Addition of 24-chromosome microarray analysis to standard testing identifies a probable or definitive cause in over 90% of recurrent miscarriages

http://www.ucl.ac.uk/

The new method of 24 Chromosome Microarray, or comprehensive chromosomal screening when added to the standard Recurrent Pregnancy Loss (RPL) evaluation of American Society for Reproductive Medicine (ASRM) could provide a probable or definitive cause in over 90% of patients reports the result of a small prospective cohort study published 1 April 2018 in Journal of Human Reproduction.

In the absence of definitive etiologies and treatment strategies, RPL is one of the most frustrating and difficult to treat entity in reproductive medicine. It affects 2%-5% of couples and a cause can be found only in 50% of the couples after undergoing the standard ASRM workup.

This single-center study included 100 patients from a private RPL clinic from 2014 to 2017. The maternal age was between 26 to 45 years.

All 100 women had two or more pregnancy losses, with a complete evaluation for RPL as defined by the ASRM, and miscarriage tissue evaluated by 24-chromosome microarray analysis after their second or subsequent miscarriage.

In 95 of 100 patients, a probable or definitive cause of pregnancy loss was identified when 24-chromosome microarray analysis was combined with the standard ASRM RPL workup evaluation at the time of second or subsequent miscarriage.

The standard ASRM RPL workup done alone could only identify an abnormality or cause of miscarriage in 45 of 100 patients while 24-chromosome microarray analysis identified an abnormality in 67 of 100 patients when performed as the initial test on miscarriage tissue.

In only 5 of 100 patients, no cause could be found even after combined testing by ASRM RPL workup and 24-chromosome microarray analysis.

The authors concluded that combining the standard workup and genetic evaluation on miscarriage tissue obtained at the time of the second and subsequent pregnancy losses could offer much more answers towards the probable or definitive cause of RPL. It should be routinely offered to couples who have had two or more consecutive pregnancy losses.

Abstract

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Low serum AMH levels doubles the risk of miscarriage after in vitro fertilization–embryo transfer

geneticliteracyproject.org

Patients with low serum antimüllerian hormone (AMH) levels face a  33% higher risk of miscarriage as compared to women with high AMH says results of a university affiliated single center cohort study published in September issue of Journal Fertility and Sterility.

The researchers looked at AMH levels of more than 2,000 patients undergoing 2,688 IVF cycles with fresh oocytes, who attained a clinical pregnancy after IVF-ET. These patients had their centralized serum AMH levels measured within 1 year before they underwent embryo transfer.

It was seen that patients with reduced AMH levels suffered significantly more pregnancy losses as compared to women with normal AMH levels which remained the same after controlling for age and ovarian response to stimulation, which indicates that AMH is also a marker of reproductive potential and not just the number of oocytes.

AMH levels lower than 1.61 ng per mL were considered low but a definite cut-off could as the values vary by the test type.

A subgroup analysis of women according to age showed that in women older than 33 (34-36 and 37 and above) low serum AMH was associated with 33% miscarriage rate as compared to women with AMH > than 5.6 ng per mL, which was nearly twice as compared to women less than 33 years.

On the other hand, in women aged 33 and below, low serum AMH resulted in 22% rate of miscarriage, compared with about 13% among women with higher AMH levels, which was not statistically significant. But, when age was taken as single variable, the results were statistically significant.

The paper was also presented at October 2016 Annual meeting of the American Society for Reproductive Medicine in Salt Lake City, Utah.

No genetic testing of the embryos transferred or expelled products of conception was carried out to link the miscarriages to abnormalities such as aneuploidy.

Luteal Start Vaginal Micronized Progesterone ups the rate of ongoing pregnancy in RPL.

vaginal micronized progesterone

Recurrent pregnancy loss (RPL) is one of the most traumatic and frustrating experience for patients and consulting obstetricians. It is an area of obstetrics lacking in evidence based diagnostic and treatment strategies. As per data by American Society for Reproductive Medicine(ASRM) it affects 15-25% of all pregnancies and in nearly 50% of cases the cause is not known.

Courtesy:Dr.Malpani Blog

Therapeutic interventions are generally based on the cause of RPL and data from observational studies and clinical experiences of the treating obstetrician. Treatment options range from active interventions in the form of hormonal supplementation to masterly inactivity (= reassurance).[i]

Progesterone (P) has long been used in the treatment of infertility because of its immunomodulator action on endometrium but it’s use is largely empirical along with other treatment regimen.  Cochrane review and meta-analysis concluded that P supplementation could improve the reproductive outcome in women with 3 or more pregnancy loss.

But, in none of these studies P was started after LH surge (luteal start) and varied route and dosing of P administration was used. [ii]

A new study published on line on January 9, 2017 in Fertility & Sterility international journal of the American Society for Reproductive Medicine assessed the effectiveness of luteal start vaginal micronized P in a recurrent pregnancy loss (RPL) cohort.

In this observational, cohort study 116 women with a history of RPL were recruited and followed prospectively. Vaginal micronized progesterone was supplemented in dose of 100–200 mg every 12 hours starting 3 days after LH surge (luteal start corresponding to day 13 of the cycle) with or without >20% increase in levels of nuclear cyclin E (nCyclinE) expression. The controls did not receive P and had normal nCyclinE (≤20%). P was continued till 10 weeks of pregnancy.

The research team lead by Dr. Mary D. Stephenson tested Nuclear cyclin E (nCyclinE) levels to assess the state of endometrium. It is an endometrial molecular marker(EFT) and a cell cycle regulator, levels more than 20% after day 20 of the menstrual cycle correlates with a history of infertility. NCyclinE expression was determined by an EB was performed 9–11 days after the LH surge in previous cycle.

Of 116 women tested, 59 had high levels of nCyclinE and 57 had normal levels.

The results of the test were very promising with 68% pregnancy rate in study group as compared to women who did not take P. The chances of successful pregnancy increased from 6% to 69% in treatment group.

Six women needs to be treated with P to achieve one additional successful pregnancy.( Number need to treat). 

This observational study cannot establish causality, the researchers believe that P is beneficial in changing the endometrial milieu and benefitting the developing embryo.   

Dr. Stephenson said “The positive results show us that next we need to study progesterone as a treatment for recurrent pregnancy loss with a prospective randomized trial to validate the findings." 

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[i] http://blog.drmalpani.com/2016/08/pgs-for-recurrent-pregnancy-loss-forget.html

[ii] Haas, M.D. and Ramsey, P.S. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013;: CD003511