Maternity After Orthotopic Liver Transplantation: Can the Use of Biological Fertility Indicators Help? Our Own Experience and Literature-based Recommendations

Over the last 5 decades, the fulfillment of maternity wishes in solid organ transplanted women has become a reality. Despite pregnancy contraindication in transplanted women during the early post-transplant period, such a condition can be overcome after 12 months if patients show a good clinical evolution and do not present other general pre-conceptional findings. This article presents the case report of a young female liver transplanted patient that used symptothermal method as a reliable family planning method. After her gestational contraindication was lifted, observation of biological fertility indicators and fertility-guided sexual intercourse helped her fulfill her maternity wish and conceive and carry out a healthy offspring. Based on this case and on the available bibliographic evidence, this paper reviews the potential implications of the use of this kind of approach as a safe and effective alternative to assisted reproduction technology in the management of potential infertility problems in the young female transplanted population, a population which according to literature has higher rates of unsuccessful parenthood and might also be more vulnerable to iatrogenicity of ovarian hyperstimulation process and to multiple pregnancy.

Solid-organ transplantation, hepatic transplantation, fertility, pregnancy, biological fertility indicators, symptothermal method, NaProTechnology, assisted reproductive technology, bioethics

Organ transplantation has become a major success in medicine, allowing patients with previously incurable diseases to return to normal life. This includes the possibility of female transplant recipients to have a normal sexual and reproductive physiology (Coscia et al. 2015; Cundy, O'Grady, and Williams 1990) and thus the ability to procreate. The available evidence provides some criteria for obstetrical counseling in transplanted women (Deshpande et al. 2013; McKay et al. 2005). Recommendations of existing transplantation guidelines include pregnancy contraindication for at least 12 months and establish good general and gynecological conditions as well as a good transplant evolution (rejection-free, no infections, good organ function) as a prerequisite of release from pregnancy contraindication (McKay et al. 2005). At least during post-transplant pregnancy contraindication, reliable contraception is considered good practice and has also found its way to evidence-based guidelines (Deshpande et al. 2013; McKay et al. 2005). The election of an appropriate method isn´t, however, exempt from difficulty due to the iatrogenicity of some of the most effective contraceptives (Curtis et al. 2016). Recently, Huete et al. first described the use of symptothermal method (STM) as a reliable method for pregnancy avoidance in a transplanted woman (Huete et al. 2020). This method is based on the identification during the menstrual cycle of biological fertility indicators that help the couple assess whether a conception is very unlikely to happen and avoid unprotected sexual intercourse during fertile days. The well-known impairment of reproductive physiology secondary to both renal or hepatic insufficiency is rapidly overcome after successful organ transplantation. Since the first successful pregnancy was reported in 1963 in a kidney transplanted woman (Murray et al. 1963), almost two thousand have been documented at the US pregnancy register (Transplant_Pregnancy_Registry_International 2020). While the achievability of pregnancy in most transplanted women at fertile age is undisputed, the incidence of infertility has been reported to be at least double as high as in the general population. According to data from the Transplant Pregnancy Register, the incidence of subfertility in their survey represents 22% of patients (Transplant_Pregnancy_Registry_International 2020). The mechanisms behind this observation have not been studied in detail. As main contributing factors, anovulation and amenorrhea associated with renal and hepatic insufficiency as well as gonadotoxicity have been postulated (Cundy, O'Grady, and Williams 1990; De Pinho and Sauer 2014; Lim et al. 1980). The use of assisted reproductive technology (ART) is progressively being introduced in this patient population (De Pinho and Sauer 2014). Whereas artificial insemination and pharmacological supporting therapy might have only a minor impact on women’s health, the use of in vitro fertilization might increase patient and graft risk, especially when gametes of autologous origin are used, due to risks associated with the oocyte retrieval process, with the presence of ovarian hyperstimulation syndrome (OHSS) and increased risk of thromboembolism (Whelan and Vlahos 2000). Besides, the increased incidence of twin-pregnancies observed after in vitro fertilization (IVF) or intra-cytoplasmatic spermatocyte injection (ICSI) is associated with significant comorbidity and poor gestational outcomes in transplanted women (Furman et al. 1999). Therefore, an appealing alternative is the use of biological fertility indicators as an alternative for the treatment of infertility. The use of fertility-targeted sexual intercourse is recommended as a first approach by the American Society of Reproductive Medicine (ASRM) in couples with suspicion of infertility (Practice_Committee_of_the_American_Society_for_Reproductive_Medicine_ASRM@asrm.org 2017). The fertile phase assessment by self-observation of biological fertility indicators and targeted intercourse during the clinical fertility window may increase the success rates of spontaneous conception. In addition, it might help both, to earlier diagnose potential alterations of the menstrual cycle that need to be addressed to accomplish conception or prevent spontaneous abortion and to initiate corrective intervention earlier. As an alternative to ART, NaProTechnology (NPT) is a holistic fertility-care system developed over the last 30 years. By using some biological indicators as universally, non-invasive, and efficient diagnostic fertility tools combined with the use of state-of-the-art medical and surgical techniques, NPT allows the treatment of gynecological and obstetric dysfunctions often leading to repeated spontaneous miscarriage and infertility (Kiani et al. 2020). Whenever pathological alterations are diagnosed, the use of fertility-guided sexual intercourse combined with supportive or restorative medicine may provide a safe and efficient alternative to ART in transplanted women. Based on the case report of a liver transplanted patient (Huete et al. 2020), in which STM was used as a natural family planning method for both pregnancy avoidance and as a conception facilitating method, this article intends to discuss the usefulness of biological fertility indicators and NPT as a potential alternative to ART for infertile transplanted women. Case Report Description and Results Use of Symptothermal Method for Pregnancy Avoidance Development of hepatopathy and transplantation In September 2011, a healthy 31-year-old Caucasian female carried out at week 41 of pregnancy a male offspring after her first complication-free pregnancy. After an initial normal puerperium, in which the baby had a mixed lactation, on day 10 post-partum, the woman referred to abdominal pain. The echographic evaluation did not show any puerperal complications and she was released with symptomatic therapy. A few days later, the patient’s clinical condition worsened and signs of hepatic dysfunction (jaundice, hyperbilirubinemia, and hypertransaminasemia) appeared. The diagnosis of fulminant idiopathic hepatic insufficiency was made. With her condition rapidly deteriorating showing severe coagulopathy, neurotoxicity, and needing intubation she initiated MARS bridging therapy and was listed for urgent hepatic transplant. Eventually, at puerperal week 6, she received orthotopic liver transplantation from a multiorgan brain death donor. The patient was discharged home on day 28 post-transplantation and follow-up performed according to local practice of the hepatic transplant program. This included routine fertility counseling with the recommendation of reliable contraceptive use until contraindication for a safe new pregnancy could be released by the medical team. Therefore, the patient and her couple were referred to our family planning unit seeking advice for reliable birth control. Methodological training and application of symptothermal method for pregnancy avoidance Given the absolute gestational contraindication, advised by one of our experienced physicians who reviewed alternatives available for reliable pregnancy avoidance, the couple opted for STM. In the general population this double control method provides the best possible efficacy of all fertility awareness-based methods of family planning, and as described in the medical literature perfect-use Pearl indices are comparable with intrauterine devices and combined hormonal contraception (Peragallo Urrutia et al. 2018; Trussell 2011). The training was performed following our standard STM protocol (Soler, Fernández Martínez, and Díaz Sáez 1995), and was followed by regular visits to our family orientation center and by phone-calls when necessary. As lactation had been discontinued since the beginning of her initial hepatic failure, patient’s prolactinemia was back to basal levels and her liver function was completely restored, at the point of initiation of STM training. Therefore, she could be expected to resume her regular sexual reproductive physiology within a reasonably short period. For this reason, the patient was immediately trained for all biological fertility indicators from the very beginning and started full observation of cervical mucus, cervix, and basal temperature. As a primary focus during this time the patient was asked to observe the evolution of cervical mucus, an estrogen-dependent biological fertility indicator (Billings et al. 1972), double-checking this evolution with self-exploration of the consistency of the cervix uteri (Parenteau-Carreau and Infante-Rivard 1988). The couple committed to avoiding unprotected sexual relationships during days deemed fertile in application of STM rules especially during days of either sensation of humidity or the presence of any kind of cervical mucus observed by the patient. By contrast, unprotected intercourse was allowed on non-consecutive “dry” days. However, the couple decided to avoid coital relationships until evidencing her first ovulation. In addition to monitoring preovulatory biological fertility indicators, for ovulation confirmation, the patient recorded her wake-up basal body temperature on a daily basis, using a clinical Gallium-column thermometer (Frank-Herrmann et al. 2005). The patient correctly identified cervical mucus across her first cycle and was able to differentiate and correctly interpret her secretion pattern evolution according to STM rules. During her puerperal phase (first follow-up period), she recorded four patches of mucus and identified four peaks of mucus, the last of which correlated with the temperature rise that diagnosed her first post-partum ovulation. Amenorrhea lasted until week 29 post-delivery (23 post-transplantation) and bleeding could be identified as real menstruation as it was preceded by ovulation, as evidenced by the characteristic biphasic pattern of observed basal body temperature initiated 61 days after admission at our unit. The first luteal phase post-partum lasted 9 days. The description of the contraceptive use of STM was the object of the previous report (Huete et al. 2020). The patient and her couple used STM as advised by her physicians consistently, without a concomitant barrier method for contraception. In their case, this approach has proven a reliable method to avoid an unplanned pregnancy for the time of medical contraindication and for several years thereafter. The Use of Biological Fertility Indicators for Pregnancy Achievement Evaluation of eligibility for safe pregnancy As per protocol, pregnancy was contraindicated by the medical team for the initial 12 months post-transplantation. During this period, the only meaningful complication was a grade 2 episode of cholestasis that occurred during the immediate post-transplantation while still hospitalized, which the treating physician attributed to an episode of clinically suspected acute rejection, that resolved without the need for change in immunosuppression. As the couple desired another baby, 14 months after transplantation, the transplant team evaluated her eligibility as per local protocol. At that time (December 2012), physicians diagnosed subclinical CMV reactivation, which was successfully treated with a two-week course of oral Valgancyclovir. Four months after completing antiviral treatment, serial quantitative PCR showed CMV viremia negativity. Being now infection-free, the patient had remained for the complete post-transplant period normotensive, normoglycemic, with stable graft and renal function, rejection-free, and without pathological findings that advised against a safe pregnancy. From the gynecological perspective, the patient condition was also unremarkable. As part of her fertility awareness follow-up, the family planning physician could evidence that the patient had a healthy cycle pattern, with the presence of ovulation in all 13 follow-up periods and reaching luteal sufficiency criteria in 11/12 cycles post amenorrhea (median length of temperature raise of 10.5; 95% CI being 9.5–11.2) as defined by 10 days of elevated temperature (Döring 1969). Course of Pregnancy In April 2013, the patient was discontinued from her daily 250 mg mycophenolate mofetil (MMF) for its teratogenic potential and remained on tacrolimus monotherapy at doses reaching target levels of 6-7 ng/ml. After the recommended 6-weeks wash-out period, the patient was clinically stable, and was released from temporal pregnancy contraindication. During the first cycle of attempt, five directed sexual intercourses during her clinical fertility window led to a planned pregnancy, without a need of progestin supplementation. Pregnancy was evidenced by both biphasic temperature shift lasting 18 days and positive urine chorionic gonadotropin elevation. The symptothermal chart of the conceptional cycle is presented as Figure 1. Right after conception, the patient experienced an acute rejection episode, which was successfully treated with methyl-prednisone boluses. After rapid transaminase normalization, the patient remained on unchanged tacrolimus levels plus 20 mg methyl-prednisone corticotherapy for the rest of the pregnancy, without further signs of rejection, and normal graft function. The patient remained also normotensive and without developing gestational diabetes mellitus. After an uncomplicated pregnancy, at week 35 + 6, the patient had premature rupture of membranes and delivered a 2.5 kg heavy girl. Despite prematurity, the baby did not show intrauterine growth retardation, showing fetal development variables (weight, cranial perimeter and length) at or above percentile 50. Neonatal evaluation only showed initial hyperbilirubinemia, which was success-fully treated with a single cycle of photo-therapy. At that time, maternal lactation by transplanted mothers was contraindicated as per protocol, and therefore the baby was fed with neonatal formula and showed a normal develop-ment. Post-partum methylprednisone was dis-continued and mycophenolate mofetil re-introduced at a dose of 1g b.i.d. As an already experienced user of STM, the patient had no problem in restarting the observation of her biological fertility indicators and applying them for safe and efficacious family planning method, for now, additional 8 years, without any unintended pregnancy.

Pregnancy Contraindication and Pre-conception Evaluation Literature and registry data show that in most transplanted patients at reproductive age pregnancy is achievable with good outcomes. However, data from the Transplant Pregnancy Registry also supports the notion that pregnancy is associated with some risks to be considered in this patient population (Transplant_Pregnancy_Registry_International 2020). Time-to-conception inversely correlates with successful and complication-free obstetric, neonatal, and transplantation outcomes (Coscia et al. 2015). General pregnancy-, health- and outcome-related risks are significantly increased in transplanted women as compared to the general population, and specific adverse event patterns can usually be observed (Shah et al. 2019; Transplant_Pregnancy_Registry_International 2020): some patients suffer a graft function deterioration which may last after delivery. At least one episode of allograft rejection is observed in 3–5% of renal or liver transplanted patients, in 8% of cardiac transplant patients, and up to 14% in lung transplant patients. A significant number of women experience gestational hypertension during pregnancy (21% liver; 48–52% kidney, heart, and combined kidney/pancreas; 60% lung) and many of those courses with preeclampsia (21% liver; 29–35% kidney, heart, and combined kidney/pancreas; 13% lung). Unfortunately, around 6% of women show a transplantation evolution leading to graft loss within 2 years post-delivery across organs. When considering thoracic transplants, maternal mortality is high (Transplant_Pregnancy_Registry_International 2020). With regards to neonatological outcome, transplanted patients have a higher risk of pathological pregnancies as compared to the general population, with increased rates of prematurity, intrauterine growth retardation, low birth weight, and an indication for C-section (Transplant_Pregnancy_Registry_International 2020). Repeated pregnancies do not increase the risk of morbidity and transplant outcome, showing that women at good condition can afford consecutive pregnancies without negatively impacting their grafts (Transplant_Pregnancy_Registry_International 2020). Safety should be a key consideration when deciding the best moment for the patient to fulfill her motherhood wishes without exposing the patient to unnecessary risks. To this end, several transplant guidelines foresee pregnancy contraindication for at least 12 months during the immediate post-transplantation period. Consequently, reliable and safe contraception must be considered part of pre-conceptional counseling, which allows bridging the time of gestational contraindication until the ideal moment for a safe pregnancy is given. The symptothermal method belongs to the most efficacious birth control methods and has been shown applicable by our group in a liver transplanted patient (Huete et al. 2020). After 12 months of good evolution, release from gestational contraindication should be based on rated transplantological and gynecological criteria. Compliance with the empirical precautionary time before pregnancy favors good patient, graft, and baby outcomes (Deshpande et al. 2013; McKay et al. 2005). The main key surrogates of adequate clinical transplant evolution are patients showing good graft function, exclusion of acute rejection episodes and absence of infections. Special attention must be paid to controlling blood pressure, excluding coagulopathies and diabetes mellitus or dietary deficiencies. All these conditions also apply to the general population, but they are more prevalent in a transplanted population. They should therefore be ruled out and deviations corrected, when applicable, before conception. Finally, standard gynecological evaluation without pathological findings should minimize the risk of further complications that may be anticipated and potentially avoided. Figure 2 shows a possible recommendation for a pre-gestational evaluation of a transplanted woman, based on the recommendations of the American Society of Transplantation (McKay et al. 2005) and the Spanish Clinical Guidelines for the follow-up of pregnancy and puerperium (Ministerio_de_Sanidad_Política_Social_e_Igualdad 2014). Despite thorough pregnancy preparation efforts, the pregnancy of organ transplanted women must remain a high-risk endeavor. To ensure the best possible outcomes, a holistic approach with the assistance of specialized and experienced high obstetric risk units and iatrogenicity-reducing approaches should be considered. Pre-gestational clinical assessment should include evaluation of immunosuppression and possible adjustments (Deshpande et al. 2013; McKay et al. 2005; Transplant_Pregnancy_Registry_International 2020). Stable immunosuppression at low maintenance doses for at least 6 months prior to conception is recommended. This helps minimize drug toxicity and secondary hyperglycemia, risk of infectious complications, and teratogenic potential of some immunosuppressive drugs. Exposure during pregnancy to calcineurin inhibitors, azathioprine, and corticosteroids has been reported for most pregnant women observed, and any of these drugs in combination are safe at maintenance doses. Evidence for the use of mTOR inhibitors is weaker, but no explicit contraindication has been recommended (Transplant_Pregnancy_Registry_International 2020). By contrast, the use of mycophenolic derivates is an independent risk factor for spontaneous abortion and fetal malformations as shown on post-authorization studies, with a fivefold increased risk (Moritz et al. 2017). Therefore, its use is contraindicated on their labels during pregnancy and discontinuation is mandatory upon onset of pregnancy, which often occurs unintendedly. Product labels recommend a wash-out period of 6 weeks before elective pregnancy (European-Medicines-Agency 1996). This period not only allows toxicity avoidance but also ensures that with the new regimen immunosuppression is adequate to avoid acute rejection. Clear guidance of pre-conceptional MMF replacement by other immunosuppressants or alternatively, simple discontinuation may depend on the transplanted organ. Often azathioprine is introduced as an alternative to mycophenolic acid derivates in organ transplantation except for hepatic transplantation. Our patient had discontinued her low dose MMF as recommended for 6 weeks and remained on low dose tacrolimus monotherapy, but 20 mg/day methyl-prednisone was introduced after the occurrence of an episode of acute rejection. Usefulness of Biological Fertility Indicators for the Treatment of General Population Infertility Infertility refers clinically to a couple’s incapacity to conceive after 12 months of unrestricted attempts to become pregnant. Unlike sterility, where physiological or anatomical causality might be assessed, clinical infertility may hide one or more predisposing conditions that might be overcome. Snick et al.(1997) prospectively followed 726 couples with unsuccessful parenthood despite at least one year of unprotected intercourse. Patients were evaluated and treated as per standard of care if needed without subjection to ART. After a mean follow-up time of 20.7 months, 52% of them had achieved conception leading to live-birth. Half of the couples did not receive any intervention during the whole observation time, accounting for a 72% success in live-birth. Women’s age is one of the most impactful factors contributing to infertility. It is known that the one-cycle probability of clinical conception declines with age more than the cumulative probability to become pregnant (Dunson, Baird, and Colombo 2004). The temporal relationship between sexual intercourse leading to successful conception and the timepoint of ovulation has been properly established, and this period defines a clinical fertility window. It covers the time between the day of ovulation and the previous days (Wilcox, Weinberg, and Baird 1995). Whereas the absolute probability to become pregnant in the course of a single cycle might be reduced with increasing women’s age, the need for the correct timing of sexual intercourse relative to ovulation remains unaltered (Dunson, Colombo, and Baird 2002). Consequently, with increasing age, time-to-conception might be increasing, but the absolute number of women cumulatively experiencing successful outcomes over a constant period remains reasonably high for many women. Observation of biological fertility indicators and adaptation of sexual activity to the wish of pregnancy might be sufficient to increase the possibility of conception by reducing overall time-to-conception. That is the main reason why fertility-targeted sexual intercourse is the first line approach recommended by different authors, including the consensus document of the ASRM for couples with infertility suspicion (Practice_Committee_of_the_American_Society_for_Reproductive_Medicine_ASRM@asrm.org 2017). There are several reasons for this strategy. Targeted intercourse during the fertile phase assessed by self-observation may increase the success rates of spontaneous conception. Our own, unpublished experience shows that often couples miss their fertility window to increase their possibility of successful conception because they ignore the best moment to achieve this goal. Many patients become pregnant simply by using a clinical fertility-based approach. Considering that women with oligo-amenorrhea secondary to polycystic ovarian syndrome have fewer opportunities of conception because of fewer ovulation events per year, this strategy might positively impact on the conception rates of the transplant population. Beyond that, the evaluation of biological fertility indicators provides helpful non-invasive diagnostic support, by identifying potential alterations of menstrual physiology, for example, anovulation or luteal insufficiency. Some very prevalent findings regarding predisposing conditions behind infertility can be addressed in this way without the need for complex technological approaches, like for example the need for hormonal supplementation. Infertile couples might be divided into good and poor prognosis categories, although allocation to good prognosis category based on a single predisposing factor might be inaccurate. In cases of women’s age under 35 years, < 36 months of infertility, normal postcoital test, and absence of sterilizing pathologies like tubal occlusion, endometriosis, or partner´s oligo-azoospermia, too early medicalization of infertility might not always be the best option. In these patients, probabilities of achieving spontaneous clinical pregnancy are similar with and without treatment (Gnoth et al. 2005). Here the option “active surveillance” with the use of fertility indicator targeted intercourse can provide excellent pregnancy results (Gnoth, Frank-Herrmann, and Freundl 2002). This strategy has a huge impact, as shown by the fact that the ASRM recommends it as a first-line approach to unexplained infertility (Practice_Committee_of_the_American_Society_for_Reproductive_Medicine_ASRM@asrm.org 2017). Due to the efficacy of a targeted approach in subfertile couples, the ASRM consensus document further recommends recurring to specialized medical intervention if after six months of consistently using this strategy pregnancy is not achieved, as the existence of subfertility can be predicted without the need for waiting 12 months. This is further supported by the observation that in the general population targeted intercourse accounts for 90% of the successful pregnancies after the six initial follow-up periods (Gnoth et al. 2003). Cases of infertility with a poor prognosis can also be managed without the need for ART, but they often demand increased diagnostic and therapeutic efforts. Here, knowledge obtained from the female´s sexual physiology should be combined with additional diagnostic procedures, and as needed, restorative surgery or pharmacological fertility-support (Kiani et al. 2020). Over the last 30 years, NPT has been developed as an alternative to ART. This fertility-care system uses some biological indicators as universally, non-invasive, and powerful diagnostic fertility tools. The special merit of NPT has been the compilation of state-of-the-art medical and surgical techniques that combined with fertility-guided intercourse allows addressing a variety of uroandrological, gynecological, and obstetric dysfunctions often leading to repeated spontaneous miscarriage and infertility. Two big single-center experiences in Ireland (Stanford, Parnell, and Boyle 2008) and Canada (Tham, Schliep, and Stanford 2012) applying NPT to the treatment of infertility have shown excellent outcomes. The Irish experience studied 1072 infertile couples, defining infertility as being unsuccessful in achieving pregnancy for more than 12 months of attempts (Stanford, Parnell, and Boyle 2008). Despite having been unsuccessful for a mean period of 5.6 years, almost half of the patients (47%) in this study had at the time of enrollment unexplained infertility and 11% had an unexplained history of recurrent miscarriage. Especially interesting is that, while the rate of underdiagnosis of gynecological and urological conditions potentially contributing to infertility was relatively low (PCOS, endometriosis, anovulation, or male factor), 95.8% of the patients suffering from limit cervical mucus, 89.3% with suboptimal luteal progesterone and 96.8% with suboptimal luteal estrogen had not been diagnosed as a pregnancy-precluding condition. After NPT evaluation, almost all patients had at least one etiological cause diagnosed, and therapy was successful with an overall crude cumulative pregnancy rate leading to live-birth of 25.5% at 24 months, as shown in Table 1. Of note, cumulative pregnancy outcome adjusted for treatment compliance increased to up to 27.1% after 12 months and 52% after 24 months across the different age strata, including those women beyond 35 (Stanford, Parnell, and Boyle 2008). Table 1. | Canadian experience | Irish experience | Spanish ART Registry 2018, % | || |---|---|---|---|---| | Crude conception rates | Crude conception rates | ||| | 6 months | 33.3% | 14.2% | Per initiated cycle | 19.0 | | 12 months | 41.7% | 25.9% | Per patient initiating ART | 22.0 | | 24 months | 47.2% | 33.0% | || | Adjusted conception rates | Adjusted conception rates | ||| | 6 months | 37.3% | 15.9% | Per embryo transfer | 35.6 | | 12 months | 53.9% | 35.5% | || | 24 months | 73.1% | 64.8% | || | Crude live-birth rate | Crude live-birth rate | ||| | 6 months | 24.1% | 10.4% | Per initiated cycle | 13.8 | | 12 months | 32.4% | 19.1% | || | 24 months | 38.0% | 25.5% | || | Adjusted live-birth rate | Adjusted live-birth rate | ||| | 6 months | 26.6% | 11.8% | Per embryo transfer | 25.8 | | 12 months | 44.5% | 27.1% | || | 24 months | 66.0% | 52.8% | || | Multiparity | 0% | 4.5% | Multiparity | 15.2 | | Gestational age at birth | Gestational age at birth | ||| | >37 weeks | 54% | 86.0% | >37 weeks | 84.2 | | 32–37 weeks | 32% | 5.2% | 33-37 weeks | 10.9 | | <32 weeks | 15% | 2.5 kg | 78% | 85.5% | Registry does not provide | | | 1.5–2.5 kg | 5% | 4.5% | || | <1.5 kg | 10% | 1.4% | || | unknown | 7% | 8.4% | Similarly, the Canadian study with 108 infertile couples found significantly high rates of underdiagnosis, with 40% unexplained infertility and 29% unexplained recurrent miscarriage (Tham, Schliep, and Stanford 2012). Like the Irish series, underdiagnosis of existing limited cervical mucus occurred before initiation of NPT in 7/10 patients, luteal progesterone insufficiency in 55/62 patients, luteal insufficiency in 52/54 patients, and follicular estrogen insufficiency in 54/54 patients. With a NPT approach, the cumulative crude numbers of pregnancies leading to live-births were 24.1% at 6 months, 32.4 at 12 months, and 38% at 24 months. Adjusted for treatment compliance, proportions of success increase to 26.6% at 6 months, 44.5% at 12 months, and 66% at 24 months (Tham, Schliep, and Stanford 2012). Table 1 presents the main obstetric and neonatal outcomes of both studies and those from the Spanish National ART registry. Comparison between both studies and between NPT studies and the registry data is challenging. The relatively small sample size of the Canadian experience could be favoring good pregnancy and poor neonatal outcomes as compared to the 10 times bigger Irish experience. However, the last study shows neonatal outcomes comparable to those observed in the general population after natural conception, which is significantly better in terms of incidence of prematurity, low birth weight, and intrauterine growth retardation than those observed in the ART population (Qin et al. 2017). In terms of efficacy, data from the 2016 CDC Registry of ART show cumulatively that 34% of intended retrievals end in live-births, with success rates ranging from 52% in women younger than 35 years and 3.2% in women older than 42 (Center_for_Disease_Control_and_Prevention 2018). Figure 3A represents cumulative pregnancy success rates of new patients, which never had been subjected to ART. When compared with the Irish NPT experience shown in Figure 3B, live-birth proportions seem to be comparable when comparing both infertility approaches in younger patients. However, whereas ART success rates rapidly decrease with increased women´s age, outcomes remain around 50% even in females older than 40 years (Stanford, Parnell, and Boyle 2008). The Irish experience also showed that exposure to previous ART was predictive of a bad outcome of NPT, but still showing adjusted rates of live-births ranging from 61.5% in ART-naïve women, 41.9% success after one cycle, 34.9% after two cycles, and 19.8% after three or more cycles of ART. Boyle et al. (2018) recently published their series of 403 couples with a previous history of unsuccessful IVF/ICSI treatments that were treated with NPT. Women had advanced reproductive age (average 37.2 years) and almost 6 years of history of IVF/ICSI (average 2.1 cycles, range 1-9). Despite the patient’s poor reproductive prognosis, if this population is consistently treated, up to 37.5% of women achieve live-birth outcomes. Of note, 27% of successful deliveries were in women aged over 40 years; 20.1% had infertility lasting more than 9 years, and 33% had been unsuccessfully subjected to three or more cycles of IVF/ICSI. Overall, after 99 pregnancies diagnosed, 74 live-birth deliveries were achieved, with only one case of twin birth (1.4%), a low prematurity rate (8.2% in single births), and an incidence of 5.5% of low birth rate (<2.5 kg). It could be hypothesized that those patients with prolonged unsuccessful attempts of ART could have profited even more from early intervention with NPT. The Infertility Problem in Solid Organ Transplanted Women and Potential Treatment Options As previously discussed, the assessment of biological fertility indicators is a powerful tool to identify different alterations of reproductive physiology in women. According to data from the Transplant Pregnancy Register the incidence of subfertility in their survey represents 22% of patients (Transplant_Pregnancy_Registry_International 2020). However, the mechanisms behind this observation have not been studied in detail. As main contributing factors, anovulation and amenorrhea associated with renal and hepatic insufficiency (Cundy, O'Grady, and Williams 1990; Lim et al. 1980) as well as reduction of follicular reserve and direct gonadotoxicity have been postulated (De Pinho and Sauer 2014). But the exact impact of factors is not fully understood, reason for which evaluation of biological fertility indicators may put some light on the reproductive physiology and possible pathophysiological alterations leading to increased incidence of infertility in transplanted women Over the last decades, increasing experience of the use of ART has been collected (De Pinho and Sauer 2014; Transplant_Pregnancy_Registry_International 2020). Even though different series with reported good graft, patient and neonatal outcomes have been published (Norrman, Bergh, and Wennerholm 2015; Yaprak et al. 2019; Transplant_Pregnancy_Registry_International 2020), significant risks cannot be excluded. Among the 97 patients with live-births after ART (38 IVF/ICSI, 18 IUI, 41 pharmacological support) included in the 2019 Transplant Pregnancy Registry International, the total number of grafts lost were 7 (6 kidneys, one liver, 7.2%). As personally communicated by Lisa A. Coscia (unpublished data), of these graft losses five corresponded to patients with IVF/ICSI (13.2%), and one each accounted for IUI (5.5%) and pharmacological support therapy (2.8%). All graft losses were deemed to be unrelated to the procedure of ART. These data should not be overinterpreted because of small case numbers. However, it is remarkable that incidences of graft loss at 24 months post-delivery after IUI and pharmacological support therapy numerically equal those observed in naturally pregnant women with renal (5.7%) and liver (2.4%) engrafted patients, whereas the risk of graft loss after IVF/ICSI is numerically increased. In addition to the increased gestational hypertension, diabetes, preeclampsia, and acute rejection episodes, additional risks associated with IVF/ICSI might further challenge some of the patient´s allografts. OHSS is a potentially life-threatening medical complication associated with the use of hormonal cocktails, which affects in its most severe forms between 0.5 and 5% of women subjected to ovarian stimulation for gamete retrieval (Whelan and Vlahos 2000; Malherbe et al. 2020). Some cases of severe OHSS in organ transplanted women have been reported in the medical literature (Khalaf et al. 2000; Zheng, Song, and Wu 2016). Another concerning aspect of ART is the increased risk of multiple gestations. Even though the incidence has been significantly reduced over the last decades, incidences of multiple births in the EU (Wyns et al. 2020) and the US (Center_for_Disease_Control_and_Prevention 2018) are still 15.2% and 14.4%, respectively. Therefore, it can be estimated that this accounts for a 10-fold higher risk of multiparity associated with ART as compared to naturally occurring pregnancies. Multiparity has been shown to critically impact morbidity and mortality in transplanted women as well as offspring health (Furman et al. 1999). Finally, a twofold increase risk of development of thrombosis has been reported in patients subjected to hormonal treatment for ovarian hyperstimulation (De Pinho and Sauer 2014). Further Investigation Recommended Our team foresees initiating in the next months a prospective controlled study in Spain by which transplant patients using STM for pregnancy avoidance will be compared to patients using standard of care contraception to assess the applicability of this fertility awareness-based method as a safe and reliable family planning alternative. A protocol named “Fertigraft” is already designed and will be presented for ethical committee approval in Spain. However, the incidence of infertility in transplanted patients, around twice as high as compared with general population and the lack of knowledge of the pathophysiological mechanisms behind also justifies the evaluation of biological fertility indicators in this patient population. For this reason, our team foresees a sub-study, in which fertility-relevant variables assessed in patients subjected to organ transplantation that use STM for post-transplant birth control will be compared to age-matched controls. By this, we expect to better understand their reproductive physiology and potential alteration or dysfunctions, which could be therapeutically addressed as part of a reproductive health assessment. As a result of our Fertigraft study, we aim to develop a follow-up program called Fertigraft-2, which based on the knowledge generated with this sub-study, could prospectively study provide evidence based solutions to post-transplant infertility cases.

The use of biological fertility indicators described in this article as part of an alternative post-transplant patient family planning approach has not only been shown effective in avoiding unintended pregnancy (Huete et al. 2020), but also helped our patient to properly identify the best moment for achieving pregnancy. This approach led to immediate gestational success in this case. Even though this specific couple seemed not to be infertile, and therefore the example cannot be taken as a case of successful use in treating subfertility in organ transplanted women, it shows that the accurate identification of the clinical fertility window can be done with the use of biological fertility indicators. This is the basis on which spontaneous conception chances can be maximized in these patients, and it represents a valuable tool on which a potentially less iatrogenic infertility treatment approach can be built on. While scientific evidence is still missing, theoretical considerations that account for the increased incidence of obstetrical complications during pregnancy in this vulnerable patient population together with comparative advantages of NPT over ART in the general population makes the use of fertility-targeted approaches an interesting field to explore in the future. In the meantime, whether the use of NPT might be a valid alternative to ART remains to be demonstrated with a prospective clinical trial. Acknowledgments The authors sincerely acknowledge the patient and her couple for giving written informed consent for the anonymized publication; Monseñor Joaquín M. López de Andujar and his successor Monseñor Ginés García Beltrán, who supported our activities at the Fundación COF Getafe; Universidad Católica de Ávila for sponsoring a prospective trial on the applicability of biological fertility indicators for birth control in transplanted women; the medical staff of Puerta de Hierro University Hospital for their support and patient care; Prof. Daniel Candel, Associate Professor of English Literature at University of Alcalá (Madrid) for English language review. Biographical Notes Antonio Castillo, PharmD, is director of the Gianna Beretta chair in bioethics, sexuality and fertility awareness at University Alfonso X el Sabio and scientific director of the diocesan Family Orientation Center Getafe. He serves as full professor at the Health Sciences Faculty and director of Máster programs of sexuality and reproductive health at the Universidad Católica de Ávila. Visiting professor at different Spanish Academic Institutions teaching bioethics, fertility and NFP study programs. Maria Eugenia Huete, MD. PhD is expert in Sexuality, NFP and Human Fertility since 1998. Since 2009 Member of the Scientific Committee of the diocesan “COF Getafe” Foundation. From 2010-2016 she was clinical practitioner at the Fertility and Sexuality outpatient clinic of the “COFGetafe Foundation and Managing Director of the “COF-Getafe” Foundation between 2012 and 2016. She is also graduate of Family Pastoral from the Pontifical John Paul II Institute for Marriage and Family Sciences. Visiting professor at different Spanish universities teaching in postgraduate programs on Sexulity and Human Fertility. Since 2017 she serves as clinical head at the regional Blood and Tissue Bank of the Balearic Island belonging to the sanitary área of Ibiza. Tania Errasti, MD. PhD, is board certified obstetrician and gynecologist. She has completed post-graduate trainings in reproductive endocrinology at Sta. Chiara Hospital in Pisa, at Policlinico Sta. Maria alle Scotte in Siena, and at Creighton University Medical Center in Omaha, where she obtained certification as Fertility Care Medical Consultant from the Pope Paul VI Institute. Her clinical practice and research areas include gyneacological endocrinology, fertility preservation in female oncological patients and she is one of the leading specialists using NaProTechnology in Spain for the treatment of infertility. Guillermo Perez de Lema, PhD, has been postdoctoral researcher at the Ludwig-Maximilians-University in Munich in the field of immunology for 7 years. Since 2004 he has been working for different biopharmaceutical companies and today serves as Development Medical Director at Regeneron in the therapeutic area of immunoncology. He is Co-founder of Eduvida Association and teaches Sympthotermal and Billings methods since 1996. He is visiting professor at different postgraduate programs at Spanish Universities teaching Fertility and Natural Family Planning. Since 2005 he collaborates with the diocesan Family Orientation Center in Getafe. Footnotes Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. Ethics Statement: The patient was treated as per standard of care which included routine fertility recommendations according to the local hospital protocol. For contraceptive advice, she and her couple received detailed information about the family planning alternatives available and decided according to the bioethical principle of autonomy. During pregnancy assessment, the patient and her couple received detailed information about the risks of a new pregnancy and followed all procedures foreseen in clinical guidelines for risk minimization. Obstetrical and transplant follow-up was performed by a multidisciplinary team of transplant internists and high-risk obstetricians at the patient’s transplantation hospital. The patient and her couple gave written informed consent for the publication of her anonymized data. ORCID iDs Antonio Castillo, PharmD https://orcid.org/0000-0001-8289-018X María Eugenia Huete, MD, PhD https://orcid.org/0000-0001-9887-6155 Tania Errasti, MD https://orcid.org/0000-0003-3046-0940 Guillermo Pérez de Lema, PhD https://orcid.org/0000-0002-6244-1480

- Billings E. L., Brown J. B., Billings J. J., Burger H. G. 1972. “Symptoms and Hormonal Changes Accompanying Ovulation.” The Lancet 299, 7745: 282‐284. [DOI] [PubMed] [Google Scholar] - Boyle P. C., de Groot T., Andralojc K. M., Parnell T. A. 2018. “Healthy Singleton Pregnancies From Restorative Reproductive Medicine (RRM) After Failed IVF.” Frontiers in Medicine 5: 210. 10.3389/fmed.2018.00210. [DOI] [PMC free article] [PubMed] [Google Scholar] - Center_for_Disease_Control_and_Prevention . 2018. Assisted Reproductive Technology Fertility Clinic Success Rates Report 2016. Atlanta, GA: Centers for Disease Control and Prevention. [Google Scholar] - Coscia L.A., Davison J.M., Moritz M.J., Armenti V.T. 2015. “Pregnancy After Liver Transplantation.” In Contemporary Liver Transplantation, edited by Doria C.. Cham, Switzerland: Springer. [Google Scholar] - Cundy T. F., O'Grady J. G., Williams R. 1990. “Recovery of Menstruation and Pregnancy after Liver Transplantation.” Gut 31, 3: 337‐338. [DOI] [PMC free article] [PubMed] [Google Scholar] - Curtis K. M., Tepper N. K., Jatlaoui T. C., Berry-Bibee E., Horton L. G., Zapata L. B., Simmons K. B., Pagano H. P., Jamieson D. J., Whiteman M. K. 2016. “U.S. Medical Eligibility Criteria for Contraceptive Use, 2016.” MMWR. Recommendations and Reports 65, 3: 1‐103. 10.15585/mmwr.rr6503a1. [DOI] [PubMed] [Google Scholar] - De Pinho J. C., Sauer M. V. 2014. “Infertility and ART After Transplantation.” Best Practice & Research Clinical Obstetrics & Gynaecology 28, 8: 1235‐1250. 10.1016/j.bpobgyn.2014.07.017. [DOI] [PubMed] [Google Scholar] - Deshpande N. A., Coscia L. A., Gomez-Lobo V., Moritz M. J., Armenti V. T. 2013. “Pregnancy After Solid Organ Transplantation: A Guide for Obstetric Management.” Reviews in Obstetrics & Gynecology 6, 3-4: 116‐25. [PMC free article] [PubMed] [Google Scholar] - Dunson D. B., Baird D. D., Colombo B. 2004. “Increased Infertility with Age in Men and Women.” Obstetrics & Gynecology 103, 1: 51‐56. 10.1097/01.AOG.0000100153.24061.45. [DOI] [PubMed] [Google Scholar] - Dunson D. B., Colombo B., Baird D. D. 2002. “Changes with Age in the Level and Duration of Fertility in the Menstrual Cycle.” Human Reproduction 17, 5: 1399‐1403. 10.1093/humrep/17.5.1399. [DOI] [PubMed] [Google Scholar] - Döring G. K. 1969. “Diagnostik Der Ovariellen Sterilitätsursachen.” DMW - Deutsche Medizinische Wochenschrift 94, 21: 1121‐1122. 10.1055/s-0028-1111178. [DOI] [PubMed] [Google Scholar] - European-Medicines-Agency . 1996. Mycophenolate Mofetil. Summary of Product Characteristics. Amsterdam, Netherlands: European Medicines Agency. http://www.ema.europa.eu/docs/es_ES/document_library/EPAR_-_Product_Information/human/000082/WC500021864.pdf. [Google Scholar] - Frank-Herrmann P., Gnoth C., Baur S., Strowitzki T., Freundl G. 2005. “Determination of the Fertile Window: Reproductive Competence of Women - European Cycle Databases.” Gynecological Endocrinology 20, 6: 305‐312. 10.1080/09513590500097507. [DOI] [PubMed] [Google Scholar] - Furman B., Wiznitzer A., Hackmon R., Gohar J., Mazor M. 1999. “Multiple Pregnancies in Women After Renal Transplantation.” European Journal of Obstetrics & Gynecology and Reproductive Biology 84, 1: 107‐110. 10.1016/s0301-2115(98)00258-9. [DOI] [PubMed] [Google Scholar] - Gnoth C., Frank-Herrmann P., Freundl G. 2002. “Opinion: Natural Family Planning and the Management of Infertility.” Archives of Gynecology and Obstetrics 267, 2: 67‐71. 10.1007/s00404-002-0293-8. [DOI] [PubMed] [Google Scholar] - Gnoth C., Godehardt D., Godehardt E., Frank-Herrmann P., Freundl G. 2003. “Time to Pregnancy: Results of the German Prospective Study and Impact on the Management of Infertility.” Human Reproduction 18, 9: 1959‐1966. 10.1093/humrep/deg366. [DOI] [PubMed] [Google Scholar] - Gnoth C., Godehardt E., Frank-Herrmann P., Friol K., Tigges J., Freundl G. 2005. “Definition and prevalence of subfertility and infertility.” Human Reproduction 20, 5: 1144‐1147. 10.1093/humrep/deh870. [DOI] [PubMed] [Google Scholar] - Huete M. E., Castillo A., Marcos H., Vargas J., Pérez de Lema G., Baños I. 2020. “Applicability of Biological Fertility Indicators for Effective Birth Control After Orthotopic Liver Transplantation.” Journal of Obstetrics and Gynaecology 40, 4: 575‐577. 10.1080/01443615.2019.1634029. [DOI] [PubMed] [Google Scholar] - Khalaf Y., Elkington N., Anderson H., Taylor A., Braude P. 2000. “Ovarian Hyperstimulation Syndrome and its Effect on Renal Function in a Renal Transplant Patient Undergoing IVF Treatment: Case Report.” Human Reproduction 15, 6: 1275‐1277. 10.1093/humrep/15.6.1275. [DOI] [PubMed] [Google Scholar] - Kiani AK, Paolacci S, Scanzano P, Michelini S, Capodicasa N, D'Agruma L, Notarangelo A, Tonini G, Piccinelli D, Farshid KR, Petralia P, Fulcheri E, Chiurazzi P, Terranova C, Plotti F, Angioli R, Castori M, Bertelli M. 2020. “Complications Related to in Vitro Reproductive Techniques Support the Implementation of Natural Procreative Technologies.” Acta Bio-Medica : Atenei Parmensis 91, 13-S: e2020018. 10.23750/abm.v91i13-S.10525. [DOI] [PMC free article] [PubMed] [Google Scholar] - Lim V. S., Henriquez C., Sievertsen G., Frohman L. A. 1980. “Ovarian Function in Chronic Renal Failure: Evidence Suggesting Hypothalamic Anovulation.” Annals of Internal Medicine 93, 1: 21‐7. 10.7326/0003-4819-93-1-21. [DOI] [PubMed] [Google Scholar] - Malherbe J. A. J., Garas G., Khor T. S., MacQuillan G. C. 2020. “Delayed Fulminant Hepatic Failure from Dydrogesterone-Related In Vitro Fertilization Therapy Requiring Liver Transplantation During Pregnancy.” American Journal of Case Reports 21: e925690. 10.12659/AJCR.925690. [DOI] [PMC free article] [PubMed] [Google Scholar] - McKay D. B., Josephson M. A., Armenti V. T., August P., Coscia L. A., Davis C. L., Davison J. M., Easterling T., Friedman J. E., Hou S., Karlix J., Lake K. D., Lindheimer M., Matas A. J., Moritz M. J., Riely C. A., Ross L. F., Scott J. R., Wagoner L. E., Wrenshall L., Adams P. L., Bumgardner G. L., Fine R. N., Goral S., Krams S. M., Martinez O. M., Tolkoff-Rubin N., Pavlakis M., Scantlebury V., Women’s Health Committee of the American Society of Transplantation . 2005. “Reproduction and Transplantation: Report on the AST Consensus Conference on Reproductive Issues and Transplantation.” American Journal of Transplantation 5, 7: 1592‐1599. 10.1111/j.1600-6143.2005.00969.x. [DOI] [PubMed] [Google Scholar] - Ministerio_de_Sanidad_Política_Social_e_Igualdad . 2014. “Guía de práctica clínica de atención en el embarazo y puerperio.” Madrid, Spain: Ministerio de Sanidad, Política Social e Igualdad. https://www.mscbs.gob.es/organizacion/sns/planCalidadSNS/pdf/Guia_practica_AEP.pdf. [Google Scholar] - Moritz M. J., Constantinescu S., Coscia L. A., Armenti D. 2017. “Mycophenolate and Pregnancy: Teratology Principles and National Transplantation Pregnancy Registry Experience.” American Journal of Transplantation 17, 2: 581‐582. 10.1111/ajt.14085. [DOI] [PubMed] [Google Scholar] - Murray J. E., Reid D. E., Harrison J. H., Merrill J. P. 1963. “Successful Pregnancies After Human Renal Transplantation.” New England Journal of Medicine 269: 341‐343. 10.1056/NEJM196308152690704. [DOI] [PubMed] [Google Scholar] - Norrman E., Bergh C., Wennerholm U.-B. 2015. “Pregnancy Outcome and Long-Term Follow-Up After in Vitro Fertilization in Women with Renal Transplantation.” Human Reproduction 30, 1: 205‐213. 10.1093/humrep/deu293. [DOI] [PubMed] [Google Scholar] - Parenteau-Carreau S, Infante-Rivard C. 1988. “Self-Palpation To Assess Cervical Changes in Relation to Mucus and Temperature.” International Journal of Fertility 33, Suppl 1: 10‐6. [PubMed] [Google Scholar] - Peragallo Urrutia R., Polis C. B., Jensen E. T., Greene M. E., Kennedy E., Stanford J. B. 2018. “Effectiveness of Fertility Awareness-Based Methods for Pregnancy Prevention.” Obstetrics & Gynecology 132, 3: 591‐604. 10.1097/AOG.0000000000002784. [DOI] [PubMed] [Google Scholar] - Practice_Committee_of_the_American_Society_for_Reproductive_Medicine_ASRM@asrm.org . 2017. “Optimizing Natural Fertility: A Committee Opinion.” Fertility and Sterility 107, 1: 52‐58. 10.1016/j.fertnstert.2016.09.029. [DOI] [PubMed] [Google Scholar] - Qin J.-B., Sheng X.-Q., Wu D., Gao S.-Y., You Y.-P., Yang T.-B., Wang H. 2017. “Worldwide Prevalence of Adverse Pregnancy Outcomes Among Singleton Pregnancies After in Vitro Fertilization/Intracytoplasmic Sperm Injection: A Systematic Review and Meta-Analysis.” Archives of Gynecology and Obstetrics 295, 2: 285‐301. 10.1007/s00404-016-4250-3. [DOI] [PubMed] [Google Scholar] - Shah S., Venkatesan R. L., Gupta A., Sanghavi M. K., Welge J., Johansen R., Kean E. B., Kaur T., Gupta A., Grant T. J., Verma P. 2019. “Pregnancy Outcomes in Women with Kidney Transplant: Metaanalysis and Systematic Review.” BMC Nephrology 20, 1: 24. 10.1186/s12882-019-1213-5. [DOI] [PMC free article] [PubMed] [Google Scholar] - Snick H. K., Snick T. S., Evers J. L., Collins J. A. 1997. “The Spontaneous Pregnancy Prognosis in Untreated Subfertile Couples: The Walcheren Primary Care Study.” Human Reproduction 12, 7: 1582‐1588. 10.1093/humrep/12.7.1582. [DOI] [PubMed] [Google Scholar] - Sociedad_Española_Fertilidad . 2020. Informe estadístico de Técnicas de Reproducción Asistida 2018. Madrid, Spain: Sociedad Española de Fertilidad. [Google Scholar] - Soler F., Fernández Martínez M., Díaz Sáez J. 1995. “[Natural Family Planning. An Alternative].” Revista de enfermeria (Barcelona, Spain) 18, 208: 69‐74. [PubMed] [Google Scholar] - Stanford J. B., Parnell T. A., Boyle P. C. 2008. “Outcomes from Treatment of Infertility with Natural Procreative Technology in an Irish General Practice.” The Journal of the American Board of Family Medicine 21, 5: 375‐384. 10.3122/jabfm.2008.05.070239. [DOI] [PubMed] [Google Scholar] - Tham E., Schliep K., Stanford J. 2012. “Natural Procreative Technology for Infertility and Recurrent Miscarriage: Outcomes in a Canadian Family Practice.” Canadian Family Physician Medecin de Famille Canadien 58, 5: e267‐74. [PMC free article] [PubMed] [Google Scholar] - Transplant_Pregnancy_Registry_International . 2020. Annual Report 2019. Philadelphia, PA:Transplant Pregnancy Registry International. [Google Scholar] - Trussell J. 2011. “Contraceptive Failure in the United States.” Contraception 83, 5: 397‐404. 10.1016/j.contraception.2011.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar] - Whelan J. G., Vlahos N. F. 2000. “The Ovarian Hyperstimulation Syndrome.” Fertility and Sterility 73, 5: 883‐896. 10.1016/s0015-0282(00)00491-x. [DOI] [PubMed] [Google Scholar] - Wilcox A. J., Weinberg C. R., Baird D. D. 1995. “Timing of Sexual Intercourse in Relation to Ovulation - Effects on the Probability of Conception, Survival of the Pregnancy, and Sex of the Baby.” New England Journal of Medicine 333, 23: 1517‐1521. 10.1056/NEJM199512073332301. [DOI] [PubMed] [Google Scholar] - Wyns C., Bergh C., Calhaz-Jorge C., De Geyter C., Kupka M. S., Motrenko T., Rugescu I., Smeenk J., Tandler-Schneider A., Vidakovic S., Goossens V., European IVF-Monitoring Consortium (EIM)‡ for the European Society of Human Reproduction and Embryology (ESHRE) . 2020. “ART in Europe, 2016: Results Generated from European Registries by ESHRE.” Human Reproduction Open 2020, 3: hoaa032. 10.1093/hropen/hoaa032. [DOI] [PMC free article] [PubMed] [Google Scholar] - Yaprak M., Doğru V., Sanhal C. Y., Özgür K., Erman M. 2019. “In Vitro Fertilization After Renal Transplantation: A Single-Center Experience.” Transplantation Proceedings 51, 4: 1089‐1092. 10.1016/j.transproceed.2019.01.105. [DOI] [PubMed] [Google Scholar] - Zheng H.-H., Song Y., Wu J.-Y. 2016. “Critical Ovarian Hyperstimulation Syndrome After In Vitro Fertilization Treatment in a Renal Transplant Recipient: A Case Report.” Transplantation Proceedings 48, 1: 267‐270. 10.1016/j.transproceed.2016.01.008. [DOI] [PubMed] [Google Scholar]