Infertility

Do You Really Have Unexplained Infertility?

Miscarriage

“Unexplained infertility” is a rapidly increasing diagnosis amongst couples who are unable to conceive. About 30% of couples will be diagnosed when routine testing can’t find a cause for why they can’t get pregnant.

I believe that this diagnosis is overused and misleading for many couples. The liberal use of this diagnosis has lead to a rapid rise in the use of more aggressive fertility treatments. These treatments may carry greater risks to the mother and child compared to natural pregnancies (13-15). There are several studies that suggest waiting longer will result in a higher number of natural pregnancies, which is safer for many reasons.

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IVF & ART Are Linked To Higher Risk Pregnancies And Complications For The Baby

 
 

Jenny is a 28-year-old school teacher who was unable to get pregnant after one year of trying.   She and her husband had been married for two years, and were looking forward to starting a family.   Jenny did not really have any medical problems except that she was somewhat overweight and was dealing with a lot of stress in her life.   Her teaching hours were long, she didn’t have a lot of time to prepare meals at home and often ate out.   She would occasionally be able to go for a run but her knees were starting to bother her and she felt depleted after exercising.   Her periods were regular and she didn’t have any real hormonal complaints except becoming very moody before her period and experiencing a lot of bloating and heartburn with certain foods.   This was worse before her cycle.   She went to the infertility specialist and after many tests, she and her husband were told that she had “unexplained infertility.”   She then tried sperm inseminations with ovulation drugs for six months, with no luck.   Her infertility specialist recommended moving on to IVF.

Infertility

In this article I will be covering the basic evaluation for infertility, the conventional treatments that are offered for unexplained infertility and the concerns with these conventional therapies. Let’s start with IVF (in-vitro fertilization and ART (assisted reproductive technology) – both are linked to higher-risk pregnancies and complications for the baby.

  • There is a higher risk of twin and triplet pregnancies, which are, by definition, higher-risk pregnancies.   These pregnancies are associated with increased chances for diabetes, growth issues in the baby, premature birth and pre-eclampsia.
  • Some centers reduce the risk of twin and triplet births by encouraging Single Embryo Transfer, however this technique may be associated with a 50-70% increase in risk of preterm birth and birth defects (10-12).
  • A retrospective review of over 2300 IVF babies reported a higher chance of birth defects in the ART group compared to controls (19).
  • According to a review of IVF pregnancies by Pandey and colleagues, pregnancies after IVF were found to be associated with higher risks of complications during pregnancy and in the neonatal period.   More bleeding during pregnancy, birth defects, high blood pressure disorders, c section, low birth weight, premature delivery, and diabetes were noted compared to natural pregnancies (22).
  • According to Dr. Esme Kamphuis’ article published in the British Medical Journal in February 2014, “Concern has also been raised about the long term health of children born through IVF.   Otherwise healthy children conceived by IVF may have higher blood pressure, adiposity, glucose levels, and more generalized vascular dysfunction than children conceived naturally.” (16-18)
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The Basic Evaluation For Infertility

 
 

Infertility

The Basic Evaluation for Infertility

Eighty-percent (80%) of couples will become pregnant after one year of unprotected sex.   Couples who are not pregnant after one year should have a basic fertility evaluation.   A basic investigation can identify patients who who should not continue trying and who need immediate treatment.

 

  1. Check out your partner’s sperm — A Semen Analysis is a test to check for male infertility. Thirty-percent (30%) of the time this is the cause of a couple’s fertility problems.   A semen analysis checks the number, shape and movement of sperm noted in the sample.   If repeat testing is not normal, a urology referral is recommended.   A thorough hormone and anatomy exam should be done to uncover the causes of male infertility.
  2. Check the uterus and fallopian tubes — A special X-Ray test, known as a hysterosalpingogram, is done to check that the inner cavity of the uterus is normal and that the fallopian tubes are not blocked.   Saline sonography is used to check that the uterine cavity does not contain any polyps, fibroids or scarring that could block implantation.
  3. Check your ovulation — 40% of infertile women and 15% of couples with infertility have problems with ovulation.   Causes include PCOS (polycystic ovarian syndrome), thyroid disease, high prolactin levels, and issues with the hypothalamus, the part of the brain that controls hormone regulation.   Often these women have irregular periods, however, women with regular periods may have issues with the normal “release” of the egg from the ovary.
  4. Check your ovarian reserve — You can do testing to see if the quality of your eggs is preventing you from getting pregnant.   “Ovarian reserve” refers to the remaining egg supply available to make a baby. Testing includes:
  • Follicle Stimulating Hormone (FSH) level — This is a blood test done on the third day of your period to measure the FSH hormone, the main hormone involved in producing mature eggs in the ovary.   Normal FSH levels are generally under 9, but be aware that normal levels do not always correlate with normal ovarian reserve.
  • Anti-mullerian Hormone levels are considered more accurate than day 3 FSH testing.   These blood tests can show if the eggs are of poorer quality.   AMH levels are lower when follicles stop growing.   Levels below 1 ng/ml are associated with decreased fertility.
  • Ultrasound ovarian antral follicle count checks the number of early follicles seen on sonogram. When only a few follicles are visible, this suggests that there are fewer eggs available to be fertilized. Many believe this to be the best tool available for estimating ovarian reserve.   An antral follicle count is performed before ovulation. Fewer than 8 antral follicles may signal a possible poor response to drugs that stimulate ovulation and lower than average pregnancy rates during IVF.

Up to 30% of the time these tests fail to find the cause of infertility.   Fertility specialists will use the diagnosis of “unexplained infertility” and recommend starting treatment.   One of my concerns with this approach is that there seems to be a very rapid move to more aggressive artificial techniques on the part of the patients and the practitioner.

In the case of a woman who is older with diminishing ovarian reserve, it makes sense to treat more quickly.   But in couples with a younger female partner, IVF is often used without necessarily allowing the couple the time and support to conceive on their own with less intervention.

A randomized trial in the US (FASST trial) compared early access to IVF to the standard treatment with inseminations and ovarian stimulation before moving to IVF.   Both groups achieved a 75% pregnancy rate by 24 months (20).

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Treatment Of Unexplained Infertility

 
 

Infertility

Treatment of Unexplained Infertility

The standard treatment for unexplained infertility does not target a specific cause of infertility but instead uses more sophisticated and costly treatments to become pregnant.   We will discuss the pros and cons of these different approaches.

 

1. Expectant management:

This hands off approach caters to couples who do not necessarily have a fertility issue, but may simply need more time to get pregnant on their own.   Studies are divided on this subject.

According to a review of 45 published studies by Guzick and colleagues, expectant management resulted in only a 4% chance of becoming pregnant (1).

Another study looked at couples on a waiting list for IVF in the Netherlands.   They noted that couples became pregnant on their own 10% of the time over a 12-month period, with younger female partners achieving higher pregnancy rates (2). These studies support the idea of going directly to fertility treatments.

However, one Dutch study of 500 couples diagnosed with unexplained infertility showed that 60% were able to conceive naturally within 12 months following their initial evaluation in a fertility clinic (6).

Additionally, studies looking at the cost effectiveness of IVF in younger women with no obvious cause of infertility do not support this option if performed within 3 years of trying to conceive (9).

  • PROS: Trying longer than 1 year is a low-cost intervention.   It is non-invasive and some couples will become pregnant if given more time to naturally conceive.   I believe that there is evidence to support continuing natural conception efforts, but this should be decided on a case by case basis.   In addition, waiting a little longer to conceive should be coupled with active efforts to address less than optimal personal health issues.
  • CONS: Waiting longer may delay treatment in patients with undiagnosed ovarian reserve issues or couples who will just not benefit from waiting longer.   Delays in starting a family can be stressful, however, this should be balanced with the cost of treatment, and potential for long term risks of pregnancy, possible birth defects and developmental risks associated with ART.

2. Laparoscopy as a treatment for infertility:

Laparoscopy, a surgical technique that requires tiny incisions and a thin telescope to view inside the abdomen, is used to diagnose endometriosis.   Endometriosis is present in 15% of infertile women and can cause infertility.   In the past, it was thought that removing endometriosis could improve pregnancy rates.   Current literature does not support performing a laparoscopy in all patients with unexplained infertility as the data supporting benefit is conflicting (3).

  • PROS: Some studies show that removing visible endometriosis at the time of laparoscopy does improve pregnancy rates (4).
  • CONS: Earlier studies that showed benefit have not been reproduced in later trials.   Because laparoscopy is of questionable benefit and carries anesthetic and surgical risks of infection, bleeding and injury, I would not advise this as a treatment option at this time.

3. Intrauterine Insemination:

This involves placing washed sperm into the uterus around the time of ovulation.   It can be timed with an ovulation kit or with medications to “boost” ovulation.   Studies show that IUI with medications to boost ovulation increased pregnancy rates compared to IUI by itself (5).

  • PROS: There is plenty of support for the use of these less invasive techniques to achieve pregnancy
  • CONS: Ovulation induction techniques may be associated with an increased risk of twins and triplets, may carry an increased risk of poor pregnancy outcomes compared to naturally conceived pregnancies and can be associated with OHSS (Ovarian Hyperstimulation Syndrome).

4. IVF/ICSI:

This technique is now responsible for over 5 million children born worldwide.   The number of IVF cycles performed for patients with unexplained infertility has risen tremendously in the last 10 years.   IVF performed for patients with unexplained infertility in the UK tripled between 2000 and 2010 (7).   Some experts believe that IVF is being used too liberally and that these couples may simply need more time to become pregnant on their own.   According to one study of 350 couples planning a first pregnancy, 95% conceived on their own within 24 months (6).   Evidence from the Netherlands suggests that a majority of couples with unexplained infertility could expect to have natural pregnancy rates of over 50% if given more time to conceive (8).

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Are We Overusing IVF?

 
 

Infertility

Are we overusing IVF?

Although IVF has helped countless couples have families in the last 35 years, their use in couples with unexplained infertility is not well studied.

The potential harms of using IVF compared to natural conception are significant.   According to a study looking at pregnancy outcomes after IVF compared to natural pregnancies, the authors concluded that IVF patients should be advised of the increased risk of adverse outcomes (21).

Until these concerns are addressed, it may be best to use caution about recommending IVF in couples where chances of natural pregnancy are reasonable.   We should consider other ways to improve chances of pregnancy that do not necessarily involve an increased risk for mom and baby.

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Next Steps...

 
 

Infertility

Next Steps…

Most couples who have been trying for over a year to get pregnant are understandably very anxious to move forward with their plans to start a family.

One fear that many women have is that they will not be able to get pregnant at all.   This fear motivates many couples to immediately move to more aggressive techniques to help achieve pregnancy quickly.   Some experts believe that the rush to these therapies may not only be unnecessary but may increase pregnancy risks for mom and baby.

It is important to understand your fertility situation clearly so that you can make a more informed decision with regard to treatment.   Should you immediately proceed to ART?   Is it reasonable for you to wait a bit longer to check to see if there are healthier alternatives to boosting your fertility?

References:

  1. Efficacy of treatment for unexplained infertility. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, Steinkampf MP Fertil Steril. 1998 Aug; 70(2):207-13.
  2. Pregnancy chances on an IVF/ICSI waiting list: a national prospective cohort study. Eijkemans MJ, Lintsen AM, Hunault CC, Bouwmans CA, Hakkaart L, Braat DD, Habbema JD Hum Reprod. 2008 Jul; 23(7):1627-32.
  3. Laparoscopic surgery for subfertility associated with endometriosis.Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Farquhar C Cochrane Database Syst Rev. 2002; (4):CD001398
  4. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. Marcoux S, Maheux R, Bérubé S N Engl J Med. 1997 Jul 24; 337(4):217-22.
  5. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. National Cooperative Reproductive Medicine Network. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, Hill JA, Mastroianni L, Buster JE, Nakajima ST, Vogel DL, Canfield RE N Engl J Med. 1999 Jan 21; 340(3):177-83.
  6. Gnoth C, Godehardt E, Frank-Herrmann P, Friol K, Tigges J, Freundl G. Definition and prevalence of subfertility and infertility. Hum Reprod 2005;20:1144-7.
  7. Brandes M, Hamilton CJCM, de Bruin JP, Nelen WLDM, Kremer JAM. The relative contribution of IVF to the total ongoing pregnancy rate in a subfertile cohort. Hum Reprod 2010;25:118-26.
  8. Steures P, van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ, Broekmans FJ, et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility
  9. Mol BW, Bonsel GJ, Collins JA, Wiegerinck MA, van der Veen F, Bossuyt PM. Cost-effectiveness of in vitro fertilization and embryo transfer. Fertil Steril 2000;73:748-54.
  10. Dar S, Librach CL, Gunby J, Bissonnette F, Cowan L, IVF Directors Group of Canadian Fertility and Andrology Society. Increased risk of preterm birth in singleton pregnancies after blastocyst versus day 3 embryo transfer: Canadian ART Register (CARTR) analysis. Hum Reprod 2013;28:924-8.
  11. Källén B, Finnström O, Lindam A, Nilsson E, Nygren K-G, Olausson PO. Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome? Fertil Steril 2010;94:1680-3.
  12. Kansal Kalra S, Ratcliffe SJ, Barnhart KT, Coutifaris C. Extended embryo culture and an increased risk of preterm delivery. Obstet Gynecol 2012;120:69-75.
  13. 13. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261.
    Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 2012;18:485-503.
  14. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta- analysis. Obstet Gynecol 2004;103:551-63.
    Barnhart KT. Assisted reproductive technologies and perinatal morbidity: interrogating the association. Fertil Steril 2013;99:299-302.
  15. Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garcin S, et al. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation 2012;125:1890-6.
  16. Hart R, Norman RJ. The longer term health outcomes for children born as a result of IVF treatment: Part I. General health outcomes. Hum Reprod Update 2013;19:232-43.
  17. Pinborg A, Wennerholm UB, Romundstad LB, Loft A, Aittomaki K, Söderström-Anttila V, et al. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta- analysis. Hum ReprodUpdate 2013;19:87-104.
  18. Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, Delemarre-van de Waal HA. Growth and development of children born after in vitro fertilization. Fertil Steril 2008;90:1662-73.
  19. J Assist Reprod Genet. 2016 Jun;33(6):711-7. doi: 10.1007/s10815-016-0714-4. Epub 2016 Apr 26.Obstetric outcome and incidence of congenital anomalies in 2351 IVF/ICSI babies.Levi Setti PE1, Moioli M2, Smeraldi A2, Cesaratto E2, Menduni F2, Livio S3, Morenghi E4, Patrizio P5
  20. Reindollar RH, Regan MM, Neumann PJ, Levine BS, Thornton KL, Alper MM, et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010;94:888-99.
  21. Jackson RA1, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004 Mar;103(3):551-63.
  22. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A.Hum Reprod Update. 2012 Sep-Oct; 18(5):485-503. Epub 2012 May 19.