By Prof. Vajira H. W. Dissanayake

Published in the News Letter of the Perinatal Society of Sri Lanka, June 2007.

Recurrent pregnancy loss, defined as the spontaneous loss of three or more consecutive pregnancies, affects between 0.5 and 3% of couples (Li et al., 2002). Several etiological factors have been proposed as a cause for recurrent pregnancy losses.

The risk of recurrent pregnancy loss is significantly increased in women with thrombophilias (Sarig et al. 2002). There are three very well recognised genetic thrombophilic polymorphisms. They are the Factor V 1691G>A, Prothrombin 20210G>A and Methylenetetrahydrofolate (MTHFR) 677C>T polymorphisms. The association of the ‘mutated’ alleles of these polymorphisms [Factor V 1691A; Prothrombin 20210A; MTHFR 677T] with recurrent pregnancy loss has been one of our interests. We have so for tested 145 women with recurrent pregnancy loss. The Factor V 1691A allele was found in 3 (2%) women and the MTHFR 677T allele was found in 34 (23%) women. The Prothrombin 20210A allele was not found in any woman. Two women were homozygote for MTHFR 677TT. One woman had both factor V 1691A and MTHFR 677T alleles. Women with the thrombophilic alleles have been provided with counselling and referred back with advice on further management which include prophylactic anticoagulation and/or folate supplementation.

At least 50% of spontaneous abortions in the first trimester are associated with genetic abnormalities (Daniely et al, 1998). When couples with recurrent pregnancy loss are subjected to karyotypic analysis however, chromosome anomalies that could give rise to recurrent pregnancy losses are noted in only 6.2% of the women and 2.6% of the men (Daniely et al 1998). This has been our experience as well, where in the year 2006, out of 57 men and 54 women karyotyped because of recurrent pregnancy loss only 3 (5%) men and 6 (11%) women had chromosome abnormalities. The abnormalities detected were 46,XY/47,XXY; 46,XY/46,XYdel(12)(q13-q14); 46,XY/46,XY, del(1)(q42-q44); 46,XX/46,XX,dup(4)(q12-q21); 46,XX/46,XX del(6)(p21.2); 46,XX / 47,XX +mar; 46,XX/46,XX t(7:14)(q36;q11.2); 46,XX/47,XX,+18; 46,XX / 47,XX +17. Among them were couples who have had many attempts at IUI and IVF/ICSI without success (Attapaththu, et al. 2006). It is clear from this data that katyotyping couples with spontaneous abortions enables the identification of a subgroup of couples who could benefit immensely by appropriate reproductive counselling and recommendation of the most appropriate assisted reproductive option giving them the best chance of success in having a baby.

It has been noted in several studies that embryos having the 45, X karyotype have a higher risk of spontaneous abortions (Hassold et al., 2006). It has been hypothesised that the loss of the second X chromosome occurs in men who have microdeletions in their Y chromosome (Oates et al., 2002). It has been reported that women whose partners have Y chromosome microdeletions are at a significantly higher risk of recurrent pregnancy loss than women whose partners do not have Y chromosome microdeletions (Simoni et al., 2004). Dewan et. al. (2006) tested the DNA of male partners in couples with recurrent pregnancy loss and found that 82% of them had at least one microdeletion in the Y-chromosome. Y-chromosome microdeletions manifest as poor quality sperm, and male partners of couples with recurrent pregnancy loss who have poor quality sperms may be candidates for testing Y-chromosome microdeletion testing. Although we have introduced Y-chromosome microderletion testing, we have had no referrals so far.

In many instances parents want to know why a fetus looks abnormal on ultrasound scanning or why a fetus was aborted. We have some experience in screening fetal material from abortus samples for aneuploidy. Since June 2006 we have screened 53 samples of amniotic fluid and 7 samples of abortus material for aneuploidy in chromosomes 13, 18, 21, X and Y using a rapid detection technique called Multiplex Ligation Probe Amplification (MLPA) which gives a result within 48 hours (Nanayakkara and Dissanayake, 2006). The aneuploidies detected in amniotic fluid were Trisomy 21 in 6 (11%); Trisomy 18 in 1 (2%) ; Monosomy X in 1 (2%); XYY in 1 (2%). The aneuploidies detected in abortus material were Monosomy X: 1 (14%) and Triplody [69 XXY] (28%). The availability of such information is sure to strengthen the hands of the obstetricians in counselling and managing couples with pregnancy loss. Anuploidies in the above mentioned chromosomes however, only account for about 60-70% of all chromosomal abnormalities detected antenatally. We hope to introduce chromosome culture and karyotyping of amniotic fluid and abortus material in the near future so that other abnormalities not detected by MLPA could also be detected.

In conclusion therefore, there is a growing body of evidence that genetic testing could help couples with recurrent pregnancy loss by giving them an answer to the reason behind their recurrent pregnancy loss, as well as enabling the obstetrician to find a solution to overcome it by selecting the appropriate assisted reproductive technique. The emerging data suggests that a genetic referral should be high on the priority of management options as the outcome of genetic testing may have a profound effect on the chosen management option.


  1. Attapaththu, M., et al. (2006). The need for genetic evaluation prior to offering intracytoplasmic sperm injection/in vitro fertilization: two case reports. Sri Lanka Journal of Obstetrics and Gynaecology 28(Supple1): 53-54.
  2. Dewan, S., et al. (2006). Y-chromosome microdeletions and recurrent pregnancy loss. Fertil Steril 85(2): 441-5.
  3. Daniely, M., et al. (1998). Detection of chromosomal aberration in fetuses arising from recurrent spontaneous abortion by comparative genomic hybridization. Hum Reprod 13(4): 805-9.
  4. Hassold, T., et al. (1988). Cytogenetic and molecular analysis of sex chromosome monosomy. Am J Hum Genet 42(4): 534-41.
  5. Li, T. C., T. Iqbal, et al. (2002). “An analysis of the pattern of pregnancy loss in women with recurrent miscarriage.” Fertil Steril 78(5): 1100-6.
  6. Nanayakkara V, Dissanayake VHW. (2006) Antenatal genetic screening for fetal aneuploidy in Sri Lanka: Preliminary results. Journal of Obstetrics and Gynaecology 28(Supple1): 21.
  7. Oates, R. D., et al. (2002). “Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI.” Hum Reprod 17(11): 2813-24.
  8. Sarig, G., et al. (2002). Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 77(2): 342-7.
  9. Simoni, M., E. Bakker, et al. (2004). “EAA/EMQN best practice guidelines for molecular diagnosis of y-chromosomal microdeletions. State of the art 2004.” Int J Androl 27(4): 240-9.

The data presented in this paper is the pooled data of tests performed at the Genetic Laboratories of the Human Genetics Unit, Faculty of Medicine, Colombo and the Genetic Laboratory of the Asiri Surgical Hospital, Colombo.