing to have a live birth from IVF.^[84]

NeoFertility’s approach includes female cycle charting using an app that doubles as a medical record, diet and lifestyle changes, diagnosing both female and male factors of infertility, and pharmacologic and surgical treatment of underlying diagnoses. Dr. Boyle demonstrated success in achieving healthy singleton pregnancies using RRM after failed IVF treatment. Live birth outcomes were comparable to those achieved through another cycle of IVF after the initial failed cycle. These patients were treated prior to the formal establishment of NeoFertility, but their outcomes demonstrate the effectiveness of this approach.^[85] More recent studies published by his group have reported effectiveness using NeoFertility for infertility and recurrent pregnancy loss.^{[86],[87],[88]}

A Note About Ovarian Stimulation

Both conventional and restorative treatments employ the use of ovarian stimulation, which can lead to improvements in ovarian function. Other alternatives such as IUI, GIFT, Natural Cycle and Minimal stimulation IVF also share the use of hormonal protocols, but there are subtle differences in the dosages and goals of each of the approaches and the number of follicles recruited. Pre-IVF protocols are milder, with a goal of only 1-2 follicles, whereas IVF requires ovarian function to be completely shut down and driven exogenously, typically leading to a greater number of follicles recruited. Restorative Reproductive Medicine protocols also have a goal of only 1-2 follicles, but cycles of ovarian stimulation may persist for longer while simultaneously treating multiple other underlying health factors.

Examples of RRM Alternatives to IVF that Need Development

A Cure for Recalcitrant Blocked or Missing Fallopian Tubes – Ovarian Tissue Transposition

As early as 1901, an American surgeon named Robert Morris reported on 12 cases of ovarian transplantation, three of which were transplants of the woman’s own ovary to a different location.^[89] This work spawned the knowledge that fertilization and early embryo development could proceed in the uterus rather than only in the fallopian tubes. Morris’s work influenced another surgeon named Estes who reported on the transplantation of ovarian tissue into the uterus^[90] and it laid the foundation for the modern treatment of fertility preservation (the removal, cryopreservation, and re-implantation of ovarian tissue harvested prior to cancer treatment.^[91] The “Estes Procedure,” as it came to be known, was used for patients with infertility due to fallopian tube pathology throughout the mid-1900s.^[92] In their 1979 article published in Fertility and Sterility, one year after the successful birth of Louise Brown by IVF, Beyth and Polishuk concluded that the Estes operation was no longer warranted in modern gynecology, even though their own literature review demonstrated an average pregnancy rate across multiple studies of 10.4% and IVF at the time was less than 1%.^[93] Furthermore, their own results were 0% out of 27 patients, the worst out of all other cited studies. Despite their conclusions, others continued to publish case studies demonstrating the value of this surgical approach.^[94]

Given the incredible developments in micro and robotic surgery since the 1970s, how much more successful could we become with the surgical approach? Practitioners of ART can claim that IVF is more cost effective for achieving pregnancy, but this is not a fair comparison given the lack of development of surgical approaches, and it also does not take into consideration the cost of perinatal complications due to IVF.^[95] Fully informed of this option, more patients may choose restoration of their fertility, especially with the knowledge that once corrected, surgical patients may go on to conceive multiple times.

A Cure for Azoospermia – Surgical, Medical, and Regenerative Intervention for Severe Male Factor

A diagnosis of azoospermia can be a traumatic event for the couple and a difficult psychological hurdle for a man to overcome. Azoospermia is diagnosed when there is not a single sperm in the man’s ejaculate, the cause of which can be genetic, congenital, or acquired.^[96] The acquired form can be further differentiated as obstructive, such as an anatomic block preventing sperm from exiting the body, or non-obstructive, such as testicular failure caused by exposure to cytotoxic chemicals such as through chemotherapy. Testicular failure can also be caused by underlying health issues and poor lifestyle choices.^[97]

Since the development of ICSI in the mid-1990s, the approach for azoospermia has been to surgically retrieve sperm directly from testicular structures and inject them into eggs retrieved during IVF.^[98] This shifts the “treatment burden” to the woman and results in a higher incidence of adverse perinatal outcomes.^[99] While ICSI can be remarkably effective using sperm that has little to no natural fertilization potential, each subsequent birth would require another procedure such as an embryo thaw and transfer or IVF/ICSI cycle.^[100]

In some cases, obstructive azoospermia can be overcome by diagnosing the anatomic position of the block with imaging techniques and then correcting this surgically.^[101] But since the application of ICSI, very little emphasis has been put on training programs and on the development of techniques or products to accomplish this. For men who have testicular failure, the most therapeutic and ethical approach would be to first investigate and determine why he has this issue. Often multiple reasons are the culprit, including infection, trauma, nutrition, or endocrine-related causes,^[102] and addressing these problems followed by the use of stimulatory drugs could result in improvement.^[103]

Other times, exposure to cytotoxic treatment drugs or environmental chemicals are the primary cause. Inside the testes are microscopic germ cells that morph into sperm in defined stages. Germ cells are essentially stem cells that normally replenish themselves and provide a constant supply of sperm precursors for men throughout their lives.^[104] Adult stem cell therapy for azoospermia caused by exposure to cytotoxic treatment drugs or environment chemicals, which is taking undeveloped stem cells from other locations of the body (such as bone marrow) and implanting them into the testes, could reseed the stem cell pool and re-initiate spermatogenesis.^[105]

Emphasizing the identification and treatment of the underlying causes of infertility may spark a renewed emphasis on surgical and reconstructive approaches. Medical device companies would then find more financially sound reasons to develop products for opening and repairing blocked ducts of the male reproductive system, like they have for the cardiovascular system. There is already excitement in the field of regenerative stem cells, but a therapy specifically for male fertility will not be pursued if the field considers anything other than IVF/ICSI a futile endeavor.

Cost Considerations for IVF vs. Medical and Surgical Restorative Options

A cost comparison of IVF and RRM is extremely complicated and deserves its own discussion. Some key points can be made, however. The IVF field is a multi-billion-dollar industry which includes about 1,000 active reproductive endocrinologists.^[106] In 2022, there were 457 clinics conducting 435,426 cycles on 251,542 patients.^[107] Using current recommendations for staffing, this would require a minimum of 5,800 embryologists^[108] and at least the same number of nursing and administrative staff. The main medical association supporting the industry boasts nearly 8,000 members.^[109] The cost to start an IVF laboratory can be between $500,000-$1,000,000^[110] and there are a huge number of medical device and consumable supply companies to support the industry, a market estimated to be worth $3.3 billion.^[111] This does not include the additional pharmaceutical companies supplying the industry. In order to keep up with such costs and make a profit, the conventional fertility industry charges $12,400-$25,000 per IVF cycle,^[112] which is mostly paid out of pocket by patients. Furthermore, there is an additional market for egg freezing and same-sex partner reproduction that is essentially an elective, boutique type of healthcare.

Comparing the costs of RRM to IVF is not exactly apples to apples and presents many challenges. RRM treats infertility as a chronic disease. It requires both the man and the woman to have multiple sustained diagnostic medical and surgical interventions that are similar to a combination of primary care and specialty OB-GYN or urology care. In addition, infertility patients need significant time investment, which requires adequate staff to support. There is currently not a good system for coding and medical reimbursement for patients and providers. To combat this, RRM clinical programs are beginning to charge a single fee for various packages,^[113] but this cost is significantly lower than IVF. For example, one clinic’s fee covering the most services includes an intake visit, 4-5 follow-ups, baseline testing and ultrasounds, eight hours with a health coach, early pregnancy management, and more for a total of $9,000.^[114] At another clinic, for surgical intervention of endometriosis, many patients may need to travel long distances and at least initially pay out of pocket with the possibility of reimbursement if submitting to insurance after the fact.^[115]

Unfortunately, the number of medical professionals who provide RRM care is small. There is a medical organization representing the field (International Institute for Restorative Reproductive Medicine, or IIRRM^[116]) which defines the discipline and provides training, publishes research, and is developing a certification process for professionals. What is most needed for the RRM field to grow is a grant process that would support research, training, and start-up costs. Such a grant process might be fashioned after the combined NICHD/Federal Fellowship in Reproductive Endocrinology program^[117] that is currently supporting the IVF industry. Less bias or a specific RRM carve-out in the NICHD/Fertility and Infertility Branch^[118] research grant selection process is needed to support more RRM projects. Funding both applied and translational projects would go a long way to moving RRM towards equity within the reproductive medicine field. It would seem prudent that we at least provide as much funding for RRM research as we do for contraception research, which is quite significant.^[119]

Conclusions

The foregoing information demonstrates that there are several options for treating infertility currently available in addition to conventional IVF, and there are other methods that could be resurrected, developed, or researched. Many of these options are less costly and more therapeutic, indicating that they should at least be attempted prior to more invasive ART procedures.

Decisions regarding which treatments receive priority for the taxpayer should not solely be in the hands of the individuals and organizations who are the primary beneficiaries. Regardless of one’s religious views, financial, bioethical, social, and legal issues arise from assisted reproductive technologies, and it is prudent to consider other methods first. Practice documents and other published research recommend this reasonable, stepwise approach to treatment, but financial and professional bias is likely playing a role in how solutions are presented to patients.

Importantly, surgical and restorative procedures have an additional benefit to the patient in that they correct underlying issues that would then allow repeat conceptions. Even when restorative methods do not result in the birth of a child, however, they may still impact the patient through reduction of painful symptoms and/or improved health. Patients with infertility deserve treatment and care that is not unreasonably financially burdensome. But these resources may need to be subject to qualifications such as age, relationship status, and health, with the potential children’s wellbeing considered foremost. Importantly, patients also deserve treatment options that do not present ethical concerns regarding the treatment of human embryos. Common sense would dictate that restorative methods should be pre-requisites to ART when they are feasible despite IVF being the solution predominantly offered by the fertility industry as the first approach, especially when they are also beneficiaries of the pro-IVF position.

Dr. Craig Turczynski completed a B.S in Animal Science at Iowa State University, a Ph.D. in Physiology of Reproduction at Texas A&M University, and a post-doctoral fellowship in reproductive endocrinology at the Women’s Research Institute in Wichita, KS. He became Assistant Professor of ObGyn at Louisiana State University Medical School-Shreveport where he developed and directed their clinical hormone, andrology, and IVF laboratories. After seven years he left the IVF field due to conflicts with the aggressive, life-denying use of the technology and went to work in the medical device industry. Since 2018, he has been rekindling his clinical science career in the field of restorative reproductive medicine by working with leaders in this developing field.

Dr. Marguerite Duane, a board-certified family physician, is co-founder and Executive Director of FACTS about Fertility, an organization dedicated to educating medical professionals and students about the science supporting fertility awareness-based methods (FABMs). She serves as an Adjunct Associate Professor at Georgetown University and as the Director of the Center for Fertility Awareness Based Education and Research at Duquesne University College of Osteopathic Medicine. Dr. Duane cares for patients via a direct primary care house-calls based practice, MD for Life. She has served on the board of the American Academy of Family Physicians and the Family Medicine Education Consortium. Dr. Duane completed her Family Medicine residency at Lancaster General Hospital. She also earned a Masters of Science in Public Health at the University of Utah, and a Masters of Health Administration at Cornell University.

Dr. Naomi Whittaker is a board-certified OBGYN, certified Creighton Model FertilityCare Instructor, and restorative reproductive medicine surgeon specializing in natural fertility and has received the Focused Practice Designation in Minimally Invasive Gynecologic Surgery by ABOG. She is a 2013 graduate of Creighton University School of Medicine, Omaha, Nebraska. She completed a residency in obstetrics and gynecology at University of Illinois College of Medicine-Peoria in 2017 and is fellowship trained in medical and surgical NaProTechnology. She is Physician Lead at UPMC Divine Mercy in Pennsylvania, which provides comprehensive gynecologic, natural fertility, as well as obstetric care. She also founded RRMacademy.org.

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[20] Ibid.

[21] von Wolff M. The role of Natural Cycle IVF in assisted reproduction. Best Pract Res Clin Endocrinol Metab. 2019 Feb;33(1):35-45, https://pubmed.ncbi.nlm.nih.gov/30473207/.

[22] Ibid.

[23] Ibid.

[24] Assisted reproductive technology in the United States: 1996 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril. 1999 May;71(5):798-807, https://pubmed.ncbi.nlm.nih.gov/10231036/.

[25] John M. Haas, “Begotten Not Made: A Catholic View of Reproductive Technology,” USCCB, accessed April 8, 2025, https://www.usccb.org/issues-and-action/human-life-and-dignity/reproductive-technology/begotten-not-made-a-catholic-view-of-reproductive-technology.

[26] Ibid.

[27] CDC, “National ART Summary,” CDC: Assisted Reproductive Technology (ART), December 10, 2024, https://www.cdc.gov/art/php/national-summary/index.html.

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[31] Stephanie Watson, “Polycystic Ovary Syndrome (PCOS) and Weight Gain,” WebMD, February 9, 2025, https://www.webmd.com/women/polycystic-ovary-syndrome-pcos-and-weight-gain.

[32] Hu X, Chen Y, Shen Y, Zhou S, Fei W, Yang Y, Que H. Correlation between Hashimoto’s thyroiditis and polycystic ovary syndrome: A systematic review and meta-analysis. Front Endocrinol (Lausanne). 2022 Oct 31;13:1025267, https://pubmed.ncbi.nlm.nih.gov/36387911/.

[33] “Polycystic Ovary Syndrome,” World Health Organization, February 7, 2025, https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome.

[34] Collée, J., Mawet, M., Tebache, L., Nisolle, M., & Brichant, G. (2021). Polycystic ovarian syndrome and infertility: overview and insights of the putative treatments. Gynecological Endocrinology, 37(10), 869–874. https://doi.org/10.1080/09513590.2021.1958310.

[35] Attia GM, Almouteri MM, Alnakhli FT. Role of Metformin in Polycystic Ovary Syndrome (PCOS)-Related Infertility. Cureus. 2023 Aug 31;15(8):e44493, https://pmc.ncbi.nlm.nih.gov/articles/PMC10544455/.

[36] See, for ex., Porth R et al. The Role of Sodium-Glucose Cotransporter-2 Inhibitors in the Treatment of Polycystic Ovary Syndrome: A Review. J Clin Med. 2024 Feb 13;13(4):1056, https://pubmed.ncbi.nlm.nih.gov/38398368/#:~:text=In%20a%20limited%20number%20of,indices%20in%20women%20with%20PCOS; Szczesnowicz A et al. Do GLP-1 Analogs Have a Place in the Treatment of PCOS? New Insights and Promising Therapies. J Clin Med. 2023 Sep 12;12(18):5915, https://pubmed.ncbi.nlm.nih.gov/37762856/.

[37] Alhilali MJ et al. Polycystic Ovary Syndrome Develops the Complications of Assisted Reproductive Technologies. Arch Razi Inst. 2022 Aug 31;77(4):1459-1464, https://pmc.ncbi.nlm.nih.gov/articles/PMC9985778/.

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[44] Ibid.; Collée et al (2021).

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[55] Bosteels et al. (2010).

[56] Watrelot A, Chauvin G (2011).

[57] “Subspeciality Procedural Volume Guidelines: Review Committee for Obstetrics and Gynecology” (ACGME, 2024), https://www.acgme.org/globalassets/pfassets/programresources/subspecialtyproceduralvolumeguidelines.pdf

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[64] Yeung et al. (2025).

[65] Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: a committee opinion. Fertil Steril. 2012 Sep;98(3):591-8, https://www.asrm.org/globalassets/_asrm/practice-guidance/practice-guidelines/pdf/endometriosis_and_infertility.pdf.

[66] Yeung et al. (2011).

[67] Whittaker, N. (2024). Diagnosis and Treatment of Four Rare Cancers: Case Series Using Systematic Mapping and Near-Contact Surgical Techniques. Virtual poster presented at the AAGL 2024 Global Congress, November 16-19, New Orleans.

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[72] Committee Opinion No. 651: Menstruation in Girls and Adolescents. Obstetrics & Gynecology 126(6):p e143-e146, December 2015, https://journals.lww.com/greenjournal/fulltext/2015/12000/committee_opinion_no__651__menstruation_in_girls.59.aspx.

[73] Brooke E. Jemelka, David W. Parker, and Renee Mirkes, “NaProTECHNOLOGY and Conscientious OB/GYN Medicine,” AMA Journal of Ethics 15, no. 3 (March 1, 2013): 213–19, https://doi.org/10.1001/virtualmentor.2013.15.3.stas1-1303.

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[77] Ibid., Table 2.

[78] Tham E, Schliep K, Stanford J. Natural procreative technology for infertility and recurrent miscarriage: outcomes in a Canadian family practice. Can Fam Physician. 2012 May;58(5):e267-74, https://pubmed.ncbi.nlm.nih.gov/22734170/.

[79] Stanford JB, Carpentier PA, Meier BL, Rollo M, Tingey B. Restorative reproductive medicine for infertility in two family medicine clinics in New England, an observational study. BMC Pregnancy Childbirth. 2021 Jul 7;21(1):495, https://pubmed.ncbi.nlm.nih.gov/34233646/.

[80] “Medical Protocols,” Reproductive Health Research Institute, accessed April 11, 2025, https://rhrinstitute.org/medical-protocols/.

[81] “About Us,” FEMM Health, accessed April 11, 2025, https://femmhealth.org/about-us/.

[82] Macharia, Sr Juliet, et al. Effectiveness of Femm Approach in Managing Women with Subfertility in Mwanza, Tanzania. East African Scholars Journal of Medical Sciences. 2024, July;7(7): 321-23, https://femmhealth.org/wp-content/uploads/2024/07/DOC-20240726-WA0003-1.pdf.

[83] Vigil P, Lyon C, Flores B, Rioseco H, Serrano F. Ovulation, A Sign of Health. The Linacre Quarterly. 2017;84(4):343-355, https://journals.sagepub.com/doi/10.1080/00243639.2017.1394053; Portales MDPV, et al. Reproductive Health Research Institute: Guidelines. 9th ed. Santiago: Asociación Instituto de Investigación en Medicina Reproductiva; (2019); Macharia, Sr Juliet, et al. Effectiveness of Femm Approach in Managing Women with Subfertility in Mwanza, Tanzania. East African Scholars Journal of Medical Sciences. 2024, July;7(7): 321-23, https://femmhealth.org/wp-content/uploads/2024/07/DOC-20240726-WA0003-1.pdf.

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[85] Ibid.

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[114] Ibid.

[115]  “Financial Investment,” Restore Center for Endometriosis, accessed June 4, 2025, https://www.restoreendo.com/paying-for-treatment.

[116] “About,” International Institute for Restorative Reproductive Medicine, accessed June 4, 2025, https://iirrm.org/about/.

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[118] “Fertility and Infertility Branch (FIB),” NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development, January 31, 2025, http://www.nichd.nih.gov/about/org/der/branches/fib.

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