Objectives: We evaluated outcomes in couples treated for infertility with natural procreative technology (NaProTechnology, NPT), a systematic medical approach for optimizing physiologic conditions for conception in vivo, from an Irish general practice.Methods: All couples receiving treatment from 2 NPT-trained family physicians between February 1998 and January 2002 were studied. The main outcome was live birth, and secondary outcomes included conceptions and multiple births. Crude proportions and adjusted life-table proportions were calculated per 100 couples.Results: A total of 1239 couples had an initial consult for NPT, of which 1072 had been trying for at least a year to conceive and initiated treatment. The average female age was 35.8 years, the mean duration of attempting to conceive was 5.6 years, 24% had a prior birth, and 33% had previously attempted treatment with assisted reproductive technology (ART). All couples were taught to identify the fertile days of the menstrual cycle with the Creighton Model FertilityCare System, and most received additional medical treatment, including clomiphene (75%). In life-table analysis, the cumulative proportion of first live births for those completing up to 24 months of NPT treatment was 52.8 per 100 couples. The crude proportion was 25.5. Younger couples and couples without previous ART attempts had higher rates of live birth. Among live births, there were 4.6% twin births.

Objectives: To determine the live birth rate for patients who chose to undergo treatment with Restorative Reproductive Medicine (RRM) after previous IVF (includes ICSI). To look at birth outcomes with RRM after IVF, particularly rates of twin and higher order pregnancies, premature birth, low birth weight, and potential cost savings achieved with RRM.Setting: Two outpatient clinics in Ireland providing advanced RRM treatment of infertility.Materials and methods: All patients presenting between January 2004 and January 2010, with a history of infertility and previous IVF treatment were included if they proceeded beyond the initial consultation and began treatment. Main outcome is live birth per couple calculated using life table analysis.Results: 403 patients met the study criteria, among which 74 had a subsequent live birth. These women had significant negative predictive characteristics for healthy live birth including: advanced reproductive age (average 37.2 years), an average of 5.8 years of infertility with 2.1 (range 1–9) previous IVF attempts, with only 5% having previously had a live birth from IVF. Despite these undesirable prognostic indicators, the overall RRM live birth rate was 32.1% (crude 18.4%). Women aged 35–38 had a live birth rate of 37.5% (crude 23.6%) and older women over 40 had a live birth rate of 27.4% (crude 16.0%). The average birth weight was 3374g (7lb 7oz) with 92% being born at 37+ weeks and no very low birth weight babies. There was only one twin pregnancy in the study population; the potential health care savings for avoidable multiple pregnancies in these patients was estimated at £205 672 (USD$284 915).Conclusions: Patients who have already tried IVF can achieve comparable live birth outcomes with RRM compared to another cycle of IVF. RRM has a low risk of twin or multiple births, and very good neonatal outcomes with a potential cost savings to the health care system.

STUDY QUESTION What is the feasibility of a prospective protocol to follow subfertile couples being treated with natural procreative technology for up to 3 years at multiple clinical sites? SUMMARY ANSWER Overall, clinical sites had missing data for about one-third of participants, the proportion of participants responding to follow-up questionnaires during time periods when participant compensation was available (about 2/3) was double that of time periods when participant compensation was not available (about 1/3), and follow-up information was most complete for pregnancies and births (obtained from both clinics and participants). WHAT IS KNOWN ALREADY Several retrospective single-clinic studies from Canada, Ireland, and the USA, with subfertile couples receiving restorative reproductive medicine, mostly natural procreative technology, have reported adjusted cumulative live birth rates ranging from 29% to 66%, for treatment for up to 2 years, with a mean women’s age of about 35 years. STUDY DESIGN, SIZE, DURATION The international Natural Procreative Technology Evaluation and Surveillance of Treatment for Subfertility (iNEST) was designed as a multi-center, prospective cohort study, to enroll subfertile couples seeking treatment for live birth, assess baseline characteristics, and follow them up for up to 3 years to report diagnoses, treatments, and outcomes of pregnancy and live birth. In addition to obtaining data from medical record abstraction, we sent follow-up questionnaires to participants (both women and men) to obtain information about treatments and pregnancy outcomes, including whether they obtained treatment elsewhere. The study was conducted from 2006 to 2016, with a total of 10 clinics participating for at least some of the study period across four countries (Canada, Poland, UK, and USA). PARTICIPANTS/MATERIALS, SETTING, METHODS The 834 participants were subfertile couples with the woman’s age 18 years or more, not pregnant, and seeking a live birth, with at least one clinic visit. Couples with known absolute infertility were excluded (i.e., bilateral tubal blockage, azoospermia). Most women were trained to use a standardized protocol for daily vulvar observation, description, and recording of cervical mucus and vaginal bleeding (the Creighton Model FertilityCare System). Couples received medical and sometimes surgical evaluation and treatments aimed to restore and optimize female and male reproductive function, to facilitate in vivo conception. MAIN RESULTS AND THE ROLE OF CHANCE The mean age of women starting treatment was 34.0 years; among those with additional demographic data, 382/478 (80%) had 16 or more years of education, and 199/593 (34%) had secondary infertility. Across 10 clinical sites in four countries (mostly private clinical practices) with family physicians or obstetrician-gynecologists, data about clinic visits were submitted for 60% of participants, and diagnostic data for 48%. For data obtained directly from the couple, 59% of couples had at least one follow-up questionnaire, and the proportion of women and men responding to fill out the follow-up questionnaires was 69% and 67%, respectively, when participant financial compensation was available, compared to 38% and 33% when compensation was not available. Among all couples, 55% had at least one pregnancy and 42% at least one live birth during the follow-up time period, based on data obtained from clinic and/or participant questionnaires. All sites reported on female pelvic surgical procedures, and among all participants 20% of females underwent a pelvic diagnostic and/or therapeutic procedure, predominantly laparoscopy and hysterosalpingography. Among the 398 (48%) of participants with diagnostic information, ovulation-related disorders were diagnosed in 81%, endometriosis in 30%, nutritional disorders in 52%, and abnormalities of semen analysis in 25%. The mean number of diagnoses per couple was 4.7. LIMITATIONS, REASONS FOR CAUTION The level of missing data was higher than anticipated, which limits both generalizability and the ability to study different components of treatment and prognosis. Loss to follow-up may also be differential and introduce bias for outcomes. Most of the participating clinicians were not surgeons, which limits the opportunity to study the impact of surgical interventions. Participants were geographically dispersed but relatively homogeneous with regard to socioeconomic status, which may limit the generalizability of current and future findings. WIDER IMPLICATIONS OF THE FINDINGS Multi-center studies are key to understanding the outcomes of subfertility treatments beyond IVF or IUI in broader populations, and the association of different prognostic factors with outcomes. We anticipate that the iNEST study will provide insight for clinical and treatment factors associated with outcomes of pregnancy and live birth, with appropriate attention to potential biases (including adjustment for potential confounders, multiple imputation for missing data, sensitivity analysis and inverse probability weighting for potential differential loss to follow-up, and assessments for clinical site heterogeneity). Future studies will need to either have: adequate funding to compensate clinics and participants for robust data collection, including targeted randomized trials; or a scaled-down, registry-based approach with targeted data points, similar to the multiple national and regional ART registries. STUDY FUNDING/COMPETING INTEREST(S) Funding for the study came from the International Institute for Restorative Reproductive Medicine, the University of Utah, Department of Family and Preventive Medicine, Health Studies Fund, the Primary Children’s Medical Foundation, the Mary Cross Tippmann Foundation, the Atlas Foundation, the St. Augustine Foundation, and the Women’s Reproductive Health Foundation. The authors declare no competing interests. TRIAL REGISTRATION NUMBER The iNEST study is registered at clinicaltrials.gov, NCT01363596

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