Outcomes From Treatment of Infertility WithNatural Procreative Technology in an Irish GeneralPractice Joseph B. Stanford, MD, MSPH, Tracey A. Parnell, MD, and Phil C. Boyle, MB Objectives: We evaluated outcomes in couples treated for infertility with natural procreative technology
(NaProTechnology, NPT), a systematic medical approach for optimizing physiologic conditions for con-
ception 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 in-
cluded 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 dura-
tion 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.

Conclusion: NPT provided by trained general practitioners had live birth rates comparable to cohort
studies of more invasive treatments, including ART. Further studies are warranted to compare NPT di-
rectly to other treatments. (J Am Board Fam Med 2008;21:375–384.)

Infertility is a common problem; one in every 7 men, has major psychosocial ramifications, and couples hoping to have a baby experiences difficul- usually requires addressing multiple issues, includ- ties achieving or maintaining pregnancy serious ing comorbid medical conditions and lifestyle, all enough to seek medical intervention.1 Infertility is key elements of primary care practice. However, a chronic problem that involves both women and treatments for infertility are largely provided byphysicians trained in subspecialties, including arti-ficial insemination, ovulation induction, and hor-monal support of the menstrual cycle.1,2 The in- This article was externally peer reviewed.
Submitted 30 October 2007; revised 11 April 2008; ac- cepted 15 April 2008.
reproductive technologies (ART), including in From the Department of Family and Preventive Medi- vitro fertilization and intracytoplasmic sperm injec- cine, University of Utah, Salt Lake City (JBS); the Depart-ment of Family Medicine, University of British Columbia, tion, has removed infertility treatment further from Vancouver, Canada (TAP); the Galway Clinic, Ireland the realm of the generalist or family physician.1,3 (PCB); and the International Institute of Restorative Repro-ductive Medicine, London, United Kingdom (JBS, TAP, ART is expensive, invasive, and involves some risk to women. These include risks of the medical and surgical procedures to retrieve oocytes,4 in- Prior presentation: Portions of this work have been pre- sented at the North American Primary Care Research Con- ference, Vancouver, Canada, 21 October 2007.
There are also concerns about short- and long- Conflict of interest: none declared.
Corresponding author: Dr. Joseph B. Stanford, MD, term outcomes for the offspring.6–9 The most MSPH, University of Utah, Department of Family and prominent concerns relate to the incidence of mul- Preventive Medicine, 375 Chipeta Way, Suite A, Salt LakeCity, UT 84108 (E-mail: [email protected]).
tiple pregnancies with ART treatment and the sub- Treatment of Infertility with Natural Procreative Technology 375 sequent perinatal complications, including low assess the outcomes of NPT as applied by trained birth weight and prematurity.10–12 Increasing the generalist physicians in Galway, Ireland. Although availability of integrated primary methods for in- NPT has been developed with both medical and fertility treatment that can be effectively provided surgical protocols, this study evaluates the medical by a trained generalist physician with low risk to protocols. We focused on the clinically relevant women and offspring would potentially improve outcomes of live birth and multiple births.
access to care for couples dealing with infertility.
Natural procreative technology (NaProTech- nology, NPT) is an integrated and systematic ap- proach to infertility that is suitable for primary care During the study period, the clinic was a single settings. It is based on a detailed study of events physician office, with the exception of January 2000 that occur during ovulation and throughout the to August 2001, when a second physician was prac- menstrual cycle.13,14 Abnormalities of the repro- ticing in the same office. The 2 physicians were ductive cycle are identified and corrected to the licensed family physicians in Ireland who had re- extent possible.15–18 Patients receive thorough ed- ceived additional training in NPT through Creigh- ucation about their fertility and are taught to mon- ton University (Omaha, Nebraska) and had suc- itor biomarkers of their own fertility cycles. In the cessfully passed all evaluations and examinations of process, they become equal partners in their own the NPT continuing medical education course.
evaluation and treatment.
The clinic primarily focuses on providing women's A standardized NPT investigation usually re- health services.
sults in the diagnosis of one or more abnormalities Data for the NPT treatment cohort were col- of reproductive function that are associated with lected from patients during their initial assessment infertility. Abnormalities commonly identified in- visit and at subsequent follow-up visits and re- clude decreased production of estrogenic cervical corded in the routine medical record for the prac- mucus, intermenstrual bleeding or spotting, short tice. Data from routine follow-up telephone con- or variable luteal phases, and suboptimal levels of tacts were also included in the medical records.
the ovarian hormones estrogen and progesterone.19 The relevant data for this study were abstracted The physician trained in NPT then determines a from medical records and entered into a comput- course of treatment that aims to correct the under- erized database, with manual verification of all en- lying abnormality, with the goal of optimizing physiologic conditions for conception in vivo.
Patients were primarily self-referred couples ex- Common interventions include induction or stim- periencing difficulty conceiving and achieving a live ulation of ovulation20; medications to enhance cer- birth. All patients from Ireland who presented be- vical mucus production, including vitamin B6, tween February 1998 and January 2002 (inclusive) guaifenesin, or one of several antibiotics21,22; and and who proceeded beyond the initial explanatory hormonal supplementation in the luteal phase.23 consultation were eligible for inclusion in this Doses of all medications are adjusted according to study. Patients who had previously attempted ART the response of biomarkers and serum levels of (including in vitro fertilization and intracytoplas- estrogen and progesterone measured in the midlu- mic sperm injection) were also included. A few teal phase.13,17 Concurrently, couples use their patients were advised after the initial consultation awareness of ovulation biomarkers to time acts of that they were not eligible for NPT, mostly be- intercourse to maximize chances of conception.24 cause of azoospermia or menopause; these patients Ongoing evaluation and support during pregnancy were not included in this analysis. We also excluded often includes supplementation with human-iden- patients that had been trying for less than a year or tical progesterone, based on periodic measurement who did not continue with the evaluation that was of progesterone levels, in an effort to reduce the recommended at the initial consultation.
risk of adverse pregnancy outcomes.25–28 The NPT infertility treatment implemented in Outcomes for NPT have been published previ- this clinic is a systematic multilevel investigation ously for a cohort of infertility patients in a spe- and treatment program.13 It begins with an initial cialty practice at its place of development (Creigh- consultation in which reproductive physiology and ton University).29 This study was undertaken to the various stages of NPT investigation and treat- 376 JABFM September–October 2008 Vol. 21 No. 5
ment are explained in detail to patients. They next we also analyzed the cumulative proportion of first learn specialized fertility tracking of daily observa- conceptions and cumulative proportion of with- tions of vaginal discharge biomarkers (bleeding and drawals. Life-table analysis was used to adjust for cervical fluid), according to the Creighton Model couples withdrawing from treatment, or that com- FertilityCare System.15,16,30 After patients gained pleted 24 months of NPT treatment without preg- competence in fertility tracking (no earlier than the nancy. Among the live births, we analyzed the pro- second month), timed blood samples were taken portion of multiple births. Secondarily, we with respect to the estimated time of ovulation as analyzed the proportion with low birth weight and prospectively identified by the woman's own fertil- ity chart.13,31 Reproductive hormones, including The study protocol was reviewed and approved estradiol and progesterone, were measured and in- by the Linacre Centre for Health care Ethics in terpreted in the context of the woman's fertility London, and the Institutional Review Board for tracking chart. Medications to correct identified Human Subjects at the University of Utah. Because hormonal abnormalities were prescribed after the data were abstracted from usual clinical data completion of these investigations, usually in the sources and patient anonymity was maintained, fourth month. The goal was to optimize physio- there was no requirement for written informed logic conditions for natural conception in each consent of participants.
menstrual cycle, including mucus discharge quality,luteal hormone levels, ovulation, and the timing of intercourse. It often takes several cycles of treat- A total of 1239 couples obtained an initial consult ment to reach optimal physiologic conditions.
for NPT during the study period. Of these, 167 Once reached, there may still be some suboptimal couples were excluded because they had tried for cycles mixed with the optimal ones; for example, a less than a year to conceive or because they did not cycle where intercourse does not occur during the continue evaluation beyond the initial consultation.
fertile time. In addition, some patients conceive The final study cohort consisted of 1072 couples and subsequently experience a spontaneous abor- that began treatment between February 1998 and tion, after which they continue in the treatment January 2002 (inclusive), with subsequent outcomes program. Patients were advised that a total of up to followed through February 1, 2008. The women 24 months may be required to complete an ade- were, on average, 35.8 years old (range, 25 to 48 quate trial of NPT to achieve pregnancy leading to years), and nearly all were white. One third (33%) a live birth. Evaluation and treatment of the male had previously attempted ART treatment. The partner also took place during this time, as indi- mean length of time that couples had attempted to cated. Hormonal assessment and support contin- conceive before NPT treatment was 5.6 years ued through pregnancy, as indicated.25 Although (range, 1 to 20 years). Approximately one fourth specialized NPT surgical treatment may also form (24%) of couples had a previous live birth. As part of the NPT program, it was not available in shown in Table 1, the 364 couples who ultimately this clinic in this time frame. A more detailed dis- conceived with NPT treatment were slightly cussion of the NPT approach to infertility is avail- younger (mean age, 34.8 years); had not been at- able elsewhere.13,19,32 tempting conception as long (mean duration, 4.8 Per-cycle pregnancy rates are not an appropriate years); were likely to have had a previous birth outcome to assess for NPT because of the longitu- (30%); and less likely to have attempted ART treat- dinal and incremental nature of the NPT treatment program.33,34 Therefore, we chose a cohort ap- In addition to teaching women to track their proach with the couple, rather than the cycle, as the fertility biomarkers with the Creighton Model in- unit of analysis. The main analyses for this study struction, the most common diagnoses given to were the cumulative proportion of couples experi- couples before and after NPT evaluation are shown encing a first live birth during discrete time periods in Table 2. Through NPT evaluation, more than after the beginning of treatment. For comparability half of the couples had suboptimal serum levels of with other reports of infertility outcomes, we as- progesterone and estradiol during the luteal phase.
signed the time of this outcome as the time of Approximately one fourth had limited cervical mu- conception leading to first live birth.35 Secondarily, cus and 10% had polycystic ovarian syndrome.
Treatment of Infertility with Natural Procreative Technology 377 Table 1. Characteristics of Couples Beginning Treatment with Natural Procreative Technology, by Subsequent
Conception Status

Patient Characteristic Eligible Couples* Woman's age (mean years 关range兴) Prior years attempting to conceive (mean Had previous live birth (percent yes) Received previous ART‡ (percent yes) *One hundred sixty-seven couples were not eligible because they had been trying for less than 1 year or because they did not completethe evaluation after the initial consultation.
†Number of couples in each category. Age was available for all women. For previous years attempting to conceive, 30 (2.8%) hadmissing data; for previous births, 30 (2.8%) had missing data; for previous ART, 20 (1.9%) had missing data.
‡Assisted reproductive technology (ART) includes in vitro fertilization with or without intracytoplasmic sperm injection.
The most common treatments given to women come) were higher: 25.9 crude and 35.5 adjusted at included clomiphene (75.3%), support of luteal 12 months, and 33.0 crude and 64.8 adjusted at 24 hormonal production with human chorionic go- months. Of conceptions within 2 years leading to a nadotropin (67%) or progesterone (18%), and live birth, 75% (205 of 273) occurred within 12 medications to enhance cervical mucus production months and 93% (255 of 273) occurred within 18 (71%). Fifty-four women (5%) conceived without medical intervention, using only Creighton Model Several couple characteristics were associated fertility charting and optimally timed intercourse.
with the probability of live birth, as shown in Table There were 354 clinically recognized concep- 4. The cumulative proportion of live births de- tions within 24 months after starting NPT treat- clined with increasing age of the woman. For ment, with cumulative crude proportions of live women under 30, the crude proportion of live birth births of 19.1 per 100 couples up to 12 months, and after 24 months was 33.7. For women over 40 the 25.5 up to 24 months, as shown in Table 3. Adjust- crude proportion was 13.9. The cumulative crude ing for withdrawals from treatment and continuing proportion of live birth also declined with increas- treatment at the end of study follow-up, the cumu- ing previous attempts to conceive (36.6 for previous lative proportion of first live births was 27.1 up to time of 1 to 3 years; 11.9 for previous time more 12 months, and 52.8 at 24 months. The propor- than 9 years), and with the number of previous tions with any conception (regardless of its out- ART attempts (30.8 for none, and 10.3 for 3 or Table 2. Common Diagnoses of Couples Receiving Treatment Before and After Evaluation with Natural Procreative

Before NPT Evaluation After NPT Evaluation Diagnostic Category Unexplained infertility Unexplained recurrent miscarriage Polycystic ovarian syndrome Limited cervical mucus Suboptimal luteal progesterone Suboptimal luteal estrogen *This table is based on the 1072 couples that initiated evaluation. Diagnostic categories sum to more than 100% because couples couldhave more than one diagnosis (other than unexplained).
378 JABFM September–October 2008 Vol. 21 No. 5
Table 3. Cumulative Outcomes per 100 Couples by Time Completed in Natural Procreative Technology Evaluation
and Treatment

Withdrawals Starting at Time Cumulative Interval Conceptions Proportion Proportion† Proportion Proportion† *Live births are assigned the time interval when the conception occurred rather than when the birth occurred.
†Adjusted by life-table analysis, where withdrawal or continuing treatment at the end of study follow-up are censoring events.
‡Proportions are not calculated beyond 24 months.
more). Women with a previous birth had a higher small numbers of women continuing treatment un- cumulative crude proportion of live birth (35.8) til 24 months (ie, fewer than 25 women).
than those without (23.1). The adjusted propor- Among all live births observed, there were 13 tions confirm the same trends but should not be twin births (4.6%) and no higher order births. At considered reliable as precise estimates because least 88% of all births were to term and did not most of the subgroup life table analyses involve have low birth weight (Table 5). None of the pa- Table 4. Live Births per 100 Couples at 24 months of Natural Procreative Technology Treatment by Characteristics
of Couples Beginning Treatment

Adjusted Proportion* Woman's age (years) Time spent attempting to conceive (years) Previous live birth Previous ART attempts (n)† *Adjusted by life-table analysis, where withdrawal or continuing treatment at the end of study follow-up are censoring events. Adjustedproportions should be interpreted with caution because of small numbers in subgroups.
†Assisted Reproductive Technology (ART) includes in vitro fertilization (IVF) with or without intracytoplasmic sperm injection(ICSI).
Treatment of Infertility with Natural Procreative Technology 379 Table 5. Outcomes for Natural Procreative Technology
sumption that may not be valid for infertility treat- Live Births (n 286)
ment.38,39 Thus, the "true" estimates for NPT suc-cess probably lie somewhere between the adjusted life-table estimates and the crude estimates that we Multiple gestation have reported.
Gestational age (weeks) We believe our study can be considered to rep- resent a "real world" effectiveness based on undif- ferentiated infertility categories because all patients who were eligible for treatment were included, as Birth weight (grams) would normally occur in clinical practice. How- ever, the population presenting in this study for NPT treatment may represent a more difficult group than would be normally seen even in somespecialist ART clinics; 33% of those presenting forNPT treatment had previously attempted ART. Inaddition, the mean duration of time spent previ- tients in this cohort experienced ovarian hyper- ously trying to conceive for this population was 5.6 stimulation syndrome. The proportion of couples years. Finally, this was a relatively older population withdrawing from treatment was 44.6 per 100 cou- of women, with a mean age at entry to treatment of ples by 12 months, and 62.7 by 24 months (Table just over 35 years. Each of these characteristics is a 1). Among couples who had a live birth, 51 couples risk factor strongly associated with lower likelihood had additional NPT treatment, resulting in 47 ad- of conception.40–44 In comparison, a recent na- ditional live births within the study period. How- tional Dutch cohort of 4928 women undergoing ever, the results reported here are either for the ART had an average age of 33.6 years and a mean first conceptions or the first live births only.
duration of attempting conception of 3.6 years,with a 1-year cumulative probability of ongoing pregnancy of 45%.35 Importantly, the duration of In this study setting, NPT, an integrative approach time attempting conception in our study is greater to infertility provided by NPT-trained family phy- than of all the studies with which we compare in the sicians, resulted in substantial live birth rates with a remaining discussion, and the mean age of the minimal risk of twin or multiple births. These re- women in our study is also greater than most of sults would suggest that NPT provided by trained generalist physicians has the potential to improve Comparison of these results to studies of other access to treatment for infertility with favorable infertility treatments must be made tentatively, be- outcomes. The question remains, however, as to cause results vary by location, diagnosis, and both how to interpret these results in relation to out- identified and unidentified risk factors.45,46 Unfor- comes from other infertility treatments.
tunately, most data about infertility treatment out- We reported the outcome of conception because comes are reported on a per-cycle basis, so preg- this is an intermediate outcome of interest to pa- nancy or birth rates may be biased by high rates of tients and because it is an outcome commonly re- discontinuation of treatment, especially for cohorts ported in infertility literature. However, we fo- that have liberal entrance criteria.33,38 However, cused on live birth as the major outcome for this some studies of infertility have used a cohort ap- study because live birth is the outcome that is most proach and can provide some benchmarks against clinically meaningful for patients seeking treatment which to evaluate our results, as detailed below.
for infertility.36,37 Crude birth rates substantially Two cohort studies have demonstrated substan- underestimate the efficacy of treatment because of tial rates of spontaneous conception in some pa- high drop-out rates that are found in most studies tients with infertility, including a population-based of infertility treatment; however, life-table analysis study with a live birth rate of 40%40 and a referral overestimates treatment efficacy because it assumes clinic population with a live birth rate of 20%,41 that those discontinuing treatment have the same both over 24 months. Both studies, however, in- prognosis as those continuing treatment, an as- cluded women with an average age of 29 and an 380 JABFM September–October 2008 Vol. 21 No. 5
average infertility duration of 2 and 3.5 years, re- mean duration of infertility 3.6 years, and no cou- spectively. Thus, the prognosis for spontaneous ples had previously failed ART; all of this suggests conception in these studies was substantially higher that the patients studied had a better prognosis than for the patients in our study. None of the than patients in our study. In a recent population- patients in the spontaneous conception studies had based cohort of couples receiving ART in the previously attempted ART, whereas 33% of the Netherlands, the cumulative pregnancy rate at 1 couples in our study had done so.
year was 45%.35 Taken together, these results sug- Another comparison of our results would be gest that the overall success rates of treatment with with population-based studies of infertility treat- NPT might be comparable to ART despite greater ment. In a 1985 quasi population-based study, per-cycle pregnancy rates with ART. Although it there was an overall conception rate of 48 per 100 may seem paradoxical that a treatment with a lower couples for all causes of infertility after 2 years of per-cycle pregnancy rate than ART may have a treatment, adjusted by life-table analysis (treat- comparable cumulative rates of pregnancy or live ments included ovulation induction, artificial in- birth, very similar results have also been found in semination, hormonal treatment, and/or sur- randomized trials of ART versus other less invasive gery).44 Again, the population in this study was therapies for couples with unexplained infertili- much younger (women's mean age, 28 years) than ty.51,52 A systematic Cochrane review concluded our study; had a much lower duration of infertility that there are insufficient data to establish that before treatment (mean duration, 2.4 years); and ART is any more effective than less intensive ther- excluded couples that had previously attempted apies for unexplained infertility.53 ART. Closer to comparison with our study, the Multiple births are one of the most notable and subgroup of women with unexplained infertility of important complications of ART as it is currently 5 or more years' duration had a 2-year adjusted practiced.6,54 The proportion of live births of mul- pregnancy rate of approximately 30%, compared tiples was much lower in this NPT cohort (4.6%) with 53% in our study.
than for ART treatment in the UK in 1998 to 1999 How do these results compare to existing data (27.1%).47,48 Although multiple birth rates from for ART? The Human Fertilisation and Embryol- ART have dropped somewhat, they remain high in ogy Authority's crude live birth rate for the year most settings, eg, 34% in the US in 2003.37,48 2000 was 23.8 per 100 women,47 which is compa- Longitudinal studies of long-term outcomes after rable to the crude live births of 22.7 in this study; NPT treatment are necessary to determine but our results are for a longer time frame of up to whether NPT treatment might have fewer long- 2 years. In the United States in 2000, registry data term health risks for resulting children than ART.
for ART indicated a 25.4% live birth rate per ART A weakness of our study is that over half of cycle initiated (excluding donor eggs or frozen em- patients withdrew from treatment before complet- bryos), but no data are available on the number of ing a full 24-month course of treatment. In com- women treated or follow-up over time.37,48 Al- parison, in cohort studies of ART of up to 5 cycles though more recent ART data are available, we in which cost was not an issue, dropout rates from have referenced 2000 data for comparability to the treatment were 69% and 55%,38,39 and in a ran- time frame during which the patients in this study domized trial of ART versus other treatments, the were treated. Given the differences in time frames, overall dropout rate was 45%.51 Thus, the dropout the fact that women's characteristics and longitu- rates from treatment in our study are comparable to dinal outcomes cannot be extracted from registry those of studies of other fertility treatments. With- data, and other dissimilarities, this comparison drawing from treatment affects pregnancy or live must only be exploratory.
birth probabilities adjusted by life-table analysis but Although life-table analysis is not possible with does not change the crude probabilities that we the existing registry data for ART, other studies have reported for all outcomes. Crude probabilities have reported cumulative pregnancy or live birth include all couples in the analysis, treating those rates in cohorts with multiple attempts at ART.
that dropped out of treatment as if they continued These results varied from a low 32%49 to a range of treatment, and therefore represent the most con- 39% to 60%,38,50 to a high of 64.7%.39 In this last servative estimate of treatment outcomes. Future study the mean age of women was 32.8 years, the studies should seek to minimize the withdrawal Treatment of Infertility with Natural Procreative Technology 381 rates to the extent possible and to define the prog- treatment, and to directly compare NPT to other nostic factors among those withdrawing to estimate forms of infertility treatment.
the differential effect of dropout on adjusted prob-abilities of pregnancy or live birth.
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Clinical and Experimental Allergy, 37, 166–173 c 2007 The Authors Journal compilation  c 2007 Blackwell Publishing Ltd Continued need of appropriate betalactam-derived skin test reagents for themanagement of allergy to betalactams M. Blanca , A. Romano , M. J. Torres , P. Demolyz and A. DeWeck‰ Allergy Service, Carlos Haya Hospital, M ´ alaga, Spain, Department of Internal Medicine and Geriatrics, UCSC-Allergy Unit, Complesso Integrato Columbus, Rome

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