NICE guideline “Ectopic pregnancy and miscarriage”: new changes and importance for the clinicist

The purpose of this publication is to summarize the current data on the effectiveness of progestogens in patients with threatened miscarriage (vaginal bleeding in the first trimester of pregnancy) and to review the updated UK National Institute for Health and Care Excel (NICE) clinical guidelines on ectopic pregnancy and miscarriage.In accordance with the opinion of the Cochrane Society experts and the updated NICE clinical guidelines for 2021, vaginal progesterone at a dose of 800 mg/day is the only intervention that has been shown to be effective in increasing live births compared to placebo for women with one or more previous miscarriages and early vaginal bleeding (relative risk 1.08, 95% confidence interval 1.02–1.15, high certainty evidence). Upon confirmation of fetal heartbeat, this treatment should be extended until 16 weeks of gestation.There is still uncertainty over the effectiveness and safety of alternative progestogen treatments (as dydrogesterone) for threatened and recurrent miscarriage. There is also no evidence of benefit of any other preparations or doses of progesterone in patients at risk of miscarriage.

Pregnancy-related complications and perinatal outcomes following progesterone supplementation before 20 weeks of pregnancy in spontaneously achieved singleton pregnancies: a systematic review and meta-analysis

Background Progesterone supplementation is widely performed in women with threatened miscarriage or a history of recurrent miscarriage; however, the effects of early progesterone supplementation on pregnancy-related complications and perinatal outcomes in later gestational weeks remain unknown. Methods Ovid MEDLINE, the Cochrane Library, Embase and ClinicalTrials.gov were searched until April 3rd, 2021. Randomized controlled trials regarding spontaneously achieved singleton pregnancies who were treated with progestogen before 20 weeks of pregnancy and were compared with those women in unexposed control groups were selected for inclusion. We performed pairwise meta-analyses with the random-effects model. The risk of bias was assessed according to the Cochrane Collaboration tool. The primary outcomes included preeclampsia (PE), and gestational diabetes mellitus (GDM), with the results presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results We identified nine eligible studies involving 6439 participants. The pooled OR of subsequent PE following early progestogen supplementation was 0.64 (95% CI 0.42–0.98, moderate quality of evidence). A lower OR for PE was observed in the progestogen group when the subgroup analysis was performed in the vaginal subgroup (OR 0.62, 95%CI 0.40–0.96). There was insufficient evidence of a difference in the rate of GDM between pregnant women with early progestogen supplementation and unexposed pregnant women (OR 1.02, 95% CI 0.79–1.32, low quality of evidence). The pooled OR of low birth weight (LBW) following oral dydrogesterone was 0.57 (95% CI 0.34–0.95, moderate quality of evidence). The results were affected by a single study and the total sample size of enrolled women did not reach the required information size. Conclusion Use of vaginal micronized progesterone (Utrogestan) in spontaneously achieved singleton pregnancies with threatened miscarriage before 20 weeks of pregnancy may reduce the risk of PE in later gestational weeks. Among spontaneously achieved singleton pregnancies with threatened miscarriage or a history of recurrent miscarriage, use of oral dydrogesterone before 20 weeks of pregnancy may result in a lower risk of LBW in later gestational weeks. However, the available data were not sufficient to reach definitive conclusions, which highlighted the need for future studies.

REGULATION OF PERIPHERAL B-LYMPHOCYTE DIFFERENTIATION IN RECURRENT MISCARRIAGE

The important role of immune disorders in recurrent miscarriage has been proven. Clarification of the character of B-lymphocyte differentiation and its regulation factors in women with threatened miscarriage and recurrent miscarriage in history is an urgent problem, since it will reveal the immune mechanisms of the pathogenesis of this pathology. Purpose: to establish the features of B-lymphocyte differentiation and factors of its regulation in women with a history of recurrent miscarriage and threatening spontaneous miscarriage at the time of examination.Were examined pregnant women aged 18-40 years at a gestation period of 5-12 weeks. The main group consisted of 60 pregnant women with a threatening spontaneous miscarriage at the time of examination and a history of recurrent miscarriage. As a control, 35 pregnant women with uncomplicated pregnancy were examined. The comparison group consisted of 25 primary pregnant women with threatened spontaneous miscarriage at the time of examination. The material for the study was peripheral venous blood. Subpopulations of B-lymphocytes CD19+, CD19+ IgD+, CD20+IgM+, CD20+IgG+ were determined by flow cytometry; CD19+CD20- CD38+, CD19+CD27- , CD19+CD27+. Serum levels of BAFF and APRIL were assessed by enzyme-linked immunosorbent assay.In the main group, an increase in the proportion of B-cells, CD20+IgM+-lymphocytes and memory cells was recorded in the peripheral blood, along with a decrease in the level of naive cells and plasma cells. In the comparison group, an increase in the proportion of immature IgM+B-cells, circulating memory cells, along with a decrease in naive B-lymphocytes, was registered. in the main group there was a pronounced decrease in the serum BAFF level compared with the control and comparison groups. Analysis of the APRIL content showed a pronounced downward trend in groups with threatened miscarriage relative to healthy pregnant women. Thus, threatening habitual and sporadic miscarriages were associated with a shift in the differentiation of B-lymphocytes towards immature forms and a lack of regulatory influence of BAFF and APRIL, which is reflected in the disruption of B-cell homeostasis and weakening of humoral effector mechanisms at the systemic level. The revealed changes may indicate a single mechanism for the development of a threatening spontaneous miscarriage, the severity of which increases with repeated loss of pregnancy. These changes can lead to an increase in effector cytotoxic mechanisms and an increase in proinflammatory cytokines, which can lead to the development of damaging reactions in the fetoplacental complex, which can be reflected in the clinical picture of the threat of termination of pregnancy.

FEATURES OF MONOCYTE POLARIZATION AT DIFFERENT OUTCOMES IN WOMEN WITH RECURRENT MISCARRIAGE

Currently, in the pathogenesis of recurrent miscarriage, a special role is given to immunological factors, in particular the role of innate immunity. The aim of the study was to assess the relative content of monocytes in the peripheral blood producing IL-4, IL-6, IL-10, IFNγ, as well as to identify new criteria for predicting the outcome of pregnancy in women with the threat of early termination and recurrent miscarriage. Materials and methods. 88 pregnant women at 5-12 weeks’ gestation were examined, the main group consisted of 59 women with recurrent miscarriage and threatened miscarriage at the time of the study, the control group – 29 women with uncomplicated pregnancy without recurrent miscarriage. The main group, depending on the outcomes of pregnancy, was subdivided into subgroups: subgroup I – 42 women whose pregnancy ended in timely delivery, subgroup II – 8 women with preterm labor, subgroup III – 9 women with abortion up to 22 weeks (spontaneous miscarriage and non-developing pregnancy). In the control group, all women had a timely delivery. Research material – peripheral venous blood. The relative content of IL-4+, IL-6+, IL-10+, IFNγ+ monocytes was assessed on a FACSCanto II flow cytometer using monoclonal antibodies. Statistical data processing was carried out using a package of standard applied programs. Results. In the group of women with recurrent miscarriage and threatened miscarriage, the relative content of IL-10+ and IL-4+ monocytes was reduced and the content of IL-6+ monocytes was increased compared to the control group (p = 0.0001 in all cases). There were no statistically significant differences in the content of IFNγ+ monocytes in the compared groups (p = 0.069). With a relative content of IL-4+ monocytes equal to 26.7% or less, preterm labor is predicted. With a relative content of IL-10+ monocytes equal to 27.0% or less, abortion (spontaneous miscarriage or miscarriage) is predicted in gestational age up to 22 weeks. An increase in the ratio of IFNγ+/ IL-4+, IFNγ+/IL-10+, IL-6+/IL-4+, IL-6+/IL-10+ monocytes was found in the main group (p < 0.0001 in all cases ). Conclusions. In women with recurrent miscarriage in all subgroups, the level of M1 monocytes prevailed over the level of M2 monocytes. The data obtained allowed the development of new prognostic criteria for termination of pregnancy up to 22 weeks and premature birth.

Placenta increta presenting with threatened miscarriage during the first trimester in rhesus-negative mother: a case report

Background Placenta accreta is known to be associated with significant maternal morbidity and mortality—primarily due to intractable bleeding during abortion or delivery at any level of gestation. The complications could be reduced if placenta accreta is suspected in a patient with a history of previous cesarean delivery and the gestational sac/placenta is located at the lower part of the uterus. Then, a proper management plan can be instituted, and complications can be reduced. The diagnosis of placenta accreta in the first trimester of pregnancy is considered uncommon. Case presentation A 34-year-old Malay, gravida 4, para 3, rhesus-negative woman was referred from a private hospital at 13 weeks owing to accreta suspicion for further management. She has a history of three previous lower-segment cesarean sections. She also had per vaginal bleeding in the early first trimester, which is considered to indicate threatened miscarriage. Transabdominal ultrasound revealed features consistent with placenta accreta spectrum. She was counseled for open laparotomy and hysterectomy because of potential major complication if she continued with the pregnancy. Histopathological examination revealed placenta increta. Conclusion A high index of suspicion of placenta previa accreta must be in practice in a patient with a history of previous cesarean deliveries and low-lying placenta upon ultrasound examination during early gestation.

O-198 Progesterone supplementation in women with threatened miscarriage: A randomised placebo-controlled clinical trial

Study question In women with threatened miscarriage, does progesterone supplementation increase the probability of live birth? Summary answer In women with threatened miscarriage, 400 mg progesterone nightly, from onset of bleeding until 12 weeks, did not increase live birth rates. What is known already Women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg. A recently published large randomised clinical trial indicated no overall benefit for progesterone until 16 weeks, although subgroup analysis in women with bleeding and at least one previous miscarriage, progesterone might be of benefit (Coomarasamy et al; N Engl J Med 2019;380:1815-1824). Study design, size, duration We performed a single centre placebo-­controlled randomised clinical trial. After informed consent, women with threatened miscarriage as apparent from vaginal bleeding under 10 weeks, were randomised to 400 mg vaginal micronized progesterone or placebo. The primary endpoint was livebirth. Secondary endpoints were perinatal outcomes, including preterm birth and birthweight. The planned sample size was 386 women. At a planned interim analysis randomisation was halted at 278 women due to lack of effectiveness and slow recruitment. Participants/materials, setting, methods Between February 2012 and April 2019 we randomised 139 women to 400 mg vaginal micronized progesterone and 139 women to placebo. Primary outcome data are available for 134 women in the progesterone arm and 130 women in the placebo arm. Mean age was 30.7 and 30.4 years. The number of women without a previous miscarriage was 68 (51%) and 55 (42%), while 66 (49%) and 75 (58%) women had at least one previous miscarriage. Main results and the role of chance The live birth rates were 113/134 (84.3%) and 112/130 (86.2%), respectively (RR 0.98, 95% CI 0.89-1.08). Among women with at least 1 miscarriage live birth rates were 55/66 (83.3%) and 65/75 (86.7%) (RR 0.96, 95% CI 0.84-1.11). The number of women with more than 1 miscarriage was limited (26 vs 33 in total), but no effect was seen from progesterone in these women. Preterm birth rates were 12.9% and 9.3% (RR 1.38; 95% CI 0.69 to 2.78). There were five pregnancy losses between 20 and 23 weeks, all in the progesterone arm. Mean birth weight was 3310 vs 3300 gram (p=.99). There were also no other differences in obstetric and perinatal outcomes. Anxiety, stress and depression scores did not differ between the groups. Limitations, reasons for caution Our study was single centre and did not reach the planned sample size. We stopped study medication at 12 weeks which might explain the difference between our study and studies that continued progesterone till 16 weeks. Wider implications of the findings In women with threatened miscarriage, 400 mg vaginal progesterone did not improve live birth rates. Trial registration number ACTRN12611000405910

P–397 Threatened Miscarriage and increase in Perinatal Morbidity

Study question Are women presenting with bleeding in the first trimester of pregnancy at a higher risk for perinatal complications later in pregnancy? Summary answer Women presenting with bleeding in the first trimester of pregnancy are more likely to experience perinatal and neonatal morbidity in pregnancy. What is known already Observational studies and a previously reported systematic review showed that women who experienced threatened miscarriage are more likely to have still birth, intra uterine growth restriction (IUGR), low birth weight, pre-eclampsia, placental abruption, placenta previa, preterm labour, preterm prelabour rupture of membrane, neonatal asphyxia and congenital anomalies in pregnancy. However, the evidence has been inconclusive and currently the women who experience threatened miscarriage receive low risk care. Study design, size, duration This was a prospective cohort study conducted on 298 women with threatened miscarriage (Cohort A) and 107 asymptomatic women (Cohort B). The women were recruited over a period of 18 months and were followed up for 9 months until delivery. Participants/materials, setting, methods Cohort A were women who presented with bleeding in the early pregnancy assessment unit and had a confirmed heartbeat on ultrasound scan between 6 weeks and 11 + 6 weeks of pregnancy and cohort B were women who were asymptomatic and booked with the community midwives as low risk. Both groups of women were followed up prospectively until delivery and data were collected on any perinatal outcomes and complications for both mother and the neonate. Main results and the role of chance The analysis showed that women who had bleeding in early pregnancy were more likely to have preterm delivery (RR 95% CI; 2.98 (1.07 – 8.27)); IUGR (unable to calculate the RR, as none of the women who continued their pregnancies beyond 24 weeks of gestation, developed IUGR in the asymptomatic control cohort. Nonetheless, IUGR occurred more frequently in the threatened miscarriage cohort than the asymptomatic cohort (P-value 0.02)); LBW (RR 95% CI; 6.14 (1.49 – 25.19), neonatal asphyxia (unable to calculate the RR, as none of the babies who were born to women in the asymptomatic control cohort develop neonatal asphyxia. Nonetheless, neonatal asphyxia occurred more frequently in the threatened miscarriage cohort than the asymptomatic cohort (P-value 0.02)). Preterm prelabour rupture of membrane was not significant with a P-value of 0.07. Limitations, reasons for caution The major limitation of this study was lower sample size and hence due to the rarity of many of the perinatal and neonatal outcomes, we were unable to calculate the relative risk. Wider implications of the findings: Current study agrees with the existing literature and reaffirms the association of perinatal and neonatal morbidities with threatened miscarriage and this group of women need to be managed as high-risk group antenatally. Trial registration number Not applicable