First trimester pregnancy losses, or early miscarriages contribute to 80 per cent of cases. Second trimester miscarriages, or late miscarriages, are less common and occur between 12 to 20 weeks gestation. At 24 weeks gestation, a pregnancy loss is classified as a stillbirth.
While a number of risk factors impact miscarriage risk, advanced maternal age, chromosomal abnormality, thrombophilias and autoimmune conditions, history of recurrent miscarriages and lifestyle factors are the most commonly reviewed in clinical practice.
As women have been waiting longer to have babies, the incidence of miscarriage has been increasing. The current percentage risks for each age group is as follows:1
< 30 years 15%
35 years 20%
40 years 40%
45 years 80%.
Despite maternal age and the number of previous miscarriages independently impacting the risk for future miscarriage,the risk of subsequent miscarriages increases to approximately 40 per cent after three consecutive miscarriages.2,3
It is also widely recognised that paternal factors including increasing age along with abnormal semen parameters impact miscarriage risk, with risk highest among couples aged ≥35 years (women) and ≥40 years (men).
Miscarriage can result from either foetal or placental abnormality, however, most spontaneous miscarriages occur as a result of spontaneous embryonic aneuploidy (trisomy or monosomy) with autosomal trisomy contributing to 50 per cent of all first-trimester miscarriages.3
The most common first trimester miscarriages are linked to Trisomy 22, followed by Trisomy 16 and Trisomy 15.4
Table1: Chromosomal abnormalities in miscarriage5
9% or 4.2% or 8%??
Structural chromosomal abnormality
2 – 5%
While these aneuploidies are typically one-off occurrences, structural or translational chromosomal abnormalities inherited from parents with chromosomal rearrangement (most typically from the mother) are another common cause of recurrent miscarriage secondary to aneuploidies.
Chromosomal testing or karyotyping is only therefore recommended after multiple miscarriages. For those couple where translocation has been shown to be present, pre-implantation genetic diagnosis is used to screen for embryos with structural abnormalities prior to IVF cycle selection.
Thrombophilias, genetic mutations and rare pathologies
In the second trimester, chromosomal abnormalities account for less than 25% of miscarriagesand other risk factors become more prevalent.
Antiphospholipid syndrome (APS), an acquired thrombophilia, has been attributed to between 10 - 15% of recurrent miscarriages6 and more commonly associated with miscarriages at or after 10 weeks.7 While the exact aetiology is unknown, the autoimmune blood clotting disorder is linked to conditions including systemic lupus erythematosus, anticardiolipin antibodies and anti-2 glycoprotein 1 antibodies.
APS most likely affects pregnancy by microthromboses causing placental insufficiency or interference with embryonic uterine implantation. Women with recurrent miscarriage and identified APS can be successfully treated with low-dose aspirin and/or heparin with appropriate management achieving between 80-90% live birth rates.8 Treatment may also include prednisolone for immunosuppression and immunoglobulin for patients where conventional treatment has not been effective or is contraindicated, or for those patients with concomitant autoimmune conditions or infections.
Similarly, inherited thrombophilias are common risk factors for second-trimester miscarriage.Factor V Leiden (mutated Factor V resistant to Factor V inactivation protein), Factor II (prothrombin) gene mutation and protein S deficiency, are the three most responsible for adverse pregnancy outcomes and have been shown to be the cause of 40 to 50% of recurrent miscarriages.9 Others include hyperhomocysteinaemia mutation and protein C deficiency. These disorders predispose women to venous and arterial thrombi prior to and after pregnancy. In pregnancy the hypercoagulable state also causes thrombi at the site of implantation or in placental blood vessels. The evidence for anticoagulation in these conditions is weaker and dependent on individual history and risk taken into account.
To a lesser degree, uterine abnormalities, including congenital uterine malformation and cervical incompetence, can lead to miscarriage. Uterine abnormalities are estimated to occur in less than 0.5% of women (between 1 in 200 to 1 in 600),3 however, anomalies have been found in around 27% of women with a reported history.3
A bicornate uterus is the most common uterine abnormality associated with miscarriage, occurring in 47% of cases.3 This is followed by a uterine septate abnormality which involves the complete or partial division of the uterus by the septum. Women with uterine septate abnormality have a 26% risk of miscarriage.3 Other congenital uterine abnormalities include uterus didelfis and unicornuate uterus, although these are more typically associated with abnormal delivery.
Miscarriages from uterine abnormalities can occur in both first and second trimesters. Assessment of uterine anatomy is recommended for all recurrent first trimester miscarriages and in all women with one or more second trimester miscarriage. Assessment can include hysteroscopy, hysterosalpingography (HSG), sonohysterogram and pelvic ultrasound.
In contrast, cervical weakness or incompetent cervix miscarriages are more common in the second trimester. Management has traditionally included insertion of the cervical cerclage between weeks 10 to 12 in women with a history of cervical insufficiency, if the cervix opens too early in second trimester, or, when the cervical length is <25mm. New studies suggest that equally efficacious is the use of progesterone pessaries with fewer risks.
Other uterine pathologies such as fibroids are implicated in miscarriage in up to 5% of caseswith miscarriage most likely to occur from submucous or intracavity fibroids as opposed to intramural and subserosal fibroids. Larger fibroids are also more likely to cause miscarriage as are fibroids within areas of embryonic implantation. HSG and sonohysterogram assessment is beneficial in women with known fibroids.
Lifestyle, chronic conditions and infections
Recently, attention has focused on the effects of smoking, drugs, alcohol, obesity and diet in miscarriage.
Heavy smoking among both mothers and fathers is probably the most strongly associated with an increased miscarriage risk with maternal smoking of more that 10 cigarettes daily considered a significant risk factor.
Similarly maternal alcohol consumption of more than 30 grams of alcohol weekly in the first trimester, increases miscarriage risk. Illegal drugs including cocaine and inhalants have also been linked to miscarriage as well as low birth weight and various birth defects.
Chronic conditions including obesity, hypertension, diabetes ad other auto-immunological conditions and endocrinopathies, are all thought to contribute to failures in implantation and placentation, increasing miscarriage in these groups.
Of the hormonal conditions, polycystic ovary syndrome (PCOS) is unique in that it impacts both fertility and miscarriage rates. PCOS is common in between 40 to 80% of miscarriages.10 For those women undergoing IVF, the presence of PCOS leads to a two-fold risk of miscarriage compared to women without PCOS.
Acute maternal infections including listeriosis, toxoplasmosis, infection with parvovirus B19, German measles, herpes simplex, cytomegalovirus or lymphocytic choriomeningitis virus, can all lead to miscarriage as a result of foetal or placental infection. More recently Zika virus has been added to the list of aetiological agents associated with miscarriage. Vaccination along with food-borne illness precautions, pre-natal care and safe-sex practices can reduce these risks.
How ART helps to reduce miscarriage rates
Assisted reproductive technologies can assist in multiple ways from minimally invasive managements, including ovulation induction with medications such as Letrozole and previously used clomiphene, for those women with oligo/anovulation, which confers a more synchronous embryo to endometrium communication leading to a decrease in implantation failure and miscarriage; to the use of IVF technologies including Preimplantation Genetic testing (PGT) and single gene testing, to assist in the transfer of euploid embryos in women where the risk of aneuploidy is high, either as a result of increasing age, or, from an inherited chromosomal or genetic anomaly. ARTs are extended to ensuring management for certain conditions are commenced at optimal times of implantation in women, for example, with thrombophilias and for those with a history of previous miscarriage as a result of incompetent cervix.
In many conditions the use of In vitro fertilisation (IVF) per se can be avoided, but discussion with a fertility specialist to discuss investigations, decreasing the time to pregnancy, and family planning given each couples’ personal circumstances, should be mandatory in women with at least two consecutive miscarriages.
Dr Izurieta is an accredited Obstetrician, Gynaecologist and Fertility Subspecialist.
She has had appointments as a fertility specialist at IVF Australia, and VMO and staff specialist at The Royal Hospital for Women where she was responsible for the coordination of the GP antenatal shared care program and the postgraduate educational program for GPs practicing women's health in the community.
Dr Izurieta is currently conjoint lecturer and examiner at UNSW, involved with teaching, training and mentoring undergraduate and postgraduate students, where she prides herself on a dynamic approach to teaching.
Dr Izurieta is committed to the many challenges women face in their journey from adolescence to menopause and endeavours to provide expert continuity of care from conception to delivery, easing the roller coaster throughout a woman's reproductive and post reproductive life.
T (02) 9165 6941
Hurstville Private Hospital
37 Gloucester Road
Hurstville, NSW, 2220
1. Nybo Anderson AM, Wohlfart J, Christens P, Olsen J, Melbye M. Maternal age and foetal loss: population based register linkage study. BMJ 200;320:1708-12.
2. The investigation and treatment of couples with recurrent first-trimester and second-trimester miscarriage. RCOG Clinical Guides. Green-top Guideline No 17. Available at https://www.ranzcog.edu.au/RAN... [last accessed Jan 2019].
4. Culic V et al. Full trisomy 5 in a sample of spontaneous abortion and arias stella reaction. Med Sci Monit. 2011:17(10:CS116-CS119. doi: 10.12659/MSM.881969
5. Julie A Gainer. Obstetric Imaging: Fetal diagnosis and care (2nd Edition), 2018. (ref 4).
6. Fosca A F Dr Prima et al. Antiphsopholipid syndrome during pregnancy: the state of the art. J Prenat Med. 2011 Apri-Jun;5(2):41-53.
7. Tulandi et al. Spontaneous abortion: Risk factors, etiology, clinical manifestations, and diagnostic evaluation. UpToDate. 2018. Available at https://www.uptodate.com/conte... [last accessed Jan 2019].
8. Paolo Simioni. Thrombosis risk in purely obstetric APS. Blood. 2012 119:2435-2436; doi:https://doi.org/10.1182/blood-2012-01-398735.
9. Adel Abu-Heija. Thrombophilia and recurrent pregnancy loss. Is heparin sill the drug of choice? Sultan Qaboos Univ Med J 2014 Feb;14(1):e26-e36.
10. Palomba S et al. Effect of preconceptional metformin on abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2009 Nov;92(5):1646-1658.