Miscarriage care in Scotland: delivery framework

Annex G

Assessment and Management after Three or More Miscarriages

Fetal genetic abnormalities

Fetal genetic abnormalities are a recognised cause for both sporadic and recurrent pregnancy loss (RPL). The prevalence of genetic abnormalities is estimated to be at least 45% for a single pregnancy loss and 39% where a pregnancy loss is preceded by RPL history. There is emerging data suggesting that genetic testing of pregnancy tissue may have some prognostic value. The primary reason for determining the genetic status of pregnancy tissue is to identify a possible cause, thus potentially offering women and their partners some closure. Pregnancy tissue should be collected in a dry specimen pot without formalin. The recommended test is array-based comparative genomic hybridisation (array-CGH). Where an unbalanced translocation is identified in the pregnancy tissue, parental karyotyping should be organised. People with abnormal karyotypes should be offered a referral to clinical genetics. Women should be counselled that in some circumstances cytogenetic analysis cannot be performed on the pregnancy tissue that is sent due to contamination with maternal tissue, or lack of fetal tissue. A robust system should be in place for debriefing couples and discussing the results of their cytogenetic analysis. This requires dedicated specialist consultant level staff and nursing support adequate to the service needs of a Board.

Anatomical uterine abnormalities

Anatomical uterine abnormalities can be divided into congenital (CUA) and acquired uterine anomalies (AUA). CUAs refer to Müllerian tract malformations which include septate, unicornuate, bicornuate and didelphic uteri. Their prevalence is higher in women with recurrent pregnancy loss (RPL) (13.3%) compared to the general population (5.5%). CUA are associated with increased risks of adverse outcomes during pregnancy. Women with a uterine septum or bicornuate uterus are at increased risk of first-trimester miscarriage, preterm birth and fetal malpresentation. Women with uterine didelphys have an increased risk of preterm labour and fetal malpresentation. Various hypotheses have been put forward to explain the pathophysiology. It has been suggested that the endometrium overlying a uterine septum is suboptimal for implantation, with an insufficient blood supply to support placentation and embryo growth. Other studies have suggested that there is also reduced uterine capacity and uncoordinated uterine contractions.

AUAs include submucosal fibroids, endometrial polyps and intrauterine adhesions (IUA). Their prevalence is poorly researched amongst the RPL population, however, and can be as high as 12.9%. Risk factors for IUA include recurrent miscarriage and dilatation and curettage procedures, however the clinical relevance of IUA with regards to conception and miscarriage is unclear. Evidence for treatment is confined to a limited number of small observational studies and the rationales for treatment are similar to the hypotheses given for CUA. It is good practice to have a multi-disciplinary team (MDT) to discuss management of anatomical uterine abnormalities in conjunction with specialist fertility or gynaecology teams.

Traditionally, abdominal/laparoscopic metroplasty was performed in order to restore the shape of the uterus in women with bicornuate or didelphic uteri. However, due to significant adverse effects (prolonged hospital stay, intrauterine adhesion formation, uterine rupture during subsequent pregnancy) with no improvement in pregnancy outcome, this is no longer offered. The only congenital uterine anomaly with recognised treatment is uterine septum, where the treatment is hysteroscopic resection. However, reproductive outcome data is scarce and conflicting. There is no clear evidence suggesting that endometrial polypectomy is associated with a lower risk of future miscarriage in RPL patients. However, as polyps can be removed at the same time as hysteroscopic diagnosis with minimal additional risk, treatment is advised. There is no available trial data on the effect of submucosal fibroid resection or intrauterine adhesiolysis on the miscarriage rate specifically in recurrent miscarriage patients. However, there is limited observational data suggesting a benefit with treatment.

Parental karyotyping

Some couples who have had recurrent pregnancy loss may require parental karyotyping to identify a chromosomal abnormality. The presence of a balanced translocation leads to abnormal chromosomal arrangements in the gametes, and therefore aneuploidy in the embryo.

The prevalence of abnormal parental karyotypes in couples with a history of recurrent pregnancy losses is estimated to be 1.9 – 3.8%. This is a 5-10-fold increase compared to the general population. However, it should be noted that although couples affected with a balanced translocation also have a good chance of having a healthy child from natural conception there is also an increased chance of a severely disabled child as a result of unbalanced genetic material.

The risk of recurrent pregnancy loss depends on the nature of the genetic abnormalities found. There is a higher risk of miscarriage in those with balanced translocations and inversions compared to those with Robertsonian translocations or other types of genetic differences. Some translocations also confer an increased risk of seriously affected stillborn or live born infants, so detailed genetic guidance should always be obtained. Pre-implantation genetic testing for structural rearrangements (PGT-SR) offers a solution for couples with balanced translocations wishing to avoid any risk of a pregnancy with unbalanced genetic material.

The probability of abnormal parental karyotypes in unselected population is estimated to be very low. In particular, parental genetic testing is likely to be of limited value for couples whose age(s) is/are higher. Genetic analysis of parents should be considered following individual assessment of the clinical history or if indicated by the results of genetic analysis of pregnancy tissue from previous losses, or consideration of number of losses. Where an unbalanced translocation is identified in the pregnancy tissue, parental karyotyping should be organised, with onward referral to clinical genetics in the case of abnormal results.

Progesterone supplementation

If someone with recurrent miscarriages presents with a threatened miscarriage and a scan shows a viable or potentially viable intrauterine pregnancy NICE guidelines recommend treatment with vaginal micronised progesterone pessaries (400mg bd) can be continued until 16 weeks of gestation. Progesterone treatment should not be commenced in women who present with symptoms (pain or vaginal bleeding) who are diagnosed as a pregnancy of unknown location (PUL) where there is a risk of ectopic pregnancy. This is based on the PRISM trial that showed that for women with three or more previous miscarriages who presented with early pregnancy bleeding, there were 15% more livebirths in the progesterone group compared to placebo (livebirth rate 72% with progesterone, 57% with placebo, RR 1.28 (95%CI 1.08-1.51), P=0.004).

The PROMISE trial, the largest multicentre Randomised Control Trial to date, which was adequately powered and with a very low risk of bias, showed that routine progesterone supplementation in women with recurrent miscarriage did not result in a significantly higher rate of live births (progesterone 65.8% vs placebo 63.3% Difference 2.5% (95%CI -4.0 – 9.0)). However, the efficacy seemed to change based on number of previous miscarriages. The livebirth rate was not higher for women with a history of 3 miscarriages (RR 1.01 CI 0.89-1.14, P=0.91). There was a trend to a benefit for women with 4 or more miscarriages (63% vs 58%, P=0.07). NHS Scotland National Guidance on the Use of Progesterone in the Management of Threatened Miscarriage and Recurrent Miscarriage recommends offering progesterone supplementation in women with four or more previous miscarriages.

Asymptomatic women with four or more previous miscarriages should be offered vaginal micronised progesterone (400 mg twice daily) from a positive urine pregnancy test until 12 weeks of gestation, where clinically appropriate. This regimen is based on the PROMISE study protocol that informed this advice. As progesterone could be harmful in the event of an abnormally located (ectopic) pregnancy an ultrasound scan should be provided at 6 weeks gestation for these women, in order to confirm intrauterine gestation and potential viability. Where women are already on progesterone and a diagnosis of PUL is made on ultrasound scan progesterone supplementation should be discontinued and hCG estimations used to inform diagnosis and management.

Common side effects of vaginal micronised progesterone are: breast pain, drowsiness and gastrointestinal discomfort, vaginal offensive discharge and itch. Contraindications to progesterone treatment include acute porphyria, history during pregnancy of idiopathic jaundice, pemphigoid gestationis or severe pruritus, breast cancer, thromboembolism or thrombophlebitis. Caution is required in diabetes, history of depression or migraine. Take care if the woman has a soy and/or peanut allergy as components in some preparations may cause issues due to cross-sensitivity.