Miscarriage care in Scotland: delivery framework

Annex F

Impacts on Miscarriage Risk

Body mass index (BMI)

There is no clear association between a low BMI (<18.5 kg/m²) and recurrent miscarriage. Obesity, on the other hand, has been specifically linked to an increased risk of recurrent miscarriage (odds ratio [OR] 1.75, 95% confidence interval [CI] 1.24 to 2.47). Other factors, including ethnicity, play an important role in the evaluation of body weight. For example, in the Caucasian population the evidence shows that reproductive outcomes are worse in those whose BMI is ≥30 kg/m², whereas in people of Asian origin keeping a BMI lower than 27 kg/m2 should be encouraged. Pregnant women in the first trimester, and those trying to conceive, should be advised that a balanced diet, rich in fruit and vegetables, with reduced high fat, sugar or salt (HFSS) food intake, is crucial to maintaining a stable body weight and supporting embryo/fetal development. Women and men with recurrent pregnancy loss (RPL) should strive for a healthy BMI (19-25 kg/m²).

Micronutrients

Vitamin supplementation is frequently recommended for women planning pregnancy. The benefits of supplementation are to lower the risk of congenital conditions such as neural tube defects and reduce the risk of low birth weight, small for gestational age and preterm births. Data from observational studies advocate vitamin supplementation for the prevention of miscarriage, typically in the form of folate and B vitamins. A Cochrane review on vitamin supplementation for preventing miscarriage found no evidence that taking vitamin A, vitamin C, multivitamins or folic acid prior to or in early pregnancy prevented pregnancy loss. However, the evidence showed that women receiving multivitamins plus iron and folic acid had a lower risk of stillbirth compared to taking iron and folate only (RR 0.92, 95% CI 0.85 to 0.99, 10 trials, 79,851 women; high-quality evidence). Similar results with micronutrient supplementation in addition to iron +/- folic acid or with folate supplementation alone have also demonstrated no benefit in reducing pregnancy loss. Folic acid at a dose of 5 mg once daily should be considered in women with a BMI ≥30 kg/m², epilepsy, diabetes Types 1 and 2, neural tube defect in a previous pregnancy and sickle cell disease. However, folic acid has not been shown to prevent pregnancy loss in women with unexplained RPL. Supplementation doses of 10 micrograms vitamin D should be considered for all pregnant women.

Caffeine

Caffeine is a widely consumed stimulant, and up to 9 in 10 pregnant women report drinking coffee. International advisory panels have historically adopted a moderate approach to caffeine intake in pregnancy. For example, the European Food Safety Authority advises that ingesting up to 200mg of caffeine per day has not been shown to cause harm to the developing fetus, echoing advice from the American College of Obstetricians and Gynecologists (ACOG) and the UK National Health Service. However, there is growing evidence suggesting that caffeine intake may be detrimental to pregnancy. A recent systematic review of 26 studies showed that the risk of miscarriage increased by 32% in women who consumed caffeine (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.24 to 1.40). Further, for every additional two cups of coffee per day, the risk of miscarriage rose by 8%. While the effect of caffeine intake on miscarriage has been less studied in men, prospective cohort data suggest that the risk of miscarriage may be up to 73% higher in men who drink 2 cups of coffee per day in the preconception period in comparison to a daily intake of <2 cups (hazard ratio [HR] 1.73, 95% CI 1.10 to 2.72). In women and men who choose to continue consuming caffeine in the pre-conception period and during pregnancy, clinicians should advise couples that the risk of miscarriage has been shown to be higher in those ingesting 2 cups of moderate-strength coffee per day. Women with recurrent miscarriage should be advised to limit caffeine to less than 200 mg (2 cups) per day.

Alcohol

Alcohol is a powerful teratogen, leading to fetal abnormalities that range from low birth weight to severe fetal alcohol syndrome (FAS). Daily alcohol use is nonetheless reported by as many as 1 in 6 pregnant women, making it the most common preventable cause of congenital malformations and intellectual impairment. Furthermore, there is a dose-dependent relationship between maternal alcohol consumption and the severity of fetal abnormalities, with evidence showing that doses as low as 1-2 units per week may be harmful. Although there is a lack of evidence on the impact of alcohol intake specifically upon the incidence of miscarriage, the detrimental effect of alcohol on embryo development and sporadic miscarriage has been well established. A recent systematic review of 24 studies including 231,808 pregnant women showed that those exposed to alcohol during pregnancy were more likely to miscarry (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.12 to 1.28). This review also demonstrated that in women consuming 5 or fewer drinks per week, there was a 6% increase in miscarriage risk for each additional drink (OR 1.06, 95% CI 1.01 to 1.10). Alcohol consumption has also been shown to negatively affect semen volume and sperm morphology. Evidence suggests that male alcohol intake at the time of conception may lead to a fivefold increase in the risk of miscarriage. Clinicians caring for women and men with a history of recurrent pregnancy loss and ongoing issues with alcohol use should signpost patients to alcohol support services or contact their general practitioners for onward referral to an appropriate agency.

Smoking

Tobacco smoking is known to cause harm in pregnancy. It has been found to be associated with miscarriage, ectopic pregnancy, low birthweight, placental abruption and birth defects. Despite widespread campaigns promoting smoking cessation in the preconception period and during pregnancy, up to 14% of pregnant women report smoking tobacco. A recent systematic review showed that the risk of sporadic miscarriage was increased in both active (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.16 to 1.30, n = 50 studies) and passive (RR 1.32, 95% CI 1.21 to 1.44, n = 25 studies) smokers. In addition, a prospective study of 526 men identified an association between heavy paternal smoking and early pregnancy loss. Nicotine replacement therapy, in the form of patches or gum, has not been shown to be harmful in pregnancy and does not increase the risk of miscarriage. In recent years, the use of electronic cigarettes (EC) and vaping among pregnant women has also increased significantly, although it remains unclear whether EC can cause harm to the fetus. Clinicians caring for women and men with a history of miscarriage and ongoing issues with tobacco smoking should signpost patients to smoking cessation services.

Progesterone – Threatened Miscarriage

There is evidence that vaginal micronised progesterone may increase live birth rates in women with early pregnancy bleeding and a history of miscarriage. Results from the PRISM RCT, which included 4,153 women, showed that progesterone did not reduce the rate of miscarriage for those with no previous miscarriages as the live birth rate was 74% (824/1111) in the progesterone group and 75% (840/1127) in the placebo group. There was a small reduction in miscarriage for those with 1-2 previous miscarriages as the live birth rate was 76% (591/777) in the progesterone group and 72% (534/738) in the placebo group. There was a big reduction in miscarriage for those with 3 or more previous miscarriages as the live birth rate was 72% (98/137) in the progesterone group and 57% (85/148) in the placebo group. The overall live birth rate was 75% (1513/2025) in the progesterone group and 72% (1459/2013) in the placebo group. Vaginal micronised progesterone (such as utrogestan 400mg BD) in the form of a vaginal pessary is used although it is not currently licenced for this indication. NICE guidance recommends confirmation of intrauterine pregnancy using a scan to avoid masking an ectopic pregnancy. NICE guidance recommends treatment until 16 weeks of gestation and the following NICE Evidence review provides information on the evidence including duration which is on page 18 NG126 Evidence review C. Progesterone therapy should be discontinued if there is an ultrasound diagnosis of a miscarriage.

Progesterone – Recurrent Miscarriage

Progesterone is produced by the corpus luteum in the ovaries and helps to prepare the endometrium for implantation of the embryo. Progesterone is therefore an essential hormone for a successful pregnancy. The PROMISE trial, which included 836 participants, evaluated the benefit of progesterone supplementation in women with 3 or more unexplained miscarriages. A live birth after 24 weeks of gestation was considered to be a successful outcome.

The trial reported that for those who received progesterone, the live birth rate was 65.8% (262 of 398 pregnancies) and for those who received placebo, it was 63.3% (271 of 428 pregnancies). A post hoc analysis found that progesterone may be of benefit in women with a history of 4 or more miscarriages.

Therefore, in women with a history of four or more previous miscarriages, progesterone should be offered after an informed discussion. Women should ideally be provided with written information on the potential benefits and risks. Women who are being treated with progesterone supplementation should continue to be treated while viability is being determined. Progesterone therapy should be immediately discontinued if there is an ultrasound diagnosis of a miscarriage or ectopic pregnancy.

Anaemia

Iron deficiency is considered the most common nutrient deficiency in pregnant women. Supplementation with iron reduces the risk of maternal anaemia and iron deficiency in pregnancy. Significant blood loss can accompany miscarriage and anaemia should be corrected prior to subsequent pregnancy. Further studies are required to investigate the clinical significance of low ferritin in miscarriage and whether preconception prophylactic iron supplementation would improve live birth rates. However, anaemia due to iron, folate or vitamin B12 deficiency should be corrected in the pre-conception period.

Thyroid function

Thyroid dysfunction is common in women of reproductive age. Normal functioning of the thyroid gland is essential for successful conception and pregnancy. Detection of thyroid disorders prior to pregnancy is of utmost importance due to the adverse effects thyroid abnormalities have on conception and pregnancy. Uncontrolled thyrotoxicosis has been associated with reduced fertility, miscarriage, pre-eclampsia, pre-term birth, placental abruption, and fetal hyperthyroidism. Untreated hypothyroidism has been linked to adverse outcomes including impaired fertility, miscarriage, hypertensive disorders of pregnancy, placental abruption, preterm birth, and higher rates of neonatal intensive care unit admissions as well as lower intelligence scores (IQ) in the offspring.

Subclinical hyperthyroidism and subclinical hypothyroidism (SCH) are biochemical diagnoses defined by an abnormal serum thyroid stimulating hormone (TSH) concentration accompanied by normal concentrations of circulating thyroid hormones. They may represent the earliest stages of thyroid dysfunction and can progress to overt disease in later life. SCH has been linked to adverse outcomes such as subfertility, miscarriage, pre-term birth, pre-eclampsia, gestational hypertension, and perinatal mortality.

Thyroid autoimmunity (TAI) describes the presence of circulating anti-thyroid autoantibodies that are targeted against the thyroid, with or without thyroid dysfunction. Thyroid peroxidase antibodies (TPOAb) are the most common anti-thyroid autoantibody; they are present in approximately 10% of women. The presence of TPO antibodies, even in women with a normal thyroid function, has been shown to be associated with an increase in adverse pregnancy outcomes, such as miscarriage and preterm birth. However, treatment with thyroxine was not effective at reducing pregnancy associated risks.

Overt thyroid disease should be managed jointly with endocrinologists. Overt hypothyroidism or hyperthyroidism should be treated accordingly. If sub-clinical hypothyroidism (TSH >4.0 mU/L with normal free T4) is diagnosed, treatment with levothyroxine, with an aim for TSH <2.5 mU/L, should be commenced. For women already taking levothyroxine, an empirical dose increase should be initiated from point of conception. Women should be advised to start taking double dose on 2 days of the week and require regular TFT monitoring starting at 7-9 weeks gestation. Women should be advised not to become pregnant until TFTs are in normal range.

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an acquired systemic autoimmune disease where the body’s immune system produces antibodies that affect phospholipids. APS is found in approximately 15-20% of women with recurrent pregnancy loss (RPL), representing the most frequently identifiable risk factor amenable to treatment. APS can be found as a lone diagnosis but may occur concomitantly with other autoimmune diseases. For example, patients with APS may also have a diagnosis of Systemic Lupus Erythematosus (SLE). APS presents with a range of clinical phenotypes, including poor reproductive outcomes (recurrent pregnancy loss, preeclampsia, preterm birth, fetal growth restriction and stillbirth), venous and arterial thrombosis, and rash.

Women with RPL should be tested for APS by obtaining blood and testing for lupus anticoagulant (LA) and anti-cardiolipin (aCL) (IgM and IgG) antibodies. A long time between taking the blood sample and laboratory processing can quench the lupus anticoagulant and yield a false negative result. The diagnosis is made with the detection of LA or aCL on two separate occasions, twelve weeks apart. Repeat testing is only recommended if an initial APS antibody test is positive or indeterminate. Some women require a third ‘decider’ test. Testing should be postponed 6 weeks following a pregnancy (loss). Women with APS should receive specialist pre-conception counselling and joint obstetric-haematology ‘high-risk’ care. The general practitioner (GP) should be informed due to the long-term increased risk of arterial and vascular disease.

If a first test for APS is negative no further tests are required. If the first test for APS is positive a second test should be performed at least 12 weeks later. If this is negative no further testing or treatment is required. If the second test is indeterminate then a third test would be required after an additional 12 weeks. If that is not negative treatment would be recommended. Those with a confirmed positive APS on the second test also require treatment. Women with APS should receive: Aspirin 75 mg once daily from the time of a positive pregnancy test and low molecular weight heparin (LMWH) at a weight-adjusted prophylactic dose from confirmation of an intrauterine pregnancy on ultrasound scan, to be continued for six weeks postnatally. The dose of aspirin should be reviewed at the woman’s booking appointment and increased to 150 mg once daily for the prevention of preeclampsia where applicable. Those with APS will require signposting to the general practitioner for ongoing post-pregnancy surveillance as this has life-long implications.