Successful pregnancy with restorative reproductive medicine after 16 years of infertility, three recurrent miscarriages, and eight unsuccessful embryo transfers with in vitro fertilization/intracytoplasmic sperm injection: a case report

Involuntary childlessness affects 1 couple in every 6. It is a common problem and can result in years of expensive investigations and treatment. Many couples choose in vitro fertilization (IVF) to try to solve their infertility. In our practice, we use a strategy of restorative reproductive medicine (RRM) to investigate and treat subfertility [1, 2]. We ask the women/couples to learn to identify the day of presumed ovulation using a combination of cervical mucus, a rise in basal body temperature, and urinary luteinizing hormone (LH) assessment [3]. In our experience, this is best achieved with the support of a specially trained fertility advisor/teacher. Our couples typically need at least three sessions of specific instruction with additional ongoing support from their teacher. They usually record their fertility chart with our charting app at www.​ChartNeo.​com.

Using key information from the fertility chart, we assess the quality of ovulation initially on the basis of measuring the maximum surge of progesterone and estradiol, 7 days after presumed ovulation, and later confirmed by ultrasound. This is a significant departure from the typical day 21 progesterone blood test. Clinically, we find that day 21 progesterone testing is a crude assessment, with minimal benefit, because the actual day of ovulation can occur at or after day 21 in a substantial number of cycles [4]. In addition, simply using a threshold value for ovulation does not necessarily indicate optimized follicular function [5, 6]. Using our new approach, we ask two key questions: First, do you have optimal progesterone and estradiol 6–9 days after presumed ovulation? We use higher values and insist that progesterone must exceed 60 nmol/l (19 ng/ml) and estradiol exceed 400 pmol/l (109 pg/ml) for a healthy or optimal ovulation event. Blood levels below this range are considered suboptimal with a higher likelihood of subfertility (infertility and miscarriage). The second question we ask is: Have you had proven follicle rupture by ultrasound? This is necessary because we often see a lack of follicular rupture in subfertile patients [7]. See Table 1.

This case demonstrates the chronic nature of subfertility that requires multiple and sustained interventions over several cycles to restore optimal reproductive function. Ideally RRM treatment should be considered prior to IVF, but it may also be effective after years of infertility and repeated unsuccessful embryo transfers. We hope that this case may encourage doctors working with subfertility to consider additional investigations and treatments rather than progressing to IVF prematurely.

Recurrent implantation failure (RIF) refers to unsuccessful implantation after repeated transfers of morphologically good-quality embryos into a normal uterus [14]. Most treatment strategies focus on refining IVF treatment with (a) better embryo selection (through preimplantation genetic screening (PGS) or time-lapse imaging during embryonic incubation), (b) enhancing endometrial receptivity with an endometrial scratch, or (c) novel immunological treatments. We propose a different treatment strategy with RRM, trying to identify and treat the root causes of subfertility and restore optimal reproductive function. A key strategy of RRM is to record the menstrual cycle with a fertility chart. In this way, we have a simple and reproducible way to identify the fertile window, bleeding pattern, day of presumed ovulation, and length of luteal phase. We also have a record of days used for intercourse to allow natural conception. Our fertility app at www.​chartneo.​com allows us to additionally record all medications taken and blood results each cycle. It is also useful to confirm the date of conception. The ongoing guidance and support of a trained fertility advisor/teacher is central to our success.

This case demonstrates the principles of restorative reproductive medicine (RRM).

First, with ongoing evaluation, she had multiple diagnoses requiring attention:

Having implemented a strategy to restore optimal reproductive function, we sought to optimize conditions for natural conception and healthy pregnancy in a comprehensive, iterative fashion, as follows:

Initially, she conceived on her second optimized cycle, but miscarried. This prompted additional evaluation and intervention. We wanted surgical assessment before conceiving again, and this delayed us by 6 months due to COVID restrictions. After surgery, she had three medicated optimal cycles, conceived again, and had a successful outcome.

We identified and treated the principal factors preventing conception, and we restored normal function. This allowed the couple to conceive naturally with a lower risk of miscarriage.

A limitation with our approach is that we cannot select the best embryo free of a balanced translocation as you could with IVF and preimplantation genetic selection (PGS). It is likely our first miscarriage was due to this factor, but the second conception was healthy, resulting in a successful pregnancy.

When we achieve optimal medical and surgical conditions for pregnancy to occur, we remind couples that it is normal to take up to 12 cycles to conceive [15]. We need to have a single mature follicle that ruptures, with optimal progesterone and estradiol in the mid-luteal phase. It is important to record the fertility cycle pattern daily, check monthly blood tests for progesterone and estradiol, 7 days post ovulation, and periodically assess follicle rupture by ultrasound. We may persist for up to 12 optimized cycles, because in healthy couples with normal reproductive function, it is normal to take 12 cycles to conceive.

There has been a theoretical concern that prolonged treatment with clomiphene may increase the lifetime risk of developing ovarian cancer, through excessive stimulation of follicles [16]. To the extent that this is an important concern, we believe it would be related to the intensity of follicular stimulation. If we restore optimal cycles with one mature follicle each month, it is likely to be less harmful than ovarian stimulation for a cycle of IVF.

RRM treatment seeks to produce one mature follicle and maintain optimal cycles, avoiding excessive stimulation. Many clinics discontinue ovulation induction too quickly because of concerns regarding excessive follicle stimulation. However, moving prematurely to IVF can cause more intense follicle stimulation, with a risk of ovarian hyperstimulation syndrome. In contrast, repeat optimized cycles with less stimulation are low risk and can achieve a successful pregnancy even with long-standing infertility, recurrent miscarriage, and multiple unsuccessful embryo transfers. We propose that a full evaluation of underlying factors, and up to 12 cycles of cycle optimization, should be offered to subfertile patients before considering IVF treatment.