ACCEPT Group Condensed Position Paper on the Management of Recurrent Pregnancy Loss.

Factors, such as male obesity, smoking, alcohol, environmental and occupational exposures, have been associated with RPL [ 3 ]. Findings between semen analyses and RPL are inconsistent [ 25 ]. Sperm DNA fragmentation (which is affected by lifestyle) appears to increase the risk of RPL [ 26 ]. A complete history and examination of the male is important in assessing a couple with RPL. This should include a lifestyle assessment including smoking, exercise, recreational substance use, alcohol consumption and body weight. Cessation of smoking, reduction of alcohol intake, limiting occupational exposures, and normalisation of body weight with moderate exercise and good diet are recommended. Semen analyses and DNA fragmentation index (DFI) should be arranged. In males with elevated DFI, testicular ultrasound for varicoceles is advised, with urological consultation if present. Antioxidants and lifestyle changes may improve DFI and are recommended due to their low risk [ 27 ]. If conservative measures have failed, then IVF with advanced sperm selection techniques could be considered.

Underlying factors contributing to RPL can include: chromosome, anatomical, thrombophilia, endocrine, autoimmune, infective, inflammatory, endometrial, environmental, male causes or unexplained.

Maternal endocrine disorders, such as thyroid disease, hyperprolactinaemia, polycystic ovarian syndrome, and glucose intolerance, have been associated with RPL. There is a clear increased risk of pregnancy loss (spontaneous or recurrent) in certain thyroid disorders (Table  1 ). As there are no specific thyroid‐stimulating hormone (TSH) reference ranges for fertility populations, population‐based trimester‐specific ranges have been recommended [ 14 ]. Thyroid investigations in women with RPL. Abbreviations: FT3, free triiodothyronine; FT4, free thyroxine; mIU/L, milli‐international units per litre; RPL, recurrent pregnancy loss; Tg, thyroglobulin; TPO, thyroid peroxidase; TRAb, thyroid receptor antibody; TSH, thyroid‐stimulating hormone. Investigations for thyroid disorder are listed in Table  2 . Levothyroxine significantly reduces the risk of pregnancy loss in hypothyroidism (up to 81% reduction) [ 15 ]. In cases of hyperthyroidism, it is recommended to achieve a euthyroid state prior to pregnancy with the involvement of an endocrinologist. Antithyroid medications are recommended to be ceased at the diagnosis of pregnancy due to teratogenicity [ 14 ]. The management of euthyroid women with thyroid antibodies is unclear. It is recommended for this group to have TSH levels measured every 4 weeks until mid‐gestation [ 14 ]. Evidence regarding the treatment of subclinical hypothyroidism is conflicting, with some guidelines recommending initiating levothyroxine once TSH is ≥ 4.0 mIU/L [ 14 ]. Summary of pregnancy loss associations and management of thyroid disorders in women with RPL. ↑ TSH and ↓ free T4 level Treat with L‐T4 ↓ TSH and ↑ free T4 and/or T3 Consider definitive treatment prior to pregnancy, such as surgery Cease antithyroid medication prior to pregnancy due to teratogenicity If moderate to severe disease, can consider using lowest effective dose of propylthiouracil (PTU) in first trimester Normal TSH Two management strategies can be considered: Monitor TFTs every 4 weeks during pregnancy until mid‐gestation, and treat with L‐T4 if TSH ≥ 4.0 mIU/L Commence low‐dose L‐T4 (25 to 50 μg PO mane) with an aim of maintaining TSH < 4.0 mIU/L Monitor TFTs every 4 weeks during pregnancy until mid‐gestation, and treat with L‐T4 if TSH ≥ 4.0 mIU/L Commence low‐dose L‐T4 (25 to 50 μg PO mane) with an aim of maintaining TSH < 4.0 mIU/L ↑ TSH and normal free T4 Initiate L‐T4 once TSH is ≥ 4.0 mIU/L, aiming to reduce TSH to euthyroid levels Abbreviations: L‐T4, levothyroxine; mIU/L, milli‐international units per litre; PL, pregnancy loss; PTU, propylthiouracil; RPL, recurrent pregnancy loss; T4, thyroxin; TFT, thyroid function test; TSH, thyroid‐stimulating hormone. The association between hyperprolactinaemia and RPL is tenuous. Normalising prolactin levels (in hyperprolactinaemia) may improve RPL outcomes [ 1 ]. Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women. Spontaneous pregnancy loss has been reported to be mildly higher in women with PCOS compared to those without [ 16 ]. However, this association is difficult to discern given the overlapping variables associated with PCOS such as obesity, insulin resistance and elevated luteinising hormone (LH) concentrations [ 1 ]. Management of PCOS needs to be individualised, with pharmacological (e.g., metformin) and non‐pharmacological measures (e.g., diet and lifestyle interventions). There is an association between maternal obesity and RPL [ 1 ]. Weight loss may improve live birth rates. Given the numerous benefits regarding healthy weight for general health and pregnancy, couples should aim for a healthy body mass index (BMI). Glucose intolerance includes impaired fasting glucose, impaired glucose tolerance (IGT), and overt diabetes mellitus (DM). There is conflicting evidence about whether glucose intolerance is associated with RPL [ 1 ]. Glucose intolerance should be screened with a fasting blood glucose level and glycated haemoglobin (HbA1c). If either is abnormal, then consider a formal 75‐g oral glucose tolerance test. If this is abnormal, management may require coordination with an endocrinologist. A euglycaemic state should be targeted. Progesterone supplementation has been hypothesised to support women with RPL by enhancing endometrial receptivity [ 1 ]. There is some evidence suggesting benefits from progesterone supplementation in women with a threatened pregnancy loss and ≥ 3 previous losses [ 17 ]. Results from other studies are inconclusive. If supplementing with progesterone, the recommended dose is 400 mg twice daily.

There appears to be an increased prevalence of chronic endometritis in women with RPL, but no strong evidence confirming causation [ 3 ]. An endometrial biopsy is needed to diagnose chronic endometritis and should be considered for women with unexplained RPL. While evidence is limited, antibiotic treatment for chronic endometritis may improve live birth rates [ 23 ]. Endometriosis has the potential to impact oocyte quality, endometrial receptivity and early pregnancy outcomes. There is some weak evidence to suggest endometriosis is associated with RPL [ 3 ]. The relationship between adenomyosis and RPL is less clear. There is currently no evidence for the treatment of endometriosis to improve outcomes in RPL [ 3 ].

Anatomical abnormalities of the uterus and/or cervix, congenital or acquired, can be associated with RPL. These can include Mullerian anomalies, leiomyoma or intrauterine adhesions (Asherman's syndrome). Müllerian anomalies are nearly twice as common in women with RPL, compared to the general population [ 8 ]. Certain types of leiomyoma (or fibroid) such as intramural and submucosal, increase the risk of pregnancy loss [ 9 ]. While intrauterine adhesions are often seen as an incidental finding in the general population, they are reported more frequently in women with RPL [ 10 ]. Endometrial polyps have a similar prevalence between women with and without RPL, with no increased risk of pregnancy loss [ 11 ]. Combined hysteroscopy and laparoscopy is the gold standard for investigating Mullerian anomalies. However, the combination of two‐dimensional (2D)/three‐dimensional (3D) ultrasonography with sonohysterogram is appropriate as a non‐invasive first‐line investigation. Sonohysterogram can be useful with suspected fibroids, and magnetic resonance imaging (MRI) helpful for Müllerian anomalies. There is no strong evidence that surgical correction of Müllerian anomalies reduces pregnancy loss or increases live birth rates [ 12 ]. However, hysteroscopic septum resection is reasonable after appropriate counselling [ 1 ]. Removal of an endometrial polyp may improve the clinical pregnancy rate. Surgical treatment of intramural fibroids to improve fertility lacks sufficient evidence, while hysteroscopic myomectomy of submucosal fibroids appears to improve pregnancy outcomes [ 9 ]. Hysteroscopic lysis of intrauterine adhesions is recommended, with studies showing a live birth rate of up to 71% [ 13 ].

It has been hypothesised that immunogenic factors have a potential relationship with RPL. Human leukocyte antigen (HLA) antibodies or the lack of maternal blocking antibodies may contribute to RPL by triggering immune responses against the developing embryo. Uterine natural killer (NK) cells play a key role in supporting implantation and maintaining pregnancy, with conflicting data on association with RPL. Killer immunoglobulin‐like receptors (KIRs) determine the NK cell function, with interactions between maternal and fetal HLAs and KIRs potentially affecting placentation and increasing the risk of RPL in certain combinations [ 20 ]. The presence of antinuclear antibodies (ANAs) with a high titre may increase the risk of RPL, regardless of whether an autoimmune disorder is also present. However, it is uncertain which ANA pattern of immunofluorescence is associated with RPL [ 21 ]. Further research is required to determine the possible association between RPL and factors such as cytokines and poorly managed coeliac disease. Investigations for autoimmune factors should be limited to the assessment of coeliac antibodies in those who are symptomatic or have a significant family history only [ 3 ]. Testing NK cells and HLA antibodies in women with RPL is not recommended outside of research settings due to insufficient evidence. Further research is required to determine the utility of ANA titre cut‐offs in RPL. Research on immunotherapies, such as IVIg, corticosteroids, intralipids and granulocyte colony‐stimulating factor (G‐CSF), for RPL has mixed findings. There is emerging data suggesting IVIg may increase live birth rate in women who have had ≥ 4 unexplained pregnancy losses, and as such may be considered in certain populations [ 22 ]. Other immunotherapies appear to currently lack clear benefit, and women should be counselled on available evidence as well as potential associated adverse effects.

Couples with two or more pregnancy losses should receive a thorough evaluation and management plan for RPL. This includes a detailed history, physical examination, and appropriate investigations as outlined in Figure  1 . Referral to a specialised RPL unit should be considered. Summary of approach to recurrent pregnancy loss. APS, antiphospholipid syndrome; B.D., twice daily; BMI, body mass index; CGH, comparative genomic hybridisation; DFI DNA, fragmentation index; fBGL, fasting blood glucose level; FT3, free T3; FT4, free T4; HbA1c, haemoglobin A1c; IVF, in vitro fertilisation; OGTT, oral glucose tolerance test; PGT‐A, preimplantation genetic testing‐aneuploidy; PGT‐SR, preimplantation genetic testing‐structural rearrangement; POC, products of conception; SNP, single‐nucleotide polymorphism; TFT, thyroid function tests; Tg, thyroglobulin; TPO, thyroid peroxidase; TRAb, thyroid receptor antibody; TSH, thyroid‐stimulating hormone; US, ultrasound.

Embryo aneuploidy and parental chromosomal rearrangements can be implicated in RPL. Aneuploidy is the most common cause of first trimester loss in RPL and is strongly linked to maternal age. Chromosomal rearrangement (specifically balanced translocations) is found in 4.7% of RPL couples [ 4 ]. This increases the likelihood of creating unbalanced embryos, leading to a greater chance of pregnancy loss [ 4 ]. If available, products of conception (POC) tissue should be analysed using molecular methods (array‐CGH or SNP array) to assess for aneuploidy, which can confirm chromosomal abnormalities in about two‐thirds of pregnancy loss cases [ 5 ]. Parental karyotype should be part of the initial RPL workup. Couples with chromosomal rearrangement should receive genetic counselling and be offered preimplantation genetic testing‐structural arrangement (PGT‐SR), which can result in up to a 52% live birth rate after embryo transfer [ 6 ]. For those with a normal karyotype, preimplantation genetic testing‐aneuploidy (PGT‐A) may increase live birth rate if a euploid embryo is transferred, though the likelihood of achieving a euploid transfer decreases with maternal age [ 7 ].

RPL remains unexplained in 50%–75% of cases [ 3 ]. This provides a challenge in treating these couples. Once identifiable causes of RPL have been excluded, empirical treatment may involve progesterone supplementation, IVF with PGT, and monitoring closely with supportive care.

The authors declare no conflicts of interest.

There is some evidence to suggest an increased risk of spontaneous pregnancy loss with environmental factors and exposure to certain substances [ 3 ]. These are summarised in Table  5 . Summary of associations between environmental exposure and RPL. Inconclusive evidence on association with RPL Micronutrient deficiency (zinc and copper) may have an association with RPL Abbreviations: BPA, bisphenol A; DBP, dibutyl phthalate; RPL, recurrent pregnancy loss. There is a lack of high‐quality studies on managing environmental and lifestyle factors in RPL. Management involves advising couples to follow general health guidelines, quit smoking, avoid alcohol, limit caffeine, and reduce exposure to heavy metals, plastics and chemicals. There is some evidence to show improved pregnancy outcomes in RPL through supportive care alone [ 24 ]. A specialised multidisciplinary approach should be used.

Inherited thrombophilias have an uncertain link to RPL, while acquired thrombophilias are strongly associated (Table  3 ) [ 3 ]. Inherited and acquired thrombophilias, and associations with RPL. Abbreviation: RPL, recurrent pregnancy loss. Antiphospholipid syndrome (APS) is the most common acquired thrombophilia, involving both biochemical and clinical criteria for diagnosis (Table  4 ). It is strongly correlated with RPL, particularly in the presence of anti‐cardiolipin antibody [ 19 ]. Updated International Consensus Sydney (ICS) criteria for antiphospholipid syndrome [ 18 ]. Venous or arterial Anti‐cardiolipin antibody Lupus anticoagulant β2 glycoprotein antibody Multiple unexplained pregnancy losses (≥ 3 losses < 10 weeks' gestation) ≥ 1 unexplained fetal death (≥ 20 weeks' gestation) ≥ 1 preterm birth (34 weeks' gestation) due to eclampsia, preeclampsia, or recognised features of placental insufficiency Women with RPL should be screened for APS. If APS is diagnosed and there is a positive pregnancy test, treatment with low‐dose aspirin and heparin should be commenced. Screening for inherited thrombophilias in women with RPL is not recommended. There is no strong evidence for antithrombotic therapy in those with inherited thrombophilias or those with unexplained RPL.