8.1

Introduction

Recurrent miscarriage (RM) is defined as loss of three or more consecutive pregnancies prior to 20 weeks of gestation, though some authors describe RM as two or more consecutive pregnancy losses.

The incidence of RM has been reported to be around 0.5%–2.3% and is rising in relation to the prevalence of obesity. It has been estimated that 1%–2% of second-trimester pregnancies miscarry before 24 weeks of gestation.

Approximately in 50% of couples with RM, the underlying cause remains unexplained after all investigations. Though this is reassuring it can be distressing for the couple.

In the United Kingdom, obesity affects one-fifth of the female population. Maternal obesity has been reported as a risk factor for adulthood obesity in offspring. Obesity may also lead to a poor pregnancy outcome like as sudden and unexplained intrauterine death.

Increased body mass index (BMI) has also been suggested as the second most significant factor predicting early pregnancy loss after advanced female age.

8.2

Obesity and miscarriage

Obesity is associated with low levels of adiponectin but raised levels of leptin in both serum and follicular fluid.

Higher levels of leptin can impair ovarian steroidogenesis. Low levels of adiponectin lead to higher levels of serum insulin levels which is one of the factors that increases levels of circulating androgens.

Therefore, obesity itself creates quite a hostile biochemical environment for the early stages of the developing gamete and pregnancy.

8.3

Obesity and recurrent miscarriage

A recent systematic review and meta-analysis has reported a significant association between excess weight and RM, independent of age as a risk factor.

The exact mechanism by which obesity increases the risk of miscarriage and RM is still not very clear. It is unlikely that the increased risk of miscarriage among obese patients can solely be attributed to Polycystic ovarian syndrome (PCOS) because of the low prevalence of PCOS in the general population with mostly spontaneous miscarriage.

The possible theories for the association between obesity and RM include the effect of obesity on endometrial development and the effect on oocyte quality.

8.4

Aetiologies of recurrent miscarriage

8.5

Polycystic ovarian syndrome

PCOS is the most common endocrine disorder in women of reproductive age. It is associated with menstrual irregularity, ovarian dysfunction, and symptoms of hyperandrogenism. Approximately half of women with PCOS are obese.

Polycystic ovary syndrome has been linked to an increased risk of miscarriage but the exact mechanism remains unclear. Polycystic ovarian morphology, elevated serum luteinising hormone levels, or elevated serum testosterone levels, although used as markers of PCOS, do not predict an increased risk of future pregnancy loss among ovulatory women with a history of RM who conceive spontaneously. The increased risk of miscarriage in women with PCOS has been recently attributed to insulin resistance (IR), hyperinsulinaemia, and hyperandrogenaemia. The prevalence of IR is increased in women with RM compared with matched fertile controls. An elevated free androgen index (FAI) appears to be a prognostic factor for a subsequent miscarriage in women with RM.

A combination of high serum levels of androgens (testosterone, dehydroepiandrosterone sulfate, androstenedione) including a high peripheral IR and compensatory hyperinsulinaemia. The raised leptin levels have been reported in obese women, causing a detrimental effect on ovarian steroidogenesis.

There is a possible negative association between FAI and oocyte quality or fertilisation in women with PCOS.

Hyperinsulinaemia is associated with increased levels of plasminogen activator inhibitor 1 (PAI-1) that is strongly associated with an increased risk of miscarriage and RM. Also hyperinsulinaemia by itself is a significant independent risk factor for miscarriage and also is believed to play a key role in implantation failure by suppression of circulating glycodelin and insulin-like growth factor binding protein.

8.6

Ovarian dysfunction

Studies comparing the outcome of assisted reproduction in obese women with nonobese women found that obese women have a significantly lower number of mature oocytes and oocytes with reduced diameter.

Overweight women’s embryos also had a lower potential for development and IVF and a lower rate of blastocyst formation.

Intrafollicular human chorionic gonadotrophin concentration appears to be inversely related to BMI and may be related to concurrent decrease in embryo quality and rates of pregnancy.

8.7

Endometrial changes in obesity

Implantation of the embryo and a successful pregnancy require a receptive endometrium and obesity may affect the endometrium or its environment causing implantation failure and pregnancy losses.

The precise impact of obesity on the molecular and histopathological aspects of the endometrium is not fully understood.

Progesterone induces secretory changes in the lining of the uterus, which is needed for implantation of the embryo. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone.

8.8

Immunological factors

The hypotheses of human leucocyte antigen incompatibility between couples, the absence of maternal leucocytotoxic antibodies, or the absence of maternal blocking antibodies do not have clear evidence and therefore should not be offered routinely in the investigation of couples with RM.

Natural killer (NK) cells are found in peripheral blood and the uterine mucosa. Peripheral blood NK cells are phenotypically and functionally different from uterine NK (uNK) cells. There is no clear evidence that altered peripheral blood NK cells are related to RM. The uNK cells which have been investigated as playing a role in later stages in implantation may in turn result in miscarriage. Studies of peripheral blood and endometrial uNK cells have suggested that they may play a role, but it is unclear at present.

Therefore, testing for peripheral blood NK cells as a surrogate marker of the events at the maternal–foetal interface is inappropriate and should not be offered routinely in the investigation of couples with RM.

There is a suggestion that uNK cells may play a role in trophoblastic invasion and angiogenesis in addition to the local maternal immune response to pathogens. The largest study examining the relationship between uNK cell numbers and future pregnancy outcome reported that raised uNK cell numbers in women with RM was not associated with an increased risk of miscarriage.

This remains a research field and testing for uNK cells should not be offered routinely in the investigation of RM.

Cytokines are immune molecules that control both immune and other cells. Cytokine responses are generally characterised either as T-helper-1 (Th-1) type, with production of the proinflammatory cytokines interleukin 2, interferon, and tumour necrosis factor (TNF) alpha, or as T-helper-2 (Th-2) type, with production of the anti-inflammatory cytokines interleukins 4, 6, and 10. It has been suggested that normal pregnancy might be the result of a predominantly Th-2 cytokine response, whereas women with RM have a bias towards mounting a Th-1 cytokine response. A meta-analysis concluded that the available data are not consistent with more than modest associations between cytokine polymorphisms and RM. Further research is required to assess the contribution that disordered cytokines make to RM before routine cytokine tests can be introduced to clinical practice.

Obesity is associated with chronic inflammation. Women with idiopathic RM and some other obstetric complications are known to have higher levels of inflammatory markers (e.g., IL-6 and CRP). Chronic inflammation, therefore, could be a mechanism contributing to higher risk of RM in obese women.

8.9

Management of recurrent miscarriage

Couples with RM should be informed that maternal obesity or being significantly underweight is associated with obstetric complications and could have a negative impact on their chances of a live birth and on their general health.

Gradual weight loss has been shown to improve fertility and the outcomes of fertility treatments. Striving for a healthy normal range BMI is recommended.

The management of obesity is important because exercise and diet modification are of low cost.

Alternatively, bariatric surgery is increasingly offered to obese patients with comorbidities.

The increased risk of miscarriage in women with PCOS has been attributed to IR and hyperinsulinaemia. Weight loss in obese women with PCOS, through protein-rich, very-low-calorie diet, has been shown to significantly reduce serum fasting glucose and insulin, improve insulin sensitivity, and decrease PAI-1 activity.

Insulin-sensitising agents such as metformin have been used in the treatment of obese PCOS women who have shown improvements in hyperinsulinaemia and hyperandrogenism. Metformin use appears to be safe in the first trimester. Metformin has been found to reduce miscarriage rate in women with PCOS but these are based on uncontrolled small studies.

A meta-analysis of 17 randomised controlled trials of metformin, an insulin-sensitising agent, in women with PCOS and infertility showed that metformin has no effect on the sporadic miscarriage risk when administered pre pregnancy. However, there are no randomised controlled trials to assess the role of metformin in women with RM.

Progesterone is necessary for successful implantation and the maintenance of pregnancy. This benefit of progesterone could be explained by its immunomodulatory actions in inducing a pregnancy-protective shift from proinflammatory Th-1 cytokine responses to a more favourable antiinflammatory Th-2 cytokine response. A meta-analysis to assess progesterone support for pregnancy showed that it did not reduce the sporadic miscarriage rate. However, in a subgroup analysis of trials involving women with RM, progesterone treatment offered a statistically significant decrease in miscarriage rate compared with placebo or no treatment. However, this meta-analysis was based on three small controlled studies, none of which detected a significant improvement in pregnancy outcome.

PROMISE studied 836 women with unexplained RMs at 45 hospitals in the United Kingdom and the Netherlands, and found a 3% higher live birth rate with progesterone. PRISM studied 4153 women with early pregnancy bleeding at 48 hospitals in the United Kingdom and found there was a 5% increase in the number of babies born to those who were given progesterone who had previously had one or more miscarriages, compared to those given a placebo. The benefit was even greater for the women who had previous “recurrent miscarriages” (i.e., three or more miscarriages)—with a 15% increase in the live birth rate in the progesterone group compared to the placebo group. This might suggest that we could potentially use additional progesterone support in a small selected group of patients.

A recent study concluded that for women with unexplained RM, supplementation with progestogen therapy may reduce the rate of miscarriage in subsequent pregnancies. The PRISM trial has shown that for women who had three or more miscarriages, there was a 15% increase in births for those who were given progesterone compared to those who were given a placebo.

Immunotherapy is expensive and has potentially serious adverse effects including transfusion reaction, anaphylactic shock, and hepatitis. A Cochrane systematic review has shown that the use of various forms of immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes, and intravenous immunoglobulin, in women with unexplained RM provides no significant beneficial effect over placebo in preventing further miscarriage. A 2010 meta-analysis confirmed this conclusion with respect to intravenous immunoglobulin. The use of immunotherapy should no longer be offered to women with unexplained RM.

Anti-TNF agents could potentially cause serious morbidity including lymphoma, granulomatous disease such as tuberculosis, demyelinating disease, congestive heart failure, and syndromes similar to systemic lupus erythematosus. There are no published data on the use of anti-TNF agents to improve pregnancy outcome in women with RM. Therefore, these should not be offered routinely to women with RM outside formal research studies.

8.10

Conclusion

There is a positive correlation between obesity and RM based on current evidence. Exact mechanisms are uncertain. Weight loss would seem prudent for obese women contemplating pregnancy after RM. There is limited other specific advice or treatment for women at present based on current evidence.