The European Society of Human Reproduction and Embryology (ESHRE) defines RPL as two or more consecutive miscarriages, while the American College of Obstetricians and Gynecologists (ACOG) defines it as three consecutive miscarriages>20 weeks gestation. 1,2

Risk factors for recurrent pregnancy loss include chromosomal abnormalities (60%), immunological and immunogenic, endocrinological, DNA fragmentation in the sperm, impairment in the biosensor function of the endometrium as well as lifestyle influences.

Psychological impact of RPL 

The ScreenIVF study found that both partners have a high risk of developing depression and anxiety. In the ScreenIVF study, 47.7% of women versus 19.1% of men showed an increased risk for anxiety, and 51.7% versus 19.1% increased risk for depression.3,4 

Moderate to severe depression was diagnosed in 8%–20% and post-traumatic stress disorder in 25%–39% of patients. Further, some studies revealed a higher risk for obsessive-compulsive disorder in women with early pregnancy loss.3  

Risk factors for RPL 

RPL can be differentiated into primary RPL (patients with no successful pregnancy) and secondary RPL (patients with a history of at least one live birth before the pregnancy losses).3  

Risk factors for RPL include chromosomal abnormalities (60%), immunological and immunogenic, endocrinological, DNA fragmentation in the sperm, impairment in the biosensor function of the endometrium as well as lifestyle influences. Standard investigations will be normal for many couples and the cause of RPL is deemed ‘unexplained’ in around 50% of cases.1 

Maternal age is an important predictor of the risk of miscarriage. In women ages 20 to 30, risk of miscarriage less than 20 weeks gestation is 8.9%. This increases to 74.7% for women over 40 years.5  

Maternal comorbidities such as thrombophilia, antiphospholipid antibody syndrome, extremes of maternal weight, and hypertension also increase the risk of miscarriage. Additional maternal risk factors include trauma and poor lifestyle choices.5 

Poor lifestyle choices that can result in a hostile reproductive environment for the embryo are being either overweight/obese (body mass index [BMI]>30 1.7-fold increase and a BMI >25 1.2-fold risk of RPL), or underweight (increases the risk of RPL 1.2-fold compared to those with normal BMI).1  

Interestingly, other lifestyle factors such as alcohol intake, cigarette smoking and high caffeine intake (>300mg per day) have not been shown to increase the risk of RPL.1 

However, the ESHRE guideline (2018) strongly recommends smoking cessation. Furthermore, the society states that based on the evidence, it is unclear whether caffeine intake is a risk factor for RPL.6 

ESHRE also cautions that excessive alcohol consumption is a possible risk factor for pregnancy loss and a proven risk factor for foetal problems. Couples should therefore be strongly advised to limit alcohol consumption. While exercise is advocated in pregnancy, ESHRE warns that high-intensity exercise may be a risk factor for miscarriage.6 

Another important predictor of RPL is prior obstetric history. The risk of miscarriage in a future pregnancy is about 20% after one miscarriage, 28% after two consecutive miscarriages, and 43% after three or more consecutive miscarriages.5  

More recently, researchers have postulated that progesterone deficiency – also known as known as luteal phase deficiency (LPD) – could be a cause of some miscarriages.3,7,8   

The role of progesterone  

Progesterone is a female hormone that is naturally secreted by the corpus luteum (CL), a mass of cells that forms in an ovary, as well as in the placenta. CL plays an important role in the regulation of ovulation and menstruation.9  

Progesterone prepares the endometrial lining of the uterus to allow implantation of the early embryo. It is therefore essential for the establishment as well as the maintenance of a pregnancy.3,7,9 

Progesterone maintains pregnancy specifically by preparing the endometrium, decreasing myometrial contractions for implantation, promoting gestation, and inhibiting lactation during pregnancy.9 

Furthermore, progesterone influences the production of inflammatory mediators, such as human T-cells within the uterine cavity. A loss of progesterone therefore leads to an increase in myometrial contractility, coupled with a decrease in fighting off immunologic threats.9 

It has been postulated that a dysfunction in progesterone secretion or action could contribute to RPL.  Progesterone deficiency can be primary, in which no cause is found (idiopathic), or secondary to other pathologies including thyroid or prolactin disorders.9  

One proposed diagnostic criterium for LPD is a shortened luteal phase of less than nine days from the day of ovulation to menstrual bleeding. The normal luteal phase length from ovulation to menses ranges from 11 to 17 days with most luteal phases lasting 12 to 14 days.  LPD is also suspected when spotting begins many days before mensuration without a structural or infectious cause.9 

Two mechanisms have been proposed as causes of clinical LPD: 9  

  • Impaired function of the CL resulting in insufficient progesterone (most common and likely cause) 
  • Impaired oestradiol secretion.  

Both mechanisms result in a CL with deficiencies in progesterone production. The second theory suggests an inability of the endometrium to mount a proper response to appropriate oestradiol and progesterone exposure.9 

Studies investigating the efficacy and safety of progesterone to prevent RPL 

According to Coomarasamy et al, bleeding in early pregnancy is strongly associated with pregnancy loss.  Evidence indicates that women with a past history of miscarriage or at high risk of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronised progesterone as shown by the 2015 PROgesterone in MIScarriagE (PROMISE)and the 2019 Progesterone In Spontaneous Miscarriage (PRISM) trials.3,8,10 

The aim of the two trials and subgroup analysis was to generate robust evidence on the role of progesterone therapy to prevent miscarriage and increase the live birth rate.8  

The PROMISE trial involved 836 women with idiopathic recurrent miscarriage randomised to receive either 400 mg of vaginal micronized progesterone twice daily or placebo from the time of positive pregnancy test to 12 weeks gestation.10 

The primary analysis of the PROMISE trial found the live birth rate was 66% in the progesterone group vs 63% in the placebo group (risk ratio [RR] 1.04). There was a 3% greater live birth rate with progesterone, but the trial finding was reported as not statistically significant.8  

Next, the team performed a prespecified subgroup analysis by the number of previous miscarriages.  Participants were split into two subgroups: 

  • Women who had three previous miscarriages  
  • Women who had >4 miscarriages.8 

A post-hoc subgroup analysis was also performed, which included women who had 3, 4, 5, and >6 previous miscarriages. The researchers acknowledged that the post-hoc analysis would be underpowered and could only be used for hypothesis generation.8  

However, they added, the analysis would still be useful for assessing a biological gradient in these subgroups. The findings appeared to suggest a trend for greater benefit with increasing number of previous miscarriages.8 

The PRISM trial assessed the reproducibility of this subgroup effect by the increasing number of previous miscarriages. Women (n=4153) were randomly assigned to receive vaginal suppositories containing either 400mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation.8,11  

According to the researchers, the PRISM trial was designed and conducted with methodologic rigour, appropriate randomisation, allocation concealment, double-blinding with placebo control, excellent follow-up rate, and analysis according to a prespecified statistical analysis plan.8 

The primary analysis of PRISM trial found that the live birth rate was 75% in the progesterone group vs 72% in the placebo group. For the prespecified subgroup analysis by the number of previous miscarriages, the study population was split into three subgroups: 8  

  • Women without a history of miscarriage 
  • Women with one or two previous miscarriages 
  • Women with >3 previous miscarriages. 

Two post-hoc subgroup analyses were performed to explore in detail for a possible biological gradient:8  

  • Group 1: Women who had no previous miscarriage or those who had any number of previous miscarriages  
  • Group 2: Women who had no, one, two and >3 previous miscarriages. 

The live birth rate was 75% with placebo (RR, 1.09) for the subgroup of women with one or more previous miscarriage(s) and bleeding in the current pregnancy. The benefit was even greater for the subgroup of women with >3 previous miscarriages and current pregnancy bleeding. The live birth rate was 72% with progesterone vs 57% with placebo (RR 1.28).8 

The researchers concluded that both studies showed that women who had >3 previous miscarriages benefitted most from progesterone intervention.8 

 Is progesterone intervention cost-effective? 

Ogwulu et al conducted a cost-effectiveness analysis in the UK based on the findings of the PRIMS trial. The cost of progesterone therapy in preventing pregnancy loss in women with early pregnancy vaginal bleeding was compared to placebo.12 

The analysis included women between the ages of 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. The researchers performed an incremental cost-effectiveness analysis and subgroup analyses were carried out on women with ≥1 or ≥3 previous miscarriages. The primary endpoint was cost per additional live birth at ≥34 weeks of gestation.12 

The mean cost per woman in the progesterone group was £76  more than the mean cost in the placebo group.12  

Both subgroup analyses were more favourable, especially for women who had  at least one previous miscarriage, where progesterone was more effective than placebo with an effect difference of 0.055 (an additional gain of five live births per 100 women) and this was associated with a cost saving of £322.12 

The researchers concluded that given the available evidence, progesterone is likely to be a cost-effective intervention for all women at risk, but particularly for women with previous miscarriages who present with bleeding in early pregnancy.12  

This study does not take into account either the distress that comes with miscarriages nor the subsequent resources associated with counselling and close monitoring in subsequent pregnancies, which would incur additional costs.  

What do guidelines recommend? 

According to the 2021 National Institute for Health and Care Excellence (NICE) guideline on the management of miscarriage, woman with a confirmed intrauterine pregnancy with a foetal heartbeat who presents with vaginal bleeding, but has no history of previous miscarriage, should be advised that:11 

  • If her bleeding gets worse, or persists beyond 14 days, she should return for further assessment 
  • If the bleeding stops, she should start or continue routine antenatal care. 

Furthermore, the guideline recommends that progesterone should be offered to women who experience bleeding in early pregnancy and have previously had a miscarriage. If a foetal heartbeat is confirmed, continue progesterone until 16 completed weeks of pregnancy.11 

REFERENCES:  

  1. Ng KYB, Cherian G, Kermack AJ. Systematic review and meta-analysis of female lifestyle factors and risk of recurrent pregnancy loss. Nature Systematic Reviews, 2021. 
  2. ACOG. Repeated Miscarriages. https://www.acog.org/womens-health/faqs/repeated-miscarriages#:~:text=Recurrent%20pregnancy%20loss%20is%20defined,%25)%20will%20have%20repeated%20miscarriages. 
  3. Coomasasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. NEJM, 2019. 
  4. Voss P, Schick M, Langer L, et al.  Recurrent pregnancy loss: a shared stressor: couple-orientated psychological research findings. Fertility and Sterility, 2020. 
  5. Dugas C and Slane VH. Miscarriage. [Updated 2021 Jun 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532992/ 
  6. Atik RB, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Human Reproduction Open, 2018. 
  7. Devall AJ and Coomarasamy A. Sporadic pregnancy loss and recurrent miscarriage. Best Practice & Research Clinical. Obstetrics and Gynaecology, 2020. 
  8. Coomarasamy A, Devall AJ, Brosens JJ, et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. American Journal of Obstetrics & Gynecology, 2020. 
  9. Feferkorn I and Tulandi T. The role of progesterone in miscarriage. Contemporary OB/GYN Journal, 2021. 
  10. Coomarasamy A, Williams H, Truchanowicz E, et al. A Randomized Trial of Progesterone in Women with Recurrent Miscarriages. NEJM, 2015. 
  11. Coomarasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. NEJM, 2019. 
  12. Ogwulu CBO, Goranitis I, Deval AJ, et al. The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM Trial. BJOG, 2019. 
  13. NICE guideline. Ectopic pregnancy and miscarriage: diagnosis and initial management. Updated 2021. https://www.nice.org.uk/guidance/ng126.