Unexplained Infertility Research Papers

Unexplained Infertility Treated with Acupuncture and Herbal Medicine in Korea

1Asian Medicine & Acupuncture Research, Department of Physical Medicine & Rehabilitation, University of North Carolina at Chapel Hill, NC.

2Division for Research and Education for Complementary & Integrative Medical Therapies, Harvard Medical School, Osher Research Center, Boston, MA.

3Conmaul Hospital, Seoul, Republic of Korea.

4Korea Food & Drug Administration, National Institute of Toxicological Research Biostatistics Division, Seoul, Republic of Korea.

Corresponding author.

Address correspondence to: Jongbae J. Park, K.M.D., Ph.D., Asian Medicine & Acupuncture Research, Department of Physical Medicine & Rehabilitation, University of North Carolina at Chapel Hill, 1st Floor, North Wing, UNC Hospitals, Campus Box #7200, Chapel Hill, NC 27599. E-mail:ude.cnu.dem@krap_eabgnoj

Author information ►Copyright and License information ►

Copyright 2010, Mary Ann Liebert, Inc.

Jongbae J. Park, K.M.D., Ph.D.,1,,2Myungja Kang, K.M.D., Ph.D.,3Sangseop Shin, M.D.,3Eunmi Choi, K.M.D., Ph.D.,3Sukyung Kwon, K.M.D.,3Hyosun Wee, K.M.D.,3Bonghyun Nam, Ph.D.,4 and Ted J. Kaptchuk, O.M.D.2

Abstract

Aim

We aim to determine the safety and effectiveness of a standard therapeutic package of Korean medicine for the treatment of unexplained infertility in a cross-section of women who sought treatment at an integrative hospital in Seoul, Korea.

Background

Infertility affects more than 1.2 million women in the United States alone. Treatment options for infertility vary, yet the barriers of invasiveness, cost, and access inhibit treatment use for many women. Alternative medical approaches exist for this indication, and sustain certain popularity. Therefore, we systematically studied a standard therapeutic package of Korean medicine to treat unexplained infertility in women.

Methods

Female participants included in this observational study met inclusion criteria before receiving a set of treatments including herbal medicine, acupuncture, and moxibustion. A study physician screened each patient in accordance with inclusion criteria, provided study information, and after the patients consented, performed the baseline assessment. Assessments included age, the history of assisted reproductive technology, and duration of infertility. The key outcome measure included the number who achieved pregnancy and any neo-natal morbidity and mortality at follow-up stage for those who got pregnant. Any other adverse events including aggravation of existing symptoms, and the number of dropouts, were recorded. Treatments were supposed to be completed after 6 menstrual cycles between February 2005 and April 2006.

Results

One hundred and four (104) women with unexplained infertility were included in this observational study. Participant mean age was 32 years (SD: 2.7), with a range between 26 and 41 years. The median duration of infertility after diagnosis was 33.5 weeks (interquartile range: 20.8–50.3). In total, 41 participants (39.4%) had undergone a mean number of 1.4 (SD: 2.2) assisted reproductive technology treatments prior to joining the study. The number of patients remaining in or achieving pregnancy throughout the 6-month study period was 23 (14 pregnancies), 22.1%. Six (6) participants (4.8%) reported minor adverse events including rash in the face (n = 1), diarrhea (n = 2), dizziness (n = 1), and heartburn (n = 2). Of the 14 pregnancies, there were 10 normal births, and 4 miscarriages; otherwise, no neonatal morbidity/mortality occurred. According to per protocol analysis, 14 pregnancies out of 23 total were achieved by those who remained for the entire six menstruation cycle treatments, yielding a pregnancy rate of 60.9%.

Conclusions

The standard therapeutic package for unexplained infertility in women studied here is safe for infants and the treated women, when administered by licensed professionals. While it remains challenging to have the target population complete a 6-month treatment course, during which most patients have to pay out of pocket, the extent of successfully achieved pregnancy in those who received full treatment provides meaningful outcomes, warranting further attention. A future study that includes subsidized treatment costs, encouraging the appropriate compliance rate, is warranted.

Introduction

Of the approximately 62 million American women of reproductive age in 2002, 1.2 million (2%), had an infertility-related medical appointment within the previous year, and 10% had an infertility-related medical visit at some point in the past.1 This common and frustrating medical condition can take a significant emotional and physical toll on women and their partners. The burden of infertility includes the frequent psychopathologic consequences of anxiety, depression, crisis within the relationship, divorce, and lack of self-reliance.2,3 Because of such negative consequences, it is desirable to find cost-effective and successful therapies for infertility.

Typical Western treatments for infertility include medication (hormone stimulation), surgical correction of anatomical defects, or artificial insemination. For couples who do not benefit from these treatments, the remaining options include gamete intrafallopian transfer, intracytoplasmic sperm injection, in vitro fertilization, and zygote intrafallopian transfer. Although all of these therapies can be successful, they are often expensive, invasive, and time consuming. With the introduction and integration of Eastern medicine into Western practices, there has been an increase in the acceptance and use of complementary practices in dealing with infertility.4,5 The anxiety and depression that are often associated with infertility has made alternative and combination therapies a realistic and beneficial option for those faced with varied types of infertility. Any noninvasive, non-time-consuming, and cost-effective manner of alternative therapies can also be viewed as a patient benefit. The now common use of acupuncture has proven effective for endocrine stimulatory and regulatory interventions.6

While conventional treatment options are well established, there have been few systematic reviews of CAM approaches for the treatment of infertility.7 Several studies have reported the use of acupuncture as a treatment for various gynecologic conditions,8 while others have reported case studies on the use of Traditional Chinese Medicine (including herbs and acupuncture) for treating infertility.9,10 While the proponents of these therapies value their safety, minimally invasive approaches, and minimal side-effects, there have not been thorough reviews or studies to assess the effectiveness of traditional approaches for treating infertility. Bridging the gap in knowledge and practice between Western and Eastern medicine as well as looking at how medicine is practiced in under studied medical systems11 are important issues in the fertility field.

In South Korea, where the traditional system of medicine has evolved into an integrative approach, a significant population of infertile patients seeks health services from clinics and hospitals of Korean medicine. Medicine in Korea, while it has evolved with influence from and exchange with Traditional Chinese Medicine, has developed and sustained various unique aspects. This is the rationale to use the term, Korean medicine. The Conmaul Hospital (Seoul, Korea) is well known as an infertility specialty clinic, where an integrated service between Medical Doctor (M.D.) and Korean Medicine Doctor (K.M.D.)12 is provided. The scope of its service includes diagnosis and treatment packages including herbs, moxibustion, and acupuncture. This study is a prospective observational study of the integrative care package provided to treat specifically “unexplained female infertility.” Herein we describe the participation, outcomes, and any adverse events related to this integrative care package. This population either has few established conventional treatment options, or has experienced a substantial number of failures from the prior use of conventional treatments.

Methods

This study evaluates the outcome of 104 women who received treatment using a standard therapeutic package for unexplained infertility at Conmaul Hospital in Seoul, Korea. All participants were treated for six menstrual cycles between February 2005 and April 2006. The women received treatment with a standard therapeutic package of Korean Herbal Medicine, acupuncture, and moxibustion for their unexplained infertility. Treatment was cumulative and not contingent upon use of the standard therapeutic package in consecutive months. Those study participants who missed three consecutive monthly treatments were contacted by a physician to determine the reason for discontinuation.

Inclusion criteria for study participation included all of the following: unexplained infertility confirmed with laparoscopy and ultrasonography, regular menstrual cycle of 25–35 days, no infertility factor in their male partner, clear communication skills with hospital researchers, and normal hormonal test result range. If all of the inclusion criteria were verified within the 12 months prior to initiation of participation, women were included. Women were excluded from the study when the inclusion criteria were not met, or if hormone supplementation (including clomiphene citrate13), in vitro fertilization or intrauterine insemination treatments were undertaken during the 6-month study period. Those women with minimal/mild endometriosis were included in the study, as were women over the age of 35 (age typically classified as the cutoff for high-risk pregnancies to develop).

Standard therapeutic package intervention

A study physician screened each patient in accordance with inclusion criteria, provided study information, and after obtaining consent, completed a baseline assessment. After screening, women were subjected to the standard therapeutic package for unexplained infertility for up to six menstruation cycles and ceased treatment when conception was confirmed with ultrasonography. This package included (1) water-extracted decoction (120 mL) of herbal prescription prepared through individual diagnosis given three times a day 30 minutes after meals; (2) a pack of Song Keum Dan taken with warm water 30 minutes before meals 3 times daily. This herbal medicine pill, referred to in Dong-Yi-Bo-Gam, an encyclopedia-style Korean medical text published in 1659, contains 214 mg of dried powder of Paeonia moutan, Angelica tenuissima, Panax ginseng, Angelica sinensis, Poria cocos, Angelica dahurica, Cinnamomum cassia, Marsdenia longipes, Cnidium officinale, Corydalis ternata, Paeonia albifloria, and Atractylodes japonica; and 107 mg of dried powder of Glycyrrhiza glabra and Achyranthes japonica per each pack; (3) moxibustion on umbilicus (CV8) done once daily except during the menstrual cycle; and (4) herb acupuncture (injection of extracted solution of dried Cervi Parvum Cornu and Hominis Placenta onto acupuncture points, at each point 0.3 mL containing 0.06 mg of the two herbs) on mainly CV4, BL19, and BL22. All women who achieved pregnancy during the observational period were followed up until birth.

Outcome measures

The baseline data included age, the history of assisted reproductive technology, and duration of infertility. The key outcome measure was the number of participants achieving pregnancy. Patients were also asked to inform the study physician whether they complied with the standard therapeutic package, and whether they have attempted to conceive, and to report the aggravation of any existing symptoms. Also, the number of dropouts and adverse events in the patient population were recorded.

The study protocol included the collection of details on menstruation period and related symptoms including length of menstrual cycle, the color of menstrual blood on the second or third day of menstruation using the Munsell color system, the amount of menstrual blood per day of significant bleeding during the total menstrual period, the number of pads used, and the existence of blood clots observed with the naked eye (score 0 if no clot, 1 with the diameter <1 cm, and 2 with the diameter ≥1 cm). A visual analogue scale of menstrual pain, breast pain, and breast swelling was also asked. All of the above data were to be used as indicators of reproductive health status in the patient base, including infertility and ovulation. However, these data were not analyzed due to the lack of compliance on the part of patients.

The assessment forms for each participant were given a unique identifier number and kept in a locked filing cabinet. All data analysis was done offsite at Harvard Medical School, Boston, and was securely maintained. The study IDs for each participant were maintained such that participant anonymity was never compromised. Approval for this primary study was obtained from the Institutional Review Board at Conmaul Hospital, and the data analysis of the de-identified data was approved by the Harvard Medical School Institutional Review Board. After the completion of data analysis and the drafting of the manuscript, the Principal Investigator (J.P.) moved to the University of North Carolina at Chapel Hill and finalized the manuscript.

Results

One hundred and four (104) women with unexplained infertility were included in this observational study. Their mean age was 32 years old (SD: 2.7), ranging between 26 and 41. The median duration of infertility after diagnosis was 33.5 weeks (interquartile range: 20.8–50.3). In total, 41 participants (39.4%) had undergone a mean number of 1.4 (SD: 2.2) assisted reproductive technology treatment attempts prior to joining the study.

The flow of the study is shown in Figure 1. The number of patients remaining in or achieving pregnancy throughout the entire study period of 6 months was 23 (14 pregnancies), or 22.1%. Slightly more than half (n = 55) dropped out before reporting their third menstruation cycle. The trend of dropout was high in the early stage and gradually decreased. Out of 14 pregnancies, there were 10 normal births, 4 miscarriages, and no stillbirth. Otherwise, there was no neonatal morbidity/mortality. Total monthly cost for the treatment package was about $500.

FIG. 1.

Flow of an outcome study of an infertility clinic of Korean Medicine for unexplained women's infertility.

Six (6) participants (5.8%) reported minor adverse events including rash in the face (n = 1), diarrhea (n = 2), dizziness (n = 1), and heartburn (n = 2). All of the symptoms were mild, and eased after patients stopped taking the specific herbal medicine; no hospitalization was required. Figure 2 shows reasons stated for individual dropouts. The most frequently cited reason was “personal reasons,” which may be a polite way of expressing difficulty or unwillingness to afford this treatment ($500/month).

FIG. 2.

Reasons for dropouts from an outcome study of an infertility clinic of Korean Medicine for unexplained women's infertility. Tx, treatment; AE, adverse events.

Regarding the success rate for achievement of pregnancy, 14 of 23 patients remained in the study for six menstrual cycles achieving a pregnancy rate of 60.9%. This success rate must be considered in light of the high dropout rate for participants in this study.

Discussion

The use of acupuncture, moxibustion, and herbal medicine has deep roots in women's health in Korea. In this study, we attempted to record the results of such practices pertaining to unexplained female infertility. The use of the standard therapeutic package used in this study is safe and minimally, if at all, risky. The absence of teratogenic or reported neonatal morbidity and mortality solidifies the place of such treatment packages alongside other established medical, natural, and self-administered (drug) infertility interventions. The adherent group of women achieved a successful pregnancy outcome at a rate of 60.9%. Upon assuring appropriate compliance rates (through insurance support, availability of services, positive outcomes reported in the literature, etc.), a promising outcome can be anticipated. Meanwhile, the patients' full comprehension regarding scope of treatment and willingness to comply with it when entering into the course of treatment seems crucial, as the high number of dropouts in the early study stages adversely affected the overall study.

The outcomes that were obtained in the group that completed the study as well as those that dropped out are significant. Although the success for achieving pregnancy is downplayed by the number of dropouts in the study, if more than 22.1% of the initial subject group had followed through until the end, the outcomes might have provided a strong call for the implementation of noninvasive Eastern medical practices to be more than an adjuvant therapy for infertility. Although completion rates for observational studies on infertility may range as high as 90% in studies that involve a stipend,14 it is our understanding that our completion rate of 22.1% in an observational study (which should be markedly less than any designed cohort or case–control study) that asked for a capitation payment from the subjects was acceptable. In contrast to studies where treatments were provided free of charge, in this observational study participants had to pay for their individual treatment. The personal reasons for dropping out could also include unreported illness, emotional or psychologic burden, and loss of interest, which the investigators regret we did not classify in detail. The movement of patients out of the area as well as the desire to seek other treatment options, and administrative issues in contacting participants accounted for the remainder of patients who did not complete the treatment course.

It is important to understand the complex array of effects that play into the seeking out of and adherence to treatment in regard to fertility. In the realm of unexplained in fertility, especially where patients have no pointed abnormality with hormone levels, or physical impediments that have been diagnosed, the emotional and psychologic toll is overarching. To achieve success and completion with the standard package of care in this difficult situation is promising. One interesting point to interpret in future study results will be to look at the demographic composition of women who did complete the treatment. As such a large percentage of dropouts stated that “personal reasons” were the impetus for lack of completion, it brings forth the question, why did personal reasons not get in the way of adherence for those women who completed treatment? Is this group older and therefore more prone to follow through without regard to time constraints or economic detriment? Is this group more inclined to participate in this traditional and noninvasive type of care in other aspects of their lives? Or simply, does this group live closer or have substantial economic means to achieve the final outcome of visiting for a combined six menstrual periods? In addition, are women in this group more desperate for conception than the others?

As we look at previous studies of traditional care for infertility, there is insufficient literature looking at Korean medical practices and their influence on infertility. Much of the current literature on traditional medicine and infertility deals with male infertility, includes the use of medical procedures in conjunction to Eastern medicine,7 or comes from Indian or Chinese researchers who use similar but decisively different methods from those of this study. These alternatives include the use of numerous similar yet different herbs, but exclude the use of acupuncture and herbal pills. Therefore, research in this area is to an extent novel and in its own right a worthwhile endeavor.

The use of traditional Korean medicine has become very appealing to patients as a primary or adjuvant therapeutic tool. The mixed results reported by many researchers in regard to fertility-related outcomes can be explained by the standardization of treatments and therefore lack of personalized care plans.15,16 While further discussion of the individual treatments included in the package is beyond the scope of this study, there may certainly be a benefit to this method of treatment.

This observational study into unexplained infertility treatment would further benefit from work done in the following aspects: (1) investigating the outcomes of consecutive treatment in contrast to a cumulative treatment over a number of months on the success of pregnancy and other symptoms of menstruation; (2) studying detailed categories of reasons for the discontinuation of treatments, including cost and confidence in the treatment; (3) carrying out matched comparative studies on women with unexplained infertility who did not use the standard therapeutic package from Conmaul Hospital versus women who did (introduction of a specific control); (4) investigating outcomes of the standard care package for this unexplained infertility in regard to general health and wellness. What other benefits or detriments can be associated with the package, as most herbal therapeutic packages have extensive effects; (5) looking at distinct groups of women younger than and older than 35, the age commonly designated as when pregnancies become high risk, and the possible difference in treatment outcomes; and (6) performing a similar study with free treatment. Through looking at women who are not self-selected based upon access to hospital care (through economic and motivational means), a better understanding of the population-level effectiveness of CAM fertility package therapy as a whole could be understood.

Upon completion of this study, the limitations of an observational study in the Conmaul Hospital were typified by the relatively low adherence rate of participants. At the same time, the success rate of the standard therapeutic package for treatment of unexplained infertility was strengthened. Overall, whether or not pregnancy was achieved, and whether or not participants finished treatment, or infertility persisted, the multiple psychologic and physiologic problems associated with unexplained infertility were studied and provided a baseline for future research on this meaningful complementary subject field.

In summary, this study is a starting point for future research. Although a large percentage dropped out of the study for myriad nonspecified reasons, the treatment for infertility was beneficial in the small cohort who utilized it as prescribed. Therefore, future research into the mechanisms of action for individual treatment components, the cost effectiveness of the treatment versus conventional infertility methods, and the overall success rate in a double-blind placebo-controlled study, could act to solidify this treatment method as a positive option for women with unexplained infertility.

Acknowledgments

Jongbae Park and Bonghyun Nam acknowledge the grant provided to the Harvard Medical School by the Myung Kyung Medical Foundation (account number #520-45578-225011). Ted J. Kaptchuk was supported by NIH-NCCAM grant #K24 AT004095. In addition, the assistance of Stephen Flaherty in manuscript preparation is sincerely appreciated.

Disclosure Statement

No competing financial interests exist.

References

1. Centers for Disease Control and Prevention. Assisted Reproductive Technology.http://www.cdc.gov/ART/ [Jun 16;2008 ]. http://www.cdc.gov/ART/

2. Fassino S. Garzaro L. Peris C, et al. Temperament and character in couples with fertility disorders: A double-blind, controlled study. Fertil Steril. 2002;77:1233.[PubMed]

3. Fassino S. Piero A. Boggio S, et al. Anxiety, depression and anger suppression in infertile couples: A controlled study. Hum Reprod. 2002;17:2986–2994.[PubMed]

4. Beal MW. Women's use of complementary and alternative therapies in reproductive health care. J Nurse-Midwifery. 1998;43:224–234.[PubMed]

5. Stankiewicz M. Smith C. Alvino H. Norman R. The use of complementary medicine and therapies by patients attending a reproductive medicine unit in South Australia: A prospective survey. Aust N Z J Obstet Gynaecol. 2007;47:145–149.[PubMed]

6. Dong C. Chen SR. Jiang J, et al. Clinical observation and study of mechanisms of needle-picking therapy for primary infertility of abnormal sperm. Chin Acupuncture Moxibustion. 2006;26:389–391.[PubMed]

7. Manheimer E. Zhang G. Udoff L, et al. Effects of acupuncture on rates of pregnancy and live birth among women undergoing in vitro fertilisation: Systematic review and meta-analysis. BMJ Clin Res Ed. 2008;336:545–549.[PMC free article][PubMed]

8. Chang R. Chung P. Rosenwaks Z. Role of acupuncture in the treatment of female infertility. Fertil Steril. 2002;78:1149–1153.[PubMed]

9. Stone JA. Yoder KK. Case EA. Delivery of a full-term pregnancy after TCM treatment in a previously infertile patient diagnosed with polycystic ovary syndrome. Altern Ther Health Med. 2009;15:50–52.[PubMed]

10. Du Y. Zhao Y. Ma Y, et al. Clinical observation on treatment of 2,062 cases of immune infertility with integration of traditional Chinese medicine and western medicine. J Tradit Chin Med. 2005;25:278–281.[PubMed]

11. van Balen F. Visser AP. Perspectives of reproductive health. Patient Educ Counseling. 1997;31:1–5.[PubMed]

12. Stevens L. Duarte H. Park J. Promising implications for integrative medicine for back pain: A profile of a Korean hospital. J Altern Complement Med. 2007;13:481–484.[PubMed]

13. Costello MF. Emerson S. Miranda T, et al. Case series case series of a single centre's treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination in 2002. Aust N Z J Obstet Gynaecol. 2004;44:156–159.[PubMed]

14. Hakim R. Gray R. Zacur H. Infertility and early pregnancy loss. Am J Obstet Gynecol. 1995;172:1510–1517.[PubMed]

15. Anderson BJ. Rosenthal L. Acupuncture and IVF controversies. Fertil Steril. 2007;87:1000.[PubMed]

16. Stener-Victorin E. Humaidan P. Use of acupuncture in female infertility and a summary of recent acupuncture studies related to embryo transfer. Acupunct Med. 2006;24:157–163.[PubMed]

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Abstract

STUDY QUESTION

What is the percentage of overtreatment, i.e. fertility treatment started too early, in couples with unexplained infertility who were eligible for tailored expectant management?

SUMMARY ANSWER

Overtreatment occurred in 36% of couples with unexplained infertility who were eligible for an expectant management of at least 6 months.

WHAT IS KNOWN ALREADY

Prognostic models in reproductive medicine can help to identify infertile couples that would benefit from fertility treatment. In couples with unexplained infertility with a good chance of natural conception within 1 year, based on the Hunault prediction model, an expectant management of 6–12 months, as recommended in international fertility guidelines, prevents unnecessary treatment.

STUDY DESIGN, SIZE, DURATION

A retrospective cohort study in 25 participating clinics, with follow-up of all couples who were seen for infertility in 2011–2012.

PARTICIPANTS/MATERIALS, SETTING, METHODS

In all, 9818 couples were seen for infertility in the participating clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis of natural conception (>30%) within 1 year based on the Hunault prediction model. Data to assess overtreatment were collected from medical records. Multilevel regression analyses were performed to investigate associations of overtreatment with patient and clinic characteristics.

MAIN RESULTS AND THE ROLE OF CHANCE

Five hundred and forty-four couples eligible for expectant management were included in this study. Among these, overtreatment, i.e. starting medically assisted reproduction within 6 months, occurred in 36%. The underlying quality indicators showed that in 34% no prognosis was calculated and that in 42% expectant management was not recommended. Finally, 16% of the couples for whom a correct recommendation of expectant management for at least 6 months was made, started treatment within 6 months anyway. Overtreatment was associated with childlessness, higher female age and a longer duration of infertility. No associations between overtreatment and clinic characteristics were found.

LIMITATIONS, REASONS FOR CAUTION

The response rate was low compared with other fertility studies. Evaluation of possible selection bias showed that responders had a higher socio-economic status than non-responders.

WIDER IMPLICATIONS OF THE FINDINGS

Our findings show that developing and publishing guideline recommendations on tailored expectant management (TEM) is not enough and that overtreatment still occurs frequently. Future research should focus on tailored efforts to implement guideline recommendations on TEM.

STUDY FUNDING/COMPETING INTEREST(S)

Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

TRIAL REGISTRATION NUMBER

www.trialregister.nl NTR3405.

unexplained infertility, expectant management, prognostic models, guideline adherence, implementation

Introduction

Over recent decades, the use of medically assisted reproduction (MAR) has increased enormously (Ferraretti et al., 2013). At a time where health care costs have increased greatly, it becomes even more important that fertility care is not only clinically effective and safe, but also cost-effective (Leavitt, 2001; Appleby, 2012). Regrettably, many MAR cycles are performed without evidence that such treatment is indicated or likely to be effective (Bensdorp et al., 2007; Steures et al., 2008; Veltman-Verhulst et al., 2012). Despite the growing use of MAR, the pregnancy and delivery rates have not increased over the last few years (Ferraretti et al., 2013). Due to the increasing costs not all societies can bear the costs of fertility care any longer (Chambers et al., 2012). Only a few societies fully reimburse fertility care (Jones et al., 2011). One important way to minimize societal costs, without a negative impact on couples with infertility, is to prevent overtreatment in infertile couples by reducing unnecessary MAR and related costs (van den Boogaard et al., 2013).

As well as the economic aspects, the reduction of unnecessary MAR is important to avoid exposing couples to the risks, complications and burdens associated with invasive treatments, which will not improve the chance of conception or decrease the time to pregnancy (Verhaak et al., 2002; Helmerhorst et al., 2004; Steures et al., 2008; Verberg et al., 2008; Custers et al., 2012).

To achieve a reduction of unnecessary MAR, it is important to distinguish couples who would actually benefit from MAR from the couples who do not, e.g. by the use of prognostic models (Brandes et al., 2011; Van Geloven et al., 2013). In infertile couples where no underlying cause of the infertility is found, the chances of a spontaneous pregnancy can be calculated with the Hunault prognostic model (Hunault et al., 2004; van der Steeg et al., 2007). If the chance of a natural conception within 1 year is good, meaning 30% or higher, fertility treatment does not increase the chance of an ongoing pregnancy compared with an expectant management of 6–12 months (tailored expectant management, TEM) (Steures et al., 2008; Custers et al., 2012). Therefore, for couples with unexplained infertility and a good prognosis, TEM is equally as effective as MAR and it does not expose couples to all the associated risks. Furthermore, the increasing costs of fertility care are making it necessary to improve the cost-effectiveness of current care. Therefore, current European guidelines recommend TEM for 6–12 months (e.g. National Institute of Clinical Excellence (NICE) and the Dutch Society for Obstetrics and Gynaecology (NVOG, www.nvog.nl)). Adherence to these guidelines with regard to TEM helps to prevent overtreatment.

However, previous studies have shown that implementation of TEM is limited by both professional and patient-related factors (van den Boogaard et al., 2011). The main barriers amongst professionals are limited knowledge about prognostic models and TEM, and difficulties in counselling couples for TEM. Barriers on the patient level include a lack of confidence in natural conception and not understanding the reason for expectant management. Furthermore, previous research in fertility care as well as other fields of care showed that a variety of patient and clinic characteristics can explain poor adherence to guidelines (Fine et al., 2002; Schouten et al., 2005; Hermens et al., 2011; van den Boogaard et al., 2011, 2012). However, evidence for characteristics related to TEM is scarce. More knowledge on these characteristics is important to help tailoring interventions to minimize overtreatment.

This study aims to assess overtreatment (i.e. started MAR too early) in couples with unexplained infertility that were eligible for TEM. Furthermore, we will evaluate the characteristics on patient and clinic level associated with overtreatment. The study will provide more insight in current care and will help to develop a strategy to prevent couples from starting fertility treatment too early in the future.

Materials and Methods

Study design

We conducted a retrospective cohort study in 25 Dutch clinics using medical records and a professionals' questionnaire. Furthermore, we evaluated a possible selection bias between responders and non-responders by conducting semi-structured telephone interviews with non-responders in six clinics.

Ethical approval

The institutional ethics committee of Radboud university medical center provided ethical approval for this study (CMO no. 2012/130).

Setting

Dutch fertility care

In Dutch fertility care, referral of infertile couples to secondary or tertiary care is mainly done by general practitioners (GPs), fertility doctors (medical doctors specialized in assisted reproduction), medical specialists, or on the patients' own initiative. Initial fertility work up, ovulation induction (OI) and intrauterine insemination (IUI) are carried out in all Dutch clinics. Intermediate clinics can start and monitor the IVF and ICSI treatment. The laboratory phase of IVF and embryo transfer has to be carried out in a fully licensed fertility clinic. To ensure that the 25 clinics were representative for Dutch fertility care, we selected six fully licensed fertility clinics, eleven intermediate fertility clinics and eight clinics with no IVF facilities, spread across the country, to participate. In the Netherlands, the compulsory basic insurance coverage fully reimburses all treatment cycles of OI and IUI, as well as a maximum of three IVF or ICSI cycles.

Dutch Network Guideline on Infertility

The Dutch Network Guideline on Infertility makes specific recommendations on TEM (www.nvog.nl). These recommendations are based on three steps.

The first step is correctly diagnosing and identifying couples that are eligible for TEM, i.e. calculating the chance of a natural conception within 1 year for couples with unexplained infertility with the prognostic model of Hunault (Hunault et al., 2004). The prognostic model takes four mandatory factors into account, female age (years), duration of infertility (years), type of infertility (primary/secondary) and quality of semen (percentage progressive motile sperm). Three factors are optional, referral status (GP/own initiative/professional), cervical factor (post-coital test positive/negative) and diagnosis of one-sided tubal pathology (yes/no). Professionals can have access to the prognostic model via a patient website (www.freya.nl), through local electronic patient file systems, or with the use of a paper version.

The second step is to recommend TEM for at least 6–12 months for couples with a good prognosis (>30% in 1 year) after finalizing the fertility work up.

The third step is to adhere to the advised expectant period of at least 6 months.

The first two steps have to be done by the professional. They have to correctly diagnose and identify the couple as being eligible for TEM, and subsequently have to advise an expectant management of at least 6–12 months. However, the third step is dependent on both the professional and the couple. If TEM is advised by the professionals, the guideline recommends that the couple is educated on the most fertile period, optimal coital frequency and healthy lifestyle factors to optimize the couples' chance of natural conception.

Study population

Couples were eligible to participate in our study when they have been diagnosed with unexplained infertility and had a good prognosis of a natural conception within 1 year based on Hunault's prediction model (Hunault et al., 2004). According to the Dutch fertility guidelines, the diagnosis of unexplained infertility is given if the fertility work up shows no cause for the infertility or if it shows mild abnormalities that are not significant enough to obstruct a natural conception. These include a cervical factor, one-sided tubal pathology, mild male infertility (total motile sperm count [TMSC] 3–10 million), and/or mild endometriosis (American Society of Reproductive Medicine stage I/II) (Wiersma and Nelen, 2010). Couples with previous fertility treatments, female age over 38 years, bilateral tubal pathology, anovulation or a severe male factor (TMSC <3 million) were excluded.

Recruitment

To assess overtreatment in current fertility care in the Netherlands, we aimed at including a broad patient cohort from the participating clinics. To include eligible participants, potential couples were selected by means of each clinics' financial DBC (Diagnosis/Treatment Combination code) registration database. In this national database, all patients undergoing diagnostics or treatment for infertility are identified with a specific Fertility-code for new patients (F11-code). It is not possible to distinguish patients with unexplained infertility from patients with a clear cause for their infertility with the existing databases. In order to select as many potential participants as possible we approached all couples who had an active F11-code anytime between March 2011 and February 2012. All couples were sent an informed consent form with an information letter, including five questions regarding the exclusion criteria, i.e. What is the age of the woman?, Have you had fertility treatment before 2011?, Are both Fallopian tubes occluded?, Do you usually have a regular menstrual cycle between 25 and 35 days (without medication)?, Have you been treated with ICSI since 2011?. If couples had no exclusion criteria based on these five questions, they were invited to participate in this study and give informed consent for accessing their medical record. Non-responders were sent one reminder after 3–4 weeks.

Non-responders

To evaluate a possible selection bias we compared responders to non-responders in six clinics. We selected six clinics with the lowest response rate, all types of fertility clinics were found to be represented (no/intermediate/full IVF facilities) and the clinics were spread across the country. A sample size of 15% of the non-responders in each clinic is necessary to retain a representative sample (Ronmark et al., 1999). In order to achieve this target, we decided to select a random, computer generated, sample of 20% of the non-responders in these clinics.

Outcome measures

Overtreatment

We defined overtreatment as starting fertility treatment too early when couples exhibited unexplained infertility and had a good prognosis of a natural conception within 1 year based on Hunault's prediction model. Too early means that they started treatment within 6 months after finalizing the fertility work up (date of the evaluation with the couple). To assess the process that leads to overtreatment we extracted a set of three quality indicators, based on the three steps that are necessary to follow guideline recommendations on TEM. Overtreatment is a result of at least one, or a combination of the following quality indicators.

Quality indicators

  • – The first indicator is failure to diagnose correctly and identify couples who are eligible for tailored expectant management, i.e. the prognosis of a natural conception within 1 year was not calculated.

  • – The second indicator is failure to advise the correct policy after finalizing the fertility work up, i.e. couples were not advised to undergo an expectant management of at least 6 months or couples who started fertility treatment immediately.

  • – The third indicator is failure to complete the expectant period of at least 6 months after TEM was advised, i.e. couples were advised the correct policy but started fertility treatment within 6 months anyway.

Data collection

Overtreatment and quality indicators

Data to assess overtreatment and quality indicators were abstracted from medical records using a standardized audit form. If the couple fitted the inclusion criteria, we collected the diagnostic measures and treatment related measures. Diagnostic measures included the fertility work up outcomes (e.g. semen analysis, post-coital test, hysterosalpingography, laparoscopy), the date of fertility work up completion/date of evaluation with couple (dd/mm/yy), initial diagnosis, and if calculation of prognosis was performed (yes/no). Treatment related measures included the course of treatment that was advised after fertility work up, the date of the start of treatment (mm/yy), treatment type and treatment outcome. We calculated the time interval between completion of fertility work up and start of treatment.

Patient and clinic characteristics

Data on patient characteristics were extracted from medical records using a standardized audit form. The patient characteristics are: female age(years), referral status (own initiative/GP/specialist), female obstetric history, type of infertility for the couple (primary/secondary), duration of infertility (years) and female body mass index (BMI kg/m2). Furthermore, we extracted postal area code to derive the socio-economic status (SES) of the couples (obtained from the Dutch Institute for Social Research/SC based on the mean income level in a postal area code).

Data on the clinic characteristics were obtained by sending a digital questionnaire to one gynaecologist, specialized in reproductive medicine, from each participating clinic. The questionnaire was divided in two parts. The first part contained questions about the local organization of the fertility care and the second part about the information provision. Characteristics on the organization of fertility care included IVF facilities (fully licensed/intermediate/no IVF facilities), training clinic (yes/no), professional functions (e.g. fertility doctor, fertility specialized nurse, research nurse) present in the fertility team (yes/no and number), availability of a regular fertility team meeting (yes/no and frequency), mean number of fertility consultations per gynaecologist per week, and assignment of one lead physician to each infertile couple who is responsible for every in-between evaluation and decision-making with the couple (yes/no). Characteristics on information provision included information available on TEM for couples with unexplained infertility (yes/no), and presence of checklists for information supply (yes/no).

Non-responders characteristics

Telephone interviews were performed to determine the characteristics of the non-responders by asking them the five questions that were in the information letter that was sent to all possible participants. The characteristics that we compared were female age (years), previous fertility treatment (yes/no), irregular menstrual cycle (yes/no), bilateral tubal pathology (yes/no), ICSI treatment (yes/no) and socio-economic status (high/medium/low). In order to reach as much of the selected non-responders, they were called a maximum of four times in case of no response: at least twice during daytime and twice in the evening between 5 pm and 8 pm. All interviews were performed using a standardized interview questionnaire and were recorded.

Data analysis

Collected data were entered in a database using the Statistical Package for the Social Sciences (SPSS 20.0 for Windows, SPSS, Inc., Chicago, IL, USA). Descriptive analyses were performed for overtreatment and the quality indicators, and were expressed as percentages (median and range on clinic level).

Descriptive analyses (frequencies and means) were also used to describe the patient and clinic characteristics. Series of multilevel univariate analysis were performed with overtreatment as the dependent variable. All patient and clinic characteristics acted separately as the independent variables. Variables with P < 0.20 in the univariate analysis were selected to perform correlation analysis with spearman's rho to evaluate collinearity between the selected characteristics. In case of two strongly correlating variables (rho > 0.6), only the clinically most relevant characteristic was included.

Subsequently, to assess the extent to which overtreatment could be explained by patient and clinic characteristics and taking clustering of data into account, multilevel multivariate regression analyses with manual backward elimination was carried out with the couple (level 1) nested within the clinic (level 2). Significance for multivariate analyses was set at P < 0.05.

Results

Study population

Figure 1 presents the recruitment of eligible participants in the study. Of the 9819 invited infertile couples with an F11 code between March 2011 and February 2012, 4283 (43%) infertile couples responded. While 855 couples refused participation or considered themselves ineligible, the other 3428 (80%) couples were willing to participate. Based on the answers to four of the questions in the information letter, 1965 couples were excluded prior to the medical record research. We excluded another 919 couples because medical record research revealed exclusion criteria. As a result, 544 infertile couples were included in the study.

Figure 1

Recruitment of eligible couples for participation in the study. *A combination of exclusion criteria can occur within a couple. aFertility work up not completed: Spontaneous pregnancy before completion of fertility work up (n = 144), Fertility work up completed before or after the inclusion period (n = 76).bFemale infertility: Anovulation (n = 90), Tubal pathology (n = 11), Endometriosis (n = 14).cNo infertility: recurrent miscarriage, molar pregnancy, uterine myoma, extra-uterine pregnancy, preimplantation genetic diagnosis, duration of active child wish less than a year. dOther: lesbian couple, weight reduction programme, oocyte vitrification.

Figure 1

Recruitment of eligible couples for participation in the study. *A combination of exclusion criteria can occur within a couple. aFertility work up not completed: Spontaneous pregnancy before completion of fertility work up (n = 144), Fertility work up completed before or after the inclusion period (n = 76).bFemale infertility: Anovulation (n = 90), Tubal pathology (n = 11), Endometriosis (n = 14).cNo infertility: recurrent miscarriage, molar pregnancy, uterine myoma, extra-uterine pregnancy, preimplantation genetic diagnosis, duration of active child wish less than a year. dOther: lesbian couple, weight reduction programme, oocyte vitrification.

Non-responders

In the six selected clinics 1403 couples did not respond. We tried to contact 290 of these non-responder couples (20%) and 190 (66%) were reached and willing to participate in the telephone interviews and 142 (49%) of them answered all the additional questions necessary to assess the background characteristics. We compared those background characteristics of the non-responders to the responders in all 25 participating clinics in this study (Table I

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