This chapter should be cited as follows:
Melo P, Devall A, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419043
The Continuous Textbook of Women’s Medicine Series – Obstetrics Module
Volume 19
Pregnancy shortening: etiology, prediction and prevention
Volume Editors:
Professor Arri Coomarasamy, University of Birmingham, UK
Professor Gian Carlo Di Renzo, University of Perugia, Perugia, Italy
Professor Eduardo Fonseca, Federal University of Paraiba, Brazil
Chapter
The Prevention of Miscarriage
First published: February 2024
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By completing 4 multiple-choice questions (randomly selected) after studying this chapter readers can qualify for Continuing Professional Development awards from FIGO plus a Study Completion Certificate from GLOWM
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INTRODUCTION
Miscarriage refers to the loss of a clinical pregnancy before viability, whose threshold is usually considered to be between 22 and 24 completed weeks of gestation.1 It is estimated that miscarriage affects approximately 1 in 6 clinical pregnancies, exerting huge physical and psychological burden on individuals, couples, their families and society in general, with significant implications upon countries’ workforces and healthcare resources. In the United Kingdom, for example, miscarriage costs an estimated £471 million per year.1 This is likely an underestimation, however, because pregnancy loss has far wider and more prolonged consequences which likely remain underreported.
More than half of first-trimester miscarriages result from embryonic aneuploidy, which is not correctable by any existing medical therapies.2,3 This knowledge often generates feelings of powerlessness among patients and clinicians, with the latter commonly recommending that couples continue to try after each loss without suggesting further investigations. Yet, there is evidence indicating that as the number of successive pregnancy losses increases, so does the overall percentage of miscarriages that are euploid, suggesting that other, correctable, factors appear to be at play.4
This chapter focuses on modifiable risk factors and evidence-based interventions to prevent miscarriage.
MODIFIABLE LIFESTYLE FACTORS TO PREVENT MISCARRIAGE
Weight
Pregnancy is a time of increased metabolic demand.5 Although individual energy and nutrient requirements vary between different women, a balanced diet is essential to fetal development and maternal well-being. Furthermore, women with specific health conditions (e.g., diabetes, inflammatory bowel disease [IBD], irritable bowel syndrome [IBS], celiac disease, cystic fibrosis) require dietary adjustments that have been shown to reduce the risk of miscarriage.6
In a review of cohort studies investigating more than 100,000 miscarriage sufferers, the investigators found that females with a body mass index (BMI) lower than 18.5 kg/m2 exhibited a 57% increase in the risk of miscarriage compared with women whose BMI was within a normal range of 18.5–24.9 kg/m2 (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.05 to 2.34). An increase in miscarriage risk was also identified in women whose BMI was 25–29 kg/m2 (OR 1.33, 95% CI 1.10 to 1.59) and ≥30 kg/m2 (OR 1.93, 95% CI 1.18 to 3.18) versus those with a normal BMI.1
Strategies to optimize maternal weight include a focus on weight management in the preconception period, aiming for weight-neutral pregnancies, supporting women to achieve optimum body weight in between pregnancies, offering individuals a target weight to work towards, and optimizing nutrition overall.7
Nutrition
In a recent systematic review and meta-analysis, the investigators synthesized the evidence on the association between dietary patterns and the risk of miscarriage. The data confidently demonstrated a lower risk of miscarriage in women reporting a higher intake of fruit (OR 0.39, 95% CI 0.33 to 0.46), vegetables (OR 0.59, 95% CI 0.46 to 0.76), a combination of fruit and vegetables (OR 0.63, 95% CI 0.50 to 0.81), seafood (OR 0.81, 95% CI 0.71 to 0.92), dairy products (OR 0.63, 95% CI 0.54 to 0.73), eggs (OR 0.81, 95% CI 0.72 to 0.90) and grains (OR 0.67, 95% CI 0.52 to 0.87) compared to those reporting a lower intake of these food groups. In addition, dietary patterns featuring a high antioxidant index were associated with a reduction in miscarriage risk (OR 0.43, 95% CI 0.20 to 0.91), whereas diets rich in processed foods appeared to increase the risk of miscarriage (OR 1.97, 95% CI 1.36 to 3.34).8 However, the included studies merely evaluated associations, and there was an absence of interventional data evaluating the effectiveness of periconception dietary modifications on miscarriage risk.
Vitamin supplementation is frequently recommended for women planning pregnancy. The benefits of supplementation are to lower the risk of congenital anomalies such as neural tube defects and reduce the risk of low birth weight, small for gestational age and preterm births.9 In addition, there is evidence suggesting that women with vitamin D deficiency (serum level <50 nmol/l) and insufficiency (serum level <75 nmol/l) exhibit a 60% increase in their risk of miscarriage compared to women who are vitamin D replete (>75 nmol/l).10 Therefore, women trying to conceive should consider having their serum vitamin D levels tested and corrected appropriately.11
Data from observational studies advocate supplementation of other vitamins and minerals for the prevention of miscarriage, including folate and B vitamins. However, 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,12 although the evidence showed that women receiving multivitamins plus iron and folate 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).12 In addition, folate has well-documented effectiveness in preventing neural tube defects. Therefore, all women trying to conceive should be advised to commence folate at a dose of 400 mg for at least 12 weeks before pregnancy, continuing for the duration of the first trimester of gestation. A higher folate dose 5 mg once daily should be considered in women with any of the following features: epilepsy; diabetes types 1 and 2; sulfasalazine therapy for IBD; neural tube defect in a previous pregnancy; sickle cell disease; BMI ≥30 kg/m2.13
Smoking
Smoking exerts a range of harmful effects to both female and male gametogenesis, resulting in higher rates of gamete aneuploidy and in turn increasing the risk of miscarriage. In addition, during early embryo development, active and passive exposure to smoking have been shown to limit fetal oxygenation, leading to higher rates of miscarriage and stillbirth.14 Despite widespread campaigns advocating smoking cessation in the preconception period and during pregnancy, up to 14% of expecting mothers report smoking tobacco.15
In a systematic review of 98 studies examining the association between active or passive smoking and miscarriage, the authors identified that women who reported active smoking exhibited a 23% increase in the risk of miscarriage (summary RR 1.23, 95% CI 1.16 to 1.30), and that the risk of pregnancy loss rose incrementally with the amount of cigarettes smoked (1% increase in RR per cigarette smoked per day).15 In addition, a prospective study in 526 men identified a correlation between heavy paternal smoking and early pregnancy loss.16
The review by Pineles et al.15 identified that women who had stopped smoking were not at an increased risk of miscarriage compared to those who had never smoked, yet interventional data were lacking. Nicotine replacement therapy, in the form of patches or gum, has not been shown to increase the risk of miscarriage.17 In recent years, the use of electronic cigarettes (EC) among pregnant women has also increased significantly, although it remains unclear whether EC can cause harm to the fetus.18 In a recent randomized controlled trial, investigators evaluated the effectiveness of a financial incentive for smoking cessation in pregnancy, demonstrating that financial incentives to reward smoking abstinence resulted in increased abstinence rates compared to no intervention (OR 2.45, 95% CI 1.34 to 4.49, P = 0.011). In addition, the study demonstrated a 7% reduction in the risk of a poor neonatal outcome, with 14 fewer babies experiencing an adverse neonatal event (mean difference 14, 95% CI 5 to 23), although the study did not specifically report on miscarriage rates.19
Alcohol
Alcohol is a potent 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.20 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.21
The detrimental effect of ethanol on embryo development and sporadic miscarriage is 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 (OR 1.19, 95% 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).22
Alcohol consumption has also been shown to negatively affect semen volume and sperm morphology.23 Evidence suggests that male alcohol intake at the time of conception may lead to a fivefold increase in the risk of miscarriage.24
Caffeine
Caffeine is a widely consumed stimulant, and up to 9 in 10 pregnant women report drinking coffee.25 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 200 mg of caffeine per day has not been shown to cause harm to the developing fetus,26 echoing advice from the American College of Obstetricians and Gynecologists (ACOG) and the UK National Health Service.25 However, there is a growing body of 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 (OR 1.32, 95% CI 1.24 to 1.40). Furthermore, for every additional two cups of coffee per day, the risk of miscarriage rose by 8%.27
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).28
MEDICAL INTERVENTIONS TO PREVENT MISCARRIAGE
Antioxidant therapies
Increased oxidative stress levels have been implicated in miscarriage by inducing a hostile environment in the female reproductive tract, in addition to increasing the risk of aneuploidy during oogenesis.29 Thus, studies have aimed to evaluate whether agents with antioxidant properties, including vitamins, reduce the risk of miscarriage. However, a Cochrane review published in 2016 did not identify a benefit in taking vitamin supplements for the prevention of miscarriage, although there was a positive signal for the prevention of stillbirth which warrants further research.12 A subsequent review found that in women with a history of subfertility, the use of antioxidants appeared to make little difference to the risk of miscarriage (OR 1.13, 95% CI 0.82 to 1.55), although the evidence was judged to be of low certainty.30
A recent systematic review including 16 studies and more than 1200 male participants identified a strong association between high DNA damage in sperm and the risk of miscarriage (OR 2.67, 95% CI 1.67 to 4.28).1 There is a paucity of randomized controlled trials investigating therapies to tackle high DNA fragmentation and reduce the risk of miscarriage in the overall population.31 However, a recent Cochrane systematic review focusing specifically on the use of antioxidant therapies for males with infertility identified 90 randomized controlled trials evaluating a total of 10,303 men. The evidence suggested a possible increase in live birth rates associated with the administration of antioxidants in men with subfertility (OR 1.43, 95% CI 1.07 to 1.91), yet there was no evidence of a reduction in miscarriage rates (Peto OR 1.46, 95% CI 0.75 to 2.83). For both live birth and miscarriage rates, the certainty of the evidence was deemed very low.32
Treatment for thyroid dysfunction
Thyroid dysfunction has been associated with an increased risk of miscarriage. The review by Quenby et al.1 suggested that the presence of thyroid autoantibodies in maternal serum more than doubled the odds of miscarriage irrespective of the clinical presentation (OR 2.29, 95% CI 1.86 to 2.81), and that subclinical hypothyroidism resulted in approximately a 58% increase in the rates of miscarriage compared to women with normal thyroid biochemistry (OR 1.58, 95% CI 1.18 to 2.12).1 However, there is insufficient evidence to recommend universal screening for all women trying to conceive a pregnancy.33
According to recent guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) in the United Kingdom, women with subfertility and positive thyroid peroxidase antibodies (TPO) who exhibit no symptoms of thyroid disease do not benefit from levothyroxine treatment.33 However, these women should undergo baseline thyroid function tests a 7–9 weeks' gestation, and then every trimester, because there is an 8% risk of progression to subclinical hypothyroidism in pregnancy.34 In women trying to conceive who exhibit mildly raised thyroid-stimulating hormone (TSH) levels (>4.0–10.0 mIU/l) in the absence of clinical symptoms (subclinical hypothyroidism), RCOG guidance recommends commencing levothyroxine at a dose of 1.0–1.2 μg/kg while trying to conceive, and doubling it on 2 days/week in pregnancy, aiming for a TSH level of <2.5 mIU/l as indicative of therapeutic control.33
Progesterone treatment
Progesterone is a steroid hormone secreted by the corpus luteum in early pregnancy until approximately 7–8 weeks’ gestation, at which point the placenta takes over most of the endogenous synthesis of steroid hormones.35 In the absence of a corpus luteum, pregnancy inevitable results in miscarriage unless women receive exogenous hormone replacement therapy.35,36 In addition, a relative lack of progesterone, often termed luteal defect, has been associated with infertility, failed embryo implantation in assisted conception, and miscarriage.37,38,39,40,41 This has led researchers to suggest the use of exogenous progesterone supplementation for the prevention of miscarriage. In a recent systematic review and meta-analysis, progesterone treatment was associated with an increase in live births in women with threatened miscarriage (RR 1.05, 95% CI 1.01 to 1.08) and women with recurrent miscarriage (RR 1.08, 95% CI 1.03 to 1.14).4
In its latest guideline for recurrent pregnancy loss, the European Society for Human Reproduction and Embryology (ESHRE) recommended the use of vaginal micronized progesterone at a dose of 400 mg twice daily for women with the dual risk factor of vaginal bleeding in early pregnancy and a history of three or more previous miscarriages, to be continued until 16 completed weeks of gestation.42 In the United Kingdom, the National Institute for Health and Care Excellence recommends that treatment with vaginal progesterone should be commenced for any women with threatened miscarriage in the first trimester and a history of any number (one or more) previous pregnancy losses.43
Common side effects of vaginal progesterone include breast pain, drowsiness and gastrointestinal discomfort, although women generally tolerate these adverse effects well. In addition, progesterone treatment is contraindicated in women with acute porphyria, history during pregnancy of idiopathic jaundice, pemphigoid gestationis or severe pruritus, breast cancer, thromboembolism or thrombophlebitis.44
Metformin treatment in polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is an endocrine condition affecting 10–15% of women of reproductive age.45 It is estimated that a history of PCOS increases the risk of first-trimester miscarriage by approximately 33% (OR 1.33, 95% CI 1.05 to 1.68, 27 studies, n = 22,235 participants).1 There are various mechanisms implicated in the pathophysiology of PCOS, involving close associations with obesity, hyperinsulinemia, luteinizing hormone hypersecretion, hyperandrogenism and thrombophilia.45 The knowledge that altered insulin metabolism is associated with PCOS has led to the use of metformin, a biguanide, to improve insulin resistance by inhibiting glucagon and hepatic gluconeogenesis.46
In women with PCOS, the use of metformin has been associated with a reduction in the composite outcome of late miscarriage and preterm delivery (OR 0.43 , 95% CI 0.23 to 0.79, P = 0.004).47However, there is no universally accepted regimen for metformin administration for the prevention of miscarriage in PCOS. A pragmatic regimen involves the administration of 500 mg once daily, with titration to up to 500 mg three times daily. Women should be warned about the gastrointestinal side effects of metformin, including heartburn, stomach pain, nausea and vomiting. In women who experience significant side effects of metformin, the dose should be reduced as tolerated to a minimum of 500 mg once daily. Alternatively, a modified release (MR) formulation may be prescribed. If adverse symptoms persist at this lowest dose or while taking a MR preparation, consideration should be given to discontinuation of metformin.
Importantly, metformin is contraindicated in cases of acute metabolic acidosis (including lactic acidosis and diabetic ketoacidosis). In addition, caution should be exerted when risk factors for lactic acidosis are present (e.g., chronic stable heart failure, concomitant use of drugs that can acutely impair renal function).44
Anticoagulant therapy
Thrombophilia, both inherited (e.g., factor V Leiden mutation, protein C and/or S deficiency, and prothrombin gene mutation) and acquired (antiphospholipid syndrome), are associated with recurrent pregnancy loss.11 Systematic reviews and meta-analyses have shown a reduction in miscarriage (RR 0.48, 95% CI 0.32 to 0.71, low-certainty evidence) and increase in live birth (RR 1.27, 95% CI 1.09 to 1.49, low-certainty evidence) with the combined use of low-dose aspirin and heparin compared with placebo in women with antiphospholipid syndrome and recurrent miscarriage.48,49,50,51 However, in women with inherited thrombophilia, existing evidence does not support the use of anticoagulation therapy for the prevention of further pregnancy losses.52
Treatment of anatomical uterine abnormalities
Anatomical uterine anomalies can be congenital (e.g., Müllerian duct abnormalities, including didelphic uterus, uterine septa, bicornuate uterus) or acquired (e.g., polyps and uterine fibroids). Studies suggest that the risk of first-trimester miscarriage is increased in women with septate (RR 2.65, 95% CI 1.39 to 5.06) and bicornuate uteri (RR 2.32, 95% CI 1.05 to 5.13) compared to women without uterine anomalies, whereas there has been no conclusive evidence of an association between miscarriage risk and having an arcuate, didelphic or unicornuate uterus.2 For this reason, surgical treatment of didelphic uteri is not recommended. A recent randomized controlled trial investigating surgical treatment of uterine septa did not identify any benefit in septum resection for improving live birth rates and reducing the risk of miscarriage, and therefore this procedure should not be routinely undertaken.53
There is limited evidence on the association between acquired uterine anomalies, namely fibroids, polyps and intrauterine adhesions, and women’s risk of sustaining pregnancy loss. Interventional data are also scarce, but good practice recommendations suggest that surgical treatment should be considered for endometrial fibroids, submucous fibroids and intrauterine adhesions.2 For intramural and subserosal fibroids, however, uterine surgery is not routinely recommended, and patients should be informed of procedure-related benefits and risks to enable shared decision-making.54
CONCLUSION
Miscarriage is common, occurring most often because of embryonic aneuploidy. Despite physical, psychological and societal consequences of miscarriage, research into treatments aimed at preventing miscarriage remains scarce. Existing studies on lifestyle factors contributing to pregnancy loss are largely observational, and there is a paucity of interventional data for therapies aimed at preventing miscarriage. In people with known medical comorbidities or a history of previous miscarriages, medical interventions are available, although evidence attesting to their effectiveness is lacking. For some treatments, including progesterone for the prevention of threatened miscarriage, there is nonetheless moderate-certainty evidence of effectiveness and to date no material safety concerns.
PRACTICE RECOMMENDATIONS
Nutrition and Weight
- Pregnant women in the first trimester, and those trying to conceive, should be advised that a balanced diet is crucial to support embryo/fetal development and maternal well-being.
- Women and men trying to conceive should strive for a healthy BMI (19–25 kg/m2).
- Clinicians should inform women and men trying to conceive that in the absence of known nutrient deficiencies, maintaining a balanced diet is the single most important intervention to ensure intake of the necessary amount of fiber, iron, iodine, calcium, zinc and most other micronutrients.55
- The following supplementation doses of vitamin D should be considered:
- 400 IU once daily for all pregnant women;
- 1000 IU once daily for women at high risk of vitamin D deficiency (i.e., increased skin pigmentation, reduced exposure to sunlight, BMI ≥30 kg/m2 and socially excluded women).56
- Folic acid at a dose of 5 mg once daily should be considered in women with any of the following features: epilepsy; diabetes types 1 and 2; sulfasalazine therapy for IBD; neural tube defect in a previous pregnancy; sickle cell disease; BMI ≥30 kg/m2.57
- There is no evidence that supplementation of micronutrients prior to or in early pregnancy prevents pregnancy loss. However, the use of a multivitamin provides micronutrient supplementation to aid healthy pregnancy.
- Iron deficiency anemia should be corrected in the pre-conception period.
Smoking
- Women and men trying to conceive should be advised that smoking could increase the risk of miscarriage, and hence smoking cessation should be encouraged.58
- Women seeking nicotine replacement therapy (NRT) products should be informed that there has been no clear evidence of harm to pregnancy, although this remains uncertain.59
- Women trying to conceive or pregnant who use electronic cigarettes should be advised about the lack of safety evidence on these devices.60
- Clinicians caring for women and men with a history of smoking should signpost patients to smoking cessation services, or contact their general practitioners for onward referral to an appropriate agency.
Alcohol
- Women who are pregnant, and couples trying to conceive, should be advised that the safest approach is to not drink alcohol at all, in order to minimize any risks to the baby.61
- Women who report alcohol consumption in pregnancy should be advised that consuming any amount of alcohol (even 1–2 units per week) has been linked to a higher risk of miscarriage.22
- Men should be advised that alcohol intake is known to have a negative impact on sperm quality and increase the risk of miscarriage.62
- Clinicians caring for women and men with ongoing issues with alcohol use should signpost patients to alcohol support services, or contact their general practitioners for onward referral to an appropriate agency.63
Caffeine
- Pregnant women should be advised that existing evidence does not support assumptions about safe levels of maternal or paternal caffeine consumption for the prevention of miscarriage.25
- 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.28
Progesterone
- Based on the findings of the PRISM trial, offer vaginal micronized progesterone 400 mg twice daily to women with an intrauterine pregnancy confirmed by an ultrasound scan, if they have vaginal bleeding and a history of previous miscarriage. Vaginal progesterone should be taken until 16 completed weeks of pregnancy.
Metformin
- In view of the available evidence, women with a diagnosis of PCOS and recurrent pregnancy loss should consider metformin 500 mg once daily (OD). Doses should be titrated, as tolerated, up to 500 mg three times daily (TDS).
- The use of metformin could be recommended to women throughout pregnancy, although obstetric teams may opt to amend that plan locally and the evidence supporting this practice is scarce.
Anticoagulant therapy
- Women with antiphospholipid syndrome 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 6 weeks postnatally. For example:
- <50 kg: enoxaparin 20 mg once daily
- 50–90 kg: enoxaparin 40 mg once daily
- 91–130 kg: enoxaparin 60 mg once daily.64
- The dose of aspirin should be reviewed at the woman’s booking appointment and increased to 150 mg once daily for the prevention of pre-eclampsia where applicable.
Uterine anomalies
- Congenital uterine anomalies:
- Surgical treatment of bicornuate or didelphic uteri is not recommended.
- Hysteroscopic resection of a uterine septum should not be undertaken routinely but considered on an individualized basis by experienced specialists, based upon the clinical history and size of the uterine septum, and ideally within an appropriate audit or research context.
- Acquired uterine anomalies:
- Surgical treatment may be considered for endometrial polyps, submucosal fibroids and intrauterine adhesions, although the evidence on its effectiveness remains scarce.
- Surgical removal of intramural and subserosal fibroids is not recommended.
CONFLICTS OF INTEREST
The author(s) of this chapter declare that they have no interests that conflict with the contents of the chapter.
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Online Study Assessment Option
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Medical students can receive the Study Completion Certificate only.
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