Saudi Journal of Medicine and Medical Sciences

: 2016  |  Volume : 4  |  Issue : 3  |  Page : 187--191

Etiology of recurrent pregnancy loss in Saudi females

Ahlam A Al-Ghamdi, Sawsan F Makhashen 
 Department of Obstetrics and Gynecology, King Fahd Hospital of the University, University of Dammam, Al-Khobar, Saudi Arabia

Correspondence Address:
Ahlam A Al-Ghamdi
Department of Obstetrics and Gynecology, King Fahd Hospital of the University, University of Dammam, P.O. Box 2208, Al-Khobar 31952
Saudi Arabia


Objective: The aim of our retrospective study was to assess the etiology of recurrent pregnancy loss (RPL) in Saudi couples attending a specialized RPL clinic at King Fahad Hospital of the University, Al-Khobar, Saudi Arabia. Patients and Methods: A total of 59 couples attending the RPL clinic between January 2010 and December 2013 and who had completed their workup and investigations for RPL were included in the study. Data were collected from patients' charts and computer-based laboratory results. Results: Protein S deficiency was found in 47% of patients, a chromosomal abnormality in 6.7%, uterine abnormality in 12%, antiphospholipid syndrome (APS) in 12%, and antithrombin III and Protein C deficiency in 1.7%. However, no patient had Factor V Leiden mutation. In 39% of the patients, there was no identifiable cause, and therefore, they had been diagnosed as unexplained RPL. Conclusion: The most common cause of RPL was Protein S deficiency followed by congenital uterine anomalies and APS. Almost 40% of couples with RPL remain with unknown etiology.

How to cite this article:
Al-Ghamdi AA, Makhashen SF. Etiology of recurrent pregnancy loss in Saudi females.Saudi J Med Med Sci 2016;4:187-191

How to cite this URL:
Al-Ghamdi AA, Makhashen SF. Etiology of recurrent pregnancy loss in Saudi females. Saudi J Med Med Sci [serial online] 2016 [cited 2022 Sep 25 ];4:187-191
Available from:

Full Text


Recurrent miscarriage (RM) or recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses occurring before 20 weeks post menstruation.[1],[2],[3] The incidence is estimated to occur in 1% of fertile couples. But the incidence increases to 5% when two or more losses occur.[4] Clinicians have further classified pregnancy loss into three types, preclinical, embryonic and fetal loss; preclinical loss as demise <6 weeks; embryonic loss as demise at >6 weeks but <10 weeks gestation; fetal loss as demise at >10 weeks but <20 weeks gestation. Some clinicians use the presence or absence of fetal cardiac activity to determine the stage of pregnancy loss as either embryonic (loss before fetal cardiac activity has been identified) or fetal (loss after the fetal cardiac activity has been identified).[3],[5] Other clinicians have further classified RPL as recurrent “early” pregnancy loss when this occurs before 12 weeks gestation and late loss is that which occurs after 12 weeks' and before 20 weeks' gestation.[6] The cause of RPL has been widely investigated, including parental and fetal chromosomal abnormalities, structural uterine abnormalities, antiphospholipid syndrome (APS), some thrombophilia, autoimmune disease, and endocrinological disorders such as polycystic ovarian syndrome and untreated diabetes.[4],[7],[8],[9],[10],[11] Despite intensive and thorough investigations, no identifiable cause could be found in more than 50% of couples.[12] These couples with unexplained RPL experience even further stress and higher levels of anxiety because of the uncertainty as to whether they should stop trying to conceive or continue with the knowledge that further pregnancies may also result in a loss. Providing tender loving care, support and reassurance to these couples have been known to result in a 75% success rate in a future pregnancy.[13],[14] The aim of our study is to assess the causes of RPL in Saudi couples attending a specialized RPL clinic at King Fahd Hospital of the University, Al-Khobar, Saudi Arabia.

 Patients and Methods

This is a retrospective study of all Saudi couples with RPL, who were referred to the RPL specialized clinic at King Fahd University Hospital in Al Khobar, Saudi Arabia between January 2010 and December 2013. All cases were ascertained to have had three or more spontaneous miscarriages, with pregnancies confirmed by βhCG. Demographic data, such as age, the number of live births, the number of miscarriages, and the number of early and late pregnancy losses were recorded. Peripheral karyotyping of the couple was performed. The detection of the lupus anticoagulant was based upon dilute Russell viper venom test time together with a platelet neutralization procedure. The anticardiolipin antibodies were detected by a standardized enzyme-linked immunosorbent assay, and the titer was considered elevated if medium or high titers of both IgG and IgM isotypes were present in blood. A diagnosis of APS is made if one of the following clinical criteria is present: (a) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal abnormalities excluded, or (b) one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or (c) one or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia or severe placental insufficiency. In addition, persistent abnormality of one of the following tests when measured at least twice, >6 weeks apart: (a) Lupus anticoagulant, (b) antiphospholipid antibodies.[15] Protein S, Protein C, antithrombin III, and Factor V (FV) global Protein C were also tested by functional immunosorbent assays. The uterine cavity was assessed by an office hysteroscopy or a hysterosalpingography, and uterine findings were reported as a normal uterine cavity, congenital (such as septate, bicornuate, unicornuate) or acquired abnormality (such as an endometrial polyp, submucous fibroid, or uterine synechiae). Couples who had not completed their investigations were excluded from the study.


A total of 59 Saudi couples with a history of repeated miscarriages were included. As shown in [Table 1], the mean female age was 32.83 ± 6.64 standard deviation. The number of previous miscarriages varied from 3 to 23 miscarriages. The number of early losses ranged between 2 and 16 whereas the number of late losses ranged from none to seven losses. Nineteen females out of 59 (32%) were nulliparous with no live birth while the remaining 40 (68%) had one live birth. Forty females had only early losses, (all losses <12 weeks of gestation), one had only late losses (losses >12 weeks of gestation) and 18 had mixed losses some <12 weeks of gestation and others >12 weeks of gestation. Identifiable causes of RM are shown in [Figure 1]. Uterine cavity abnormalities were found in seven women (11.9%), specifically septate uterus in two patients, endometrial polyp in three patients, uterine synechia in one patient. Cervical incompetence in one patient. Abnormal karyotype was seen in four patients (6.8%) (two females and two males) mainly robertsonian translocation and inversion. The APS was diagnosed in 7 (11.9%) women whereas Protein S deficiency was diagnosed in 28 (47.5%) women. Protein C deficiency as well as antithrombin III was found in only one female (1.7%). FV Leiden mutation was not found in any of the women studied. Finally, 23 (39%) women were diagnosed as having unexplained RM. [Table 2] shows the frequencies of the type of loss in relation to the identified cause.{Table 1}{Figure 1}{Table 2}


Our study demonstrated that the most common cause of RPL in Saudi females in the Eastern Province of Saudi Arabia was Protein S deficiency, which was found in almost half of the study population. This is followed by couples who had no identifiable cause for RPL, with a prevalence of 39%. APS and uterine cavity abnormalities were found in 12% of the patients. The most common uterine cavity abnormality was endometrial polyp followed by a uterine septum. Protein C deficiency and antithrombin III deficiency were found in 1.7% whereas FV Leiden mutation was not detected in this study population. Furthermore, our study showed a 6.7% rate of parental karyotype abnormality. All uterine cavity abnormalities were corrected at the time of diagnostic hysteroscopy either by the removal of the polyp or resection of the septum hysteroscopically. All patients who were diagnosed with thrombophilia were offered low dose aspirin and low molecular weight heparin throughout the pregnancy, and six weeks postpartum. The strength of our study is that all patients were attending a specialized RPL clinic at the same hospital and under the care of the same consultant and investigations were carried out in one laboratory. Patients who attended the clinic but did not complete their follow-up visits and investigations were not included in the study. The small sample size is due to the inclusion of only those couples who had undergone a thorough and complete investigation.

The prevalence of uterine anomalies in the RPL population has been reported to range between 1.8% and 37.6%, which is in accordance with our study. This wide range is due to the different criteria used in defining RPL (two vs. three or more consecutive pregnancy losses) as well as the different techniques and criteria used in the diagnosis of uterine anomalies.[16] It has been found that correction of a septate uterus resulted in a decline in miscarriage rate from 88% to 14%.[17] Chromosomal abnormalities of either parent has also been implicated as a cause of RPL. Furthermore, their pregnancies may result in a live birth with multiple congenital malformations and/or mental disability secondary to an unbalanced chromosomal arrangement. The composite prevalence of major chromosomal abnormalities in either parent was about 3.5%, 5 to 6 times higher than the general population, most commonly a balanced reciprocal or robertsonian translocation.[7] Our study showed a prevalence rate of 6.7% for parental karyotype abnormality, which is higher than that reported in the literature. Chromosomal abnormalities of the embryo were found to account for 30–57% of further miscarriages in couples with RPL.[5],[18],[19],[20],[21],[22] However, it has been reported that as the number of miscarriages increases, the risk of euploid pregnancy loss increases.[5],[20] Not surprisingly, it was found that advanced maternal age (older than 36) was associated with a significantly higher rate of aneuploidy. In other words, in women younger than 36, recurrent loss was due primarily to causes other than chromosomal abnormalities.[5] In our study, more than two-thirds of the population studied were younger than 36 years of age. Thrombophilias, both inherited as well as acquired, have been investigated and studied thoroughly as a cause of RPL and adverse pregnancy outcome. APS (an acquired thrombophilia) is the most treatable well-recognized cause of RPL. The prevalence of APS in our study was 12%, which is similar to several other studies, where it was reported to be approximately 15% in comparison to <2% in women with a low-risk obstetric history.[23] It has been reported that 10.9% of Saudi females with RPL had APS compared to 5.6% in normal pregnancies and 1.2% in healthy blood donors.[24] The live birth rate in women with RPL associated with APS with no pharmacological intervention has been reported to be as low as 10%.[25] It was concluded in a meta-analysis of randomized controlled trials that the only treatment or treatment combination that leads to a significant increase in the live birth rate among women with APS is aspirin plus unfractionated heparin. The reduction rate of miscarriage was 54% in patients receiving aspirin plus unfractionated heparin compared with aspirin alone: Relative risk 0.46, 95% confidence interval (0.29–0.71).[26] Recently, an increased incidence of early and recurrent fetal loss has been suggested in women with inherited thrombophilia, including FV Leiden mutation, activated Protein C resistance, prothrombin G20210A mutation, and Protein S deficiency. The incidence of FV Leiden mutation varies among different populations. Some sources revealed a frequency as high as 15% in Caucasians, with the highest incidence rate of 31.2% found in Jews.[27] The prevalence of FV Leiden mutation in the Saudi population ranged between 0.5 and 2%, which is quite low compared to that of Egyptians 16.5–18.5%, Turkish 24.6%, Greek 22.6%, Lebanese 14.65%, Tunisians 13.6%, Jewish 10%, and Italian populations 6%, but it is similar to that of Indians 1.3% and Americans 0.8–1.8%.[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38] Another study found FV Leiden was present in 6.42% and 7.04% of Kuwaitis of Iranian and Iraqi origin, respectively, but it was absent (0%) among Kuwaitis of Saudi origin.[39] This might explain why no patients in our study were diagnosed with FV Leiden mutation. Protein S deficiency and Protein C deficiency are relatively less common, where the prevalence in the general population ranges between 0 and 0.5%.[40] Surprisingly, in the Saudi population, Protein S deficiency has a prevalence rate of 14.5% while prothrombin gene mutation has a prevalence of 1.1%.[28] The association of inherited thrombophilia and fetal loss varies from one study to another. A meta-analysis has reported a consistently stronger association of inherited thrombophilia with late fetal loss than with an early loss.[10] A meta-analysis of 16 case–control studies reported that carriers of FV Leiden or prothrombin gene mutation have double the risk of experiencing RPL compared with women without these thrombophilic mutations.[41] However, some studies have reported a similar risk of fetal loss in women with the FV Leiden mutation compared to those without.[42],[43] Furthermore, several studies have found no correlation between the prothrombin gene mutation and RPL.[44],[45],[46],[47] The association of RPL and antithrombin III deficiency and Protein C deficiency is less clear. In general, the association of inherited thrombophilia with fetal loss is not as clear as APS.[48]


Our study demonstrated the uniqueness of the Saudi population in terms of their thrombophilia abnormalities compared to neighboring Middle Eastern populations. Whilst a bigger epidemiological study may shed more light, our study shows that Protein S deficiency, APS and uterine abnormality should be the first three investigations to be carried out in Saudi women with RPL. Chromosomal study reserved to selected cases, bearing in mind that in up to 40% of couples, no cause for RPL can be identified.


The authors appreciate and thank Professor Laila Bashawri, Consultant Hematologist for her guidance and interpreting the laboratory results and the hospital personnel for collection of the data.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Stirrat GM. Recurrent miscarriage. Lancet 1990;336:673-5.
2Berry CW, Brambati B, Eskes TK, Exalto N, Fox H, Geraedts JP, et al. The Euro-Team Early Pregnancy (ETEP) protocol for recurrent miscarriage. Hum Reprod 1995;10:1516-20.
3Bricker L, Farquharson RG. Types of pregnancy loss in recurrent miscarriage: Implications for research and clinical practice. Hum Reprod 2002;17:1345-50.
4Hogge WA, Byrnes AL, Lanasa MC, Surti U. The clinical use of karyotyping spontaneous abortions. Am J Obstet Gynecol 2003;189:397-400.
5Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: A case-control study. Hum Reprod 2002;17:446-51.
6Farquharson RG, Jauniaux E, Exalto N; ESHRE Special Interest Group for Early Pregnancy (SIGEP). Updated and revised nomenclature for description of early pregnancy events. Hum Reprod 2005;20:3008-11.
7Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod 2006;21:1076-82.
8Saravelos SH, Cocksedge KA, Li TC. Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: A critical appraisal. Hum Reprod Update 2008;14:415-29.
9Greaves M, Cohen H, MacHin SJ, Mackie I. Guidelines on the investigation and management of the antiphospholipid syndrome. Br J Haematol 2000;109:704-15.
10Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: A meta-analysis. Lancet 2003;361:901-8.
11Arredondo F, Noble LS. Endocrinology of recurrent pregnancy loss. Semin Reprod Med 2006;24:33-9.
12Quenby SM, Farquharson RG. Predicting recurring miscarriage: What is important? Obstet Gynecol 1993;82:132-8.
13Clifford K, Rai R, Regan L. Future pregnancy outcome in unexplained recurrent first trimester miscarriage. Hum Reprod 1997;12:387-9.
14Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod 1999;14:2868-71.
15Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 1999;42:1309-11.
16Grimbizis GF, Camus M, Tarlatzis BC, Bontis JN, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum Reprod Update 2001;7:161-74.
17Homer HA, Li TC, Cooke ID. The septate uterus: A review of management and reproductive outcome. Fertil Steril 2000;73:1-14.
18Franssen MT, Korevaar JC, van der Veen F, Leschot NJ, Bossuyt PM, Goddijn M. Reproductive outcome after chromosome analysis in couples with two or more miscarriages: Index [corrected]-control study. BMJ 2006;332:759-63.
19Carp H, Toder V, Aviram A, Daniely M, Mashiach S, Barkai G. Karyotype of the abortus in recurrent miscarriage. Fertil Steril 2001;75:678-82.
20Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000;73:300-4.
21Sullivan AE, Silver RM, LaCoursiere DY, Porter TF, Branch DW. Recurrent fetal aneuploidy and recurrent miscarriage. Obstet Gynecol 2004;104:784-8.
22Carp H, Feldman B, Oelsner G, Schiff E. Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril 2004;81:1296-301.
23Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: Results of a comprehensive screening approach. Hum Reprod 1995;10:2001-5.
24Al-Mishari AA, Gader AG, Al-Jabbari AW, Al-Momen AK, El Rab MO, Babay ZH, et al. The prevalence of lupus anticoagulant in normal pregnancy and in women with recurrent fetal loss – Recommendations for laboratory testing for lupus anticoagulant. Ann Saudi Med 2004;24:429-33.
25Rai RS, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod 1995;10:3301-4.
26Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005;2:CD002859.
27Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133-4.
28Al-Jaouni SK. Primary thrombophilia in Saudi Arabia. Saudi Med J 2003;24:614-6.
29Saour JN, Shoukri MM, Mammo LA. The Saudi thrombosis and familial thrombophilia registry. Design, rational, and preliminary results. Saudi Med J 2009;30:1286-90.
30Settin AA, Alghasham A, Ali A, Dowaidar M, Ismail H. Frequency of thrombophilic genetic polymorphisms among Saudi subjects compared with other populations. Hematology 2012;17:176-82.
31Ulu A, Elsobky E, Elsayed M, Yıldız Z, Tekin M, Akar N. Frequency of five thrombophilic polymorphisms in the Egyptian population. Turk J Hematol 2006;23:100-3.
32Bauduer F, Lacombe D. Factor V Leiden, prothrombin 20210A, methylenetetrahydrofolate reductase 677T, and population genetics. Mol Genet Metab 2005;86:91-9.
33Kalkanli S, Ayyildiz O, Tiftik N, Batun S, Isikdogan A, Ince H, et al. Factor V Leiden mutation in venous thrombosis in southeast Turkey. Angiology 2006;57:193-6.
34Mougiou A, Androutsopoulos G, Karakantza M, Theodori E, Decavalas G, Zoumbos N. Inherited thrombophilia screening in Greek women with recurrent fetal loss. Clin Exp Obstet Gynecol 2008;35:172-4.
35Bouaziz-Borgi L, Almawi WY, Mtiraoui N, Nsiri B, Keleshian SH, Kreidy R, et al. Distinct association of factor V-Leiden and prothrombin G20210A mutations with deep venous thrombosis in Tunisia and Lebanon. Am J Hematol 2006;81:641-3.
36Maalej L, Hadjkacem B, Ben Amor I, Smaoui M, Gargouri A, Gargouri J. Prevalence of factor V Leiden in South Tunisian blood donors. J Thromb Thrombolysis 2011;32:116-9.
37Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000;343:1015-8.
38Herrmann FH, Salazar-Sanchez L, Schröder W, Grimm R, Schuster G, Jimenez-Arce G, et al. Prevalence of molecular risk factors FV Leiden, FV HR2, FII 20210G>A and MTHFR 677C>T in different populations and ethnic groups of Germany, Costa Rica and India. IJHG 2001;1:33-9.
39Dashti AA, Jadaon MM. Race differences in the prevalence of the factor V Leiden mutation in Kuwaiti nationals. Mol Biol Rep 2011;38:3623-8.
40Gris JC, Quéré I, Monpeyroux F, Mercier E, Ripart-Neveu S, Tailland ML, et al. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent – The Nîmes Obstetricians and Haematologists Study5 (NOHA5). Thromb Haemost 1999;81:891-9.
41Kovalevsky G, Gracia CR, Berlin JA, Sammel MD, Barnhart KT. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: A meta-analysis. Arch Intern Med 2004;164:558-63.
42Vossen CY, Preston FE, Conard J, Fontcuberta J, Makris M, van der Meer FJ, et al. Hereditary thrombophilia and fetal loss: A prospective follow-up study. J Thromb Haemost 2004;2:592-6.
43Roqué H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004;91:290-5.
44Altintas A, Pasa S, Akdeniz N, Cil T, Yurt M, Ayyildiz O, et al. Factor V Leiden and G20210A prothrombin mutations in patients with recurrent pregnancy loss: Data from the southeast of Turkey. Ann Hematol 2007;86:727-31.
45Serrano F, Lima ML, Lopes C, Almeida JP, Branco J. Factor V Leiden and prothrombin G20210A in Portuguese women with recurrent miscarriage: Is it worthwhile to investigate? Arch Gynecol Obstet 2011;284:1127-32.
46Silver RM, Zhao Y, Spong CY, Sibai B, Wendel G Jr., Wenstrom K, et al. Prothrombin gene G20210A mutation and obstetric complications. Obstet Gynecol 2010;115:14-20.
47Rodger MA, Betancourt MT, Clark P, Lindqvist PG, Dizon-Townson D, Said J, et al. The association of factor V Leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: A systematic review and meta-analysis of prospective cohort studies. PLoS Med 2010;7:e1000292.
48Dawood, Feroza. Inherited and Acquired Thrombophilia in Pregnancy. INTECH Open Access Publisher, 2011.