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Threatened miscarriage...

Threatened miscarriage: evaluation and management

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Peer review
Alexandros Sotiriadis ( asotir{at}cc.uoi.gr ) , resident in obstetrics and gynaecology 1 ,
Stefania Papatheodorou , rural practitioner 2 ,
George Makrydimas , assistant professor of obstetrics and gynaecology 1
1 Department of Obstetrics and Gynaecology, University Hospital of Ioannina, 45500 Ioannina, Greece
2 Delvinaki Health Centre, Delvinaki, Ioannina, Greece
Correspondence to: A Sotiriadis
Accepted 3 June 2004

Introduction

Threatened miscarriage—vaginal bleeding before 20 gestational weeks—is the commonest complication in pregnancy, occurring in about a fifth of cases. w1 Miscarriage is 2.6 times as likely, 1 and 17% of cases are expected to present complications later in pregnancy. 2 Although general practitioners and gynaecologists often see this condition, management of threatened miscarriage is mostly empirical. Bed rest is routinely recommended, and about a third of women presenting with threatened miscarriage are prescribed drugs. w2 However, two thirds of the general practitioners recommending this do not believe it affects outcome. 3

In this review, we present available evidence on the initial evaluation and management of threatened miscarriage, focusing mainly on the first trimester of pregnancy and primary healthcare settings.

Sources and selection

We searched literature in English with Medline (January 1965 to April 2004), Embase (January 1980 to April 2004), and the Cochrane database using the keywords “threatened” and “abortion” or “miscarriage” and “pregnancy” and “first trimester” or “early” and “bleeding”. We scanned abstracts and got the full text of relevant articles. We also scanned the references of retrieved articles. The more recent or randomised, prospective, or large studies focusing on women with symptoms of threatened miscarriage were primarily cited; we excluded studies on recurrent pregnancy loss or women without symptoms, unless otherwise stated.

Bleeding in the first trimester can originate from the uterus, cervix, or vagina, or it can be extragenital. Thorough physical examination is essential to differentiate between genital and extragenital causes. After exclusion of extragenital causes, several parameters have been associated with prognosis ( table 1 ).

Prognostic factors in cases of threatened abortion

View inline

Older women are at increased risk of miscarriage in the general population. w3 A prospective study on women with threatened abortion reported that women older than 34 years had an odds ratio of 2.3 for miscarriage, however, the 95% confidence interval was wide (0.76 to 7.10), and the contribution of maternal age in regression analysis was not significant (P = 0.13). 4 Having had previous miscarriages is also associated with increased risk in future pregnancies, especially in older women, w4 whereas data from the general population show that the rate of fetal loss declines with advancing gestational age. 1

Summary points

One in five pregnancies is complicated by vaginal bleeding before 20 weeks' gestation

A large empty gestational sac, discrepancy between gestational age and crown to rump length, fetal bradycardia or absence of fetal heart activity at presentation, advanced maternal age, history of recurrent pregnancy loss, a maternal serum progesterone < 45 nmol/l or low maternal serum hCG or inhibin A are adverse prognostic factors

Fetal heart activity and lack of adverse prognostic factors conveys a favourable prognosis

Although bed rest and progesterone supplements are often advised, little evidence supports their effectiveness

Give anti-Rh D immune globulin to non-sensitised women with symptoms near, at, or after 12 gestational weeks

Sonographic evaluation

Sonography can usually differentiate between an intrauterine pregnancy (viable or non-viable), a molar pregnancy, or an inevitable abortion. Furthermore, sonographic features of pregnancy have been proposed as predictors.

An empty gestational sac with a diameter of at least 15 mm at seven weeks and 21 mm at eight weeks has diagnostic accuracy of 90.8% in predicting miscarriage in women with symptoms. 5 A mean sac diameter of at least 17 mm without an embryo or 13 mm without a yolk sac can predict non-viable gestation with a specificity and a positive predictive value of 100%. 6

Fetal heart activity should be visible with transvaginal sonography once the fetal pole is at least 5 mm long. w5 Most prospective series report a loss rate of 3.4-5.5% if bleeding occurs after fetal heart activity starts, 7 8 w6 and identification of fetal heart activity by ultrasound in primary healthcare settings carries a 97% likelihood for the pregnancy continuing beyond 20 weeks. 9 However, this favourable effect has not been universally repeated, as miscarriage rates of 20-30% have been reported. 10 11

Threatened miscarriage affects one in five pregnancies

Credit: YVES BEAULIEU, PUBLIPHOTO DIFFUSION/SPL

Fetal bradycardia and discrepancy between gestational age and crown to rump length are adverse prognostic factors. 1 12 Prospective data indicate that the presence of any of three risk factors (fetal bradycardia, discrepancy between gestational sac and crown to rump length, and discrepancy between menstrual and sonographic age by more than one week) increases the rate of abortion from 6% when none are present to 84% when all three are present. 4

The prognostic value of a subchorionic haematoma in ultrasound has been disputed. Although a large separation has been associated with about a threefold increase of risk of miscarriage (19% v 71%) in women with bleeding, 13 the presence or the size of haematoma did not affect miscarriage rate (10% v 11%) in another prospective series, 14 and other studies reported similar findings. 4 5 15

A prospective study of 6675 women found that the presence of an intrauterine haematoma in the first trimester of pregnancy increases the risk of severe obstetric complications, irrespective of the presence of symptoms of threatened miscarriage. 16 However, the presence of a haematoma did not influence the risk for subsequent complications in a smaller study of symptomatic women. 2

Maternal serum markers

Maternal serum biochemistry has also been proposed as a predictor. Women with threatened miscarriage in their first trimester who eventually miscarried have lower serum hCG values compared with women continuing the pregnancy and asymptomatic pregnant women. 10 A prospective study showed that a free β hCG cut-off value of 20 ng/ml could differentiate between normal (control and threatened continuing) and abnormal (non-continuing threatened miscarriage and tubal) pregnancies, with 88.3% sensitivity and 82.6% positive predictive value. 11 The bioactive to immunoreactive ratio of serum hCG was also higher in symptomatic women who continued with pregnancy than in women who eventually miscarried. w7 However, this study included only 24 women with threatened abortion and did not give data on fetal heart activity at presentation.

Progesterone concentrations show a narrow variation in the first trimester. According to data from mixed obstetric populations, the lowest serum progesterone concentration associated with a viable first trimester pregnancy is 5.1 ng/ml, w8 and a single serum progesterone measurement of at least 25 ng/ml carries a 97% likelihood for viable intrauterine pregnancy, being more sensitive than two serial hCG measurements. w9 Data from 358 women presenting with vaginal bleeding in the first 18 gestational weeks indicated that a single progesterone value of less than 45 nmol/l (14 ng/ml) is able to differentiate between abnormal and normal (ongoing) pregnancies, with a sensitivity of 87.6% and a specificity of 87.5%. 17

In a recent series, women with threatened abortion and fetal heart activity at presentation, serum inhibin A, activin A, and hCG concentrations were much lower in cases in which the women eventually miscarried; inhibin A at the cut-off of 0.553 multiples of median was the best predictor with an area under the curve 0.9856. 18

Women with threatened abortion who eventually miscarried had constant or increasing concentrations of ovarian carcinoma antigen CA125 over 5-7 days, whereas those who continued with pregnancy had a constantly low or steeply declining CA125 concentration. 19 Also, a single CA125 concentration of at least 43.1 IU/ml was associated with a greater risk of miscarriage in 200 women who had had vaginal bleeding in their first trimester. 20

Finally, although pregnancy associated placental protein A (PAPP-A) concentrations were much lower in a series of 128 symptomatic women with fetal heart activity at presentation than in normal controls, its predictive value for miscarriage was only 18.7%. 21

Doctors often prescribe bed rest and progesterone for women with symptoms of threatened miscarriage, but evidence is sparse and of low level ( table 2 ).

Pregnancy outcome in studies with various therapeutic regimens

In one study, 1228 out of 1279 (96%) general practitioners prescribed bed rest for heavy bleeding in early pregnancy, although only an eighth of them felt it was mandatory, and only one third felt it could affect outcome. 3 Only one randomised controlled trial considers the impact of bed rest on the course of threatened miscarriage 22 ; 61 women with viable pregnancies at less than eight gestational weeks and vaginal bleeding were randomly allocated into either injections of hCG, injections of placebo, or bed rest. The abortion rates in the three groups were 30%, 48%, and 75%—significant differences between hCG and bed rest groups but not between hCG and placebo groups or between placebo and bed rest groups. Although hCG performed significantly better than bed rest in this study, the lack of profound benefit over placebo, the concern about potential development of ovarian hyperstimulation syndrome, and the fact that threatened miscarriage may be the result of various conditions, irrelevant to luteal function, prevented further testing and application of hCG treatment in general obstetric practice.

In a retrospective study of 226 women who were hospitalised for reasons related to their pregnancy and previous threatened miscarriage, 16% of 146 women who were bed resting eventually miscarried, compared with a fifth of women who did not follow this option (not significant; P = 0.41). 23 In contrast, a recent observational cohort study of 230 women with threatened miscarriage who were recommended bed rest showed that women who adhered to this suggestion had a miscarriage rate of 9.9%, compared with 23.3% of women who continued their usual activities (P = 0.03). 24 The duration of vaginal bleeding, haematoma size and gestational age at diagnosis did not influence miscarriage rate. Although there is no definite evidence that bed rest can affect the course of pregnancy, abstinence from active environment for a couple of days may help women feel safer, w10 thus providing emotional relief.

Progesterone

Progesterone is prescribed in 13-40% of women with threatened miscarriage, according to published series. 3 w2 Progesterone is the main product of the corpus luteum, and giving progestogen is expected to support a potentially deficient corpus luteum gravidarum and induce relaxation of a cramping uterus. The evidence on progesterone is of low quality. Recently, a meta-analysis assessed the impact of progesterone supplementation on miscarriage rate in various clinical settings 25 ; however, it did not provide a separate analysis for progesterone in threatened miscarriage. Four published papers in the meta-analysis were assessing this relationship, w11-w14 one of them including three different regimens of progestogen, w11 and those data were reanalysed. Having miscarriage as outcome, random effects risk ratio was 1.10 (95% confidence interval 0.92 to 1.31) for progestogens group. In the only studies that provided sonographic evidence of fetal heart activity at presentation, the relative risk for miscarriage was 1.09 (90% confidence interval 0.90 to 1.33) for the progestogen group. w14 Thus, given the poor quality of the data, progesterone does not seem to improve outcome in women with threatened miscarriage. However, local application of a progestogen was found to subjectively decrease uterine cramping more rapidly than bed rest alone in one small study. w15

Other regimens

Buphenine hydrochloride (a vasodilator that is also used as a uterine muscle relaxant) was better than placebo in a randomised controlled trial. But the method of randomisation in this trial was unclear, and no other studies consider tocolysis in early threatened miscarriage. w16

Apart from its effectiveness, the extent of active support is generally questionable in cases of threatened miscarriage, since most pregnancies resulting in early fetal loss are chromosomally abnormal. w17

Rh prophylaxis

Vaginal bleeding in early pregnancy raises the question of whether to give anti-D immunoglobulin in Rh D negative women. Unfortunately, there are no conclusive data on this topic, and all evidence comes from expert or panel opinions (level C). According to the guidelines of the Royal College of Obstetricians and Gynecologists and the American College of Obstetricians and Gynaecologists, although Rh D alloimmunisation attributable to first trimester threatened miscarriage is rare, giving anti-D globulin should be considered for non-sensitised Rh D negative women with a threatened miscarriage after 12 weeks of pregnancy, or in cases of heavy or repeated bleeding or where there is associated abdominal pain, particularly as gestation approaches 12 weeks. w18 w19 In contrast, anti-D Ig is not considered necessary in women with threatened miscarriage with a viable fetus and cessation of bleeding before 12 weeks' gestation. w19

Additional educational resources

Websites for doctors.

www.update-software.com/Cochrane —The home page of Cochrane Library, where registered users can reach a large number of meta-analyses of therapeutic interventions in obstetrics

www.rcog.org.uk/mainpages.asp?SectionID=5 —The good practice page of the Royal College of Obstetricians and Gynaecologists has many evidence based clinical guidelines of obstetric interest, including that on Rhesus prophylaxis

http://www.earlypregnancy.com/ —Page of the Special Interest Group Early Pregnancy of ESHRE including useful links and updated scientific information on early pregnancy

Websites for patients

http://health.allrefer.com/health/abortion-threatened.html —Gives information on several health issues; an introduction to threatened miscarriage and miscarriage

www.emedicine.com/med/topic3308.htm —Gives useful information on threatened miscarriage and miscarriage; suitable for doctors and patients

Conclusions

Threatened miscarriage occurs often and is a serious emotional burden for women. Sonographic evaluation at presentation can usually differentiate between intrauterine and extrauterine pregnancy and offer some prognostic clues. Demonstration of fetal heart activity is generally associated with a successful pregnancy rate of 85-97%, 4 7 – 9 w6 whereas an empty large gestational sac or a discrepancy between menstrual and sonographic age of more than a week indicates a poor prognosis. 4 – 6 12 Advanced maternal age and increasing number of previous miscarriages deteriorates prognosis. 1 4 w4

Serum β hCG, progesterone, inhibin A, and CA125 concentrations may be helpful as predictors; however, these tests may not be useful in primary care settings.

Although many women with threatened miscarriage are given progestogens and are prescribed bed rest, little evidence supports these policies. There are only four old randomised controlled trials on progestogens, w11-w14 and their cumulative results show that they do not improve outcome. Data on bed rest are of even lower quality, as there is only one small randomised controlled trial, 22 one observational, 24 and one retrospective study, 23 yielding conflicting results. Although no evidence based suggestions can be made, short term abstinence from usual activity may be feasible for women if it is likely to relieve their stress.

Rhesus sensitisation is rare after first trimester threatened miscarriage; however, consensus suggests that anti-D immune globulin should be given in cases with bleeding after 12 gestational weeks or cases with heavy symptomatic bleeding near 12 weeks. w18 w19

Contributors AS and GM had the original idea and drafted the manuscript. They further developed with SP, who also contributed to the literature search. AS did statistical analysis. All authors critically revised the manuscript. GM is guarantor.

Funding None.

Competing interests None declared.

Makrydimas G ,
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Carrier JAK

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Threatened miscarriage: evaluation and management

Alexandros sotiriadis.

1 Department of Obstetrics and Gynaecology, University Hospital of Ioannina, 45500 Ioannina, Greece

Stefania Papatheodorou

2 Delvinaki Health Centre, Delvinaki, Ioannina, Greece

George Makrydimas

Associated data.

In this review, we present available evidence on the initial evaluation and management of threatened miscarriage, focusing mainly on the first trimester of pregnancy and primary healthcare settings.

Sources and selection

Prognostic factors in cases of threatened abortion

Summary points

One in five pregnancies is complicated by vaginal bleeding before 20 weeks' gestation

Fetal heart activity and lack of adverse prognostic factors conveys a favourable prognosis

Although bed rest and progesterone supplements are often advised, little evidence supports their effectiveness

Give anti-Rh D immune globulin to non-sensitised women with symptoms near, at, or after 12 gestational weeks

Sonographic evaluation

Fetal heart activity should be visible with transvaginal sonography once the fetal pole is at least 5 mm long. w5 Most prospective series report a loss rate of 3.4-5.5% if bleeding occurs after fetal heart activity starts, 7 , 8 w6 and identification of fetal heart activity by ultrasound in primary healthcare settings carries a 97% likelihood for the pregnancy continuing beyond 20 weeks. 9 However, this favourable effect has not been universally repeated, as miscarriage rates of 20-30% have been reported. 10 , 11 11

An external file that holds a picture, illustration, etc.
Object name is sota133520.f1.jpg

Threatened miscarriage affects one in five pregnancies

Credit: YVES BEAULIEU, PUBLIPHOTO DIFFUSION/SPL

Fetal bradycardia and discrepancy between gestational age and crown to rump length are adverse prognostic factors. 1 , 12 Prospective data indicate that the presence of any of three risk factors (fetal bradycardia, discrepancy between gestational sac and crown to rump length, and discrepancy between menstrual and sonographic age by more than one week) increases the rate of abortion from 6% when none are present to 84% when all three are present. 4

Maternal serum markers

Doctors often prescribe bed rest and progesterone for women with symptoms of threatened miscarriage, but evidence is sparse and of low level ( table 2 ).

Pregnancy outcome in studies with various therapeutic regimens

Progesterone

Other regimens

Rh prophylaxis

Additional educational resources

Websites for doctors

www.update-software.com/Cochrane —The home page of Cochrane Library, where registered users can reach a large number of meta-analyses of therapeutic interventions in obstetrics

www.earlypregnancy.com —Page of the Special Interest Group Early Pregnancy of ESHRE including useful links and updated scientific information on early pregnancy

Websites for patients

http://health.allrefer.com/health/abortion-threatened.html —Gives information on several health issues; an introduction to threatened miscarriage and miscarriage

www.emedicine.com/med/topic3308.htm —Gives useful information on threatened miscarriage and miscarriage; suitable for doctors and patients

Conclusions

Threatened miscarriage occurs often and is a serious emotional burden for women. Sonographic evaluation at presentation can usually differentiate between intrauterine and extrauterine pregnancy and offer some prognostic clues. Demonstration of fetal heart activity is generally associated with a successful pregnancy rate of 85-97%, 4 , 7 - 9 w6 whereas an empty large gestational sac or a discrepancy between menstrual and sonographic age of more than a week indicates a poor prognosis. 4 - 6 , 12 Advanced maternal age and increasing number of previous miscarriages deteriorates prognosis. 1 , 4 w4

Serum β hCG, progesterone, inhibin A, and CA125 concentrations may be helpful as predictors; however, these tests may not be useful in primary care settings.

Supplementary Material

Contributors: AS and GM had the original idea and drafted the manuscript. They further developed with SP, who also contributed to the literature search. AS did statistical analysis. All authors critically revised the manuscript. GM is guarantor.

Funding: None.

Competing interests: None declared.

Open access
Published: 09 September 2022

Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study

Jingying Huang 1 na1 ,
Ping Lv 2 na1 ,
Yunzhi Lian 3 na1 ,
Meihua Zhang 4 ,
Shuheng Li 6 ,
Yingxia Pan 7 , 8 ,
Jiangman Zhao 7 , 8 ,
Yue Xu 7 , 8 ,
Hui Tang 7 , 8 ,
Nan Li 9 &
Zhishan Zhang 10

BMC Pregnancy and Childbirth volume 22 , Article number: 697 ( 2022 ) Cite this article

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Metrics details

Endocannabinoid anandamide (AEA), progesterone (P4) and β-human chorionic gonadotrophin (β-hCG) are associated with the threatened miscarriage in the early stage. However, no study has investigated whether combing these three hormones could predict threatened miscarriage. Thus, we aim to establish machine learning models utilizing these three hormones to predict threatened miscarriage risk.

This is a multicentre, observational, case-control study involving 215 pregnant women. We recruited 119 normal pregnant women and 96 threatened miscarriage pregnant women including 58 women with ongoing pregnancy and 38 women with inevitable miscarriage. P4 and β-hCG levels were detected by chemiluminescence immunoassay assay. The level of AEA was tested by ultra-high-performance liquid chromatography-tandem mass spectrometry. Six predictive machine learning models were established and evaluated by the confusion matrix, area under the receiver operating characteristic (ROC) curve (AUC), accuracy and precision.

The median concentration of AEA was significantly lower in the healthy pregnant women group than that in the threatened miscarriage group, while the median concentration of P4 was significantly higher in the normal pregnancy group than that in the threatened miscarriage group. Only the median level of P4 was significantly lower in the inevitable miscarriage group than that in the ongoing pregnancy group. Moreover, AEA is strongly positively correlated with threatened miscarriage, while P4 is negatively correlated with both threatened miscarriage and inevitable miscarriage. Interestingly, AEA and P4 are negatively correlated with each other. Among six models, logistic regression (LR), support vector machine (SVM) and multilayer perceptron (MLP) models obtained the AUC values of 0.75, 0.70 and 0.70, respectively; and their accuracy and precision were all above 0.60. Among these three models, the LR model showed the highest accuracy (0.65) and precision (0.70) to predict threatened miscarriage.

Conclusions

The LR model showed the highest overall predictive power, thus machine learning combined with the level of AEA, P4 and β-hCG might be a new approach to predict the threatened miscarriage risk in the near feature.

Peer Review reports

Miscarriage is a common complication in early pregnancy, occurring in around 15% of clinically recognized pregnancies, and approximately 11% women will experience threatened miscarriage [ 1 ]. Threatened miscarriage is diagnosed by vaginal bleeding with or without abdominal pain. Surprisingly, 50% pregnancies with threatened miscarriage had an inevitable miscarriage [ 2 ].

Progesterone (P4) is secreted by the corpus luteum during pregnancy, which is essential at various stages of pregnancy. The deficiency of P4 in early pregnancy is associated with an increased miscarriage risk [ 3 ]. Therefore, P4 supplementation has been used as a treatment for threatened miscarriage to prevent spontaneous pregnancy loss [ 4 ].

Human chorionic gonadotrophin (β-hCG) is a glycoprotein secreted by the syncytiotrophoblast. Recent studies demonstrated that the concentration of serum β-hCG in early pregnancy can predict pregnancy outcome [ 5 ]. The serum β-hCG increased rapidly in the early stage of pregnancy and showed a linear increase in peak approximately 8 to 10 weeks of the pregnancy, and declined rapidly a few weeks before delivery [ 6 ].

Recent animal studies suggest that endocannabinoid anandamide (AEA) is pivotal for both blastocyst development and endometrium implantation, and low AEA levels enhances implantation success [ 7 ]. AEA is synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and binds both cannabinoid receptors (CB1 and CB2) [ 8 ]. AEA can be regulated by the enzyme named fatty acid amide hydrolase (FAAH), which metabolizes AEA into arachidonic acid (AA) and ethanolamine [ 9 ]. Studies indicated that women with spontaneous or threatened miscarriage are associated with high AEA levels and low FAAH expression [ 10 , 11 ]. The plasma AEA levels in women with threatened miscarriage are higher in those who subsequently spontaneously miscarried than in those who had live births [ 12 ]. Therefore, it is necessary to develop a reliable early warning method for threatened miscarriage that could lead to early intervention and treatment for threatened miscarriage.

In this study, we recruited 119 normal pregnancy women in their first trimester and 96 women with threatened miscarriage including 58 cases with ongoing pregnancy and 38 cases with inevitable miscarriage. We aim to use machine learning tools combining the level of AEA, P4 and β-hCG to predict the risk of threatened miscarriage.

Materials and methods

Patients and study design.

This is a multicentre, observational, case-control study. A total of 96 pregnant women with threatened miscarriages were consecutively enrolled according to the inclusion and exclusion criteria from Quanzhou First Hospital, Tengzhou Central People’s Hospital and Jincheng People’s Hospital from August 2017 to May 2019. Meanwhile, 119 normal pregnancy women were randomly selected at the same time, who were matched with threatened miscarriage patients on the basis of age and gestational age in a roughly 1: 1-1.5 case-control ratio.

The inclusion criteria were as follows [ 13 ]: i) single intrauterine pregnancy < 13 weeks of gestational age (the diagnose of intrauterine pregnancy was based on clinical assessment and evaluation by ultrasonography); ii) Threatened miscarriage group: women with pregnancy-related vagina bleeding; Normal pregnancy group: women with none pregnancy-related vagina bleeding; iii) age > 20 years. The exclusion criteria were as follows [ 13 , 14 ]: i) Women with multiple gestations; ii) Women with previous episodes of vagina bleeding or those treated with progesterone for previous vagina bleeding in the current pregnancy; iii) Women diagnosed with missed miscarriage, blighted ovum or planned termination of pregnancy; iv) Women had severe medical disease, such as severe coronary heart disease, stroke or malignant disease; v) Women who lost follow-up.

Informed consent was obtained from each patient participated in the study and the study protocol conforms to the ethical guidelines of the latest version of Declaration of Helsinki. The study protocol has been approved by Ethical Committee of the Quanzhou First Hospital, Tengzhou Central People’s Hospital and Jincheng People’s Hospital.

Detection of serum β-hCG and P4 levels

The concentrations of serum β-hCG (mIU/mL) and P4 (ng/mL) were tested in the Clinical Pathology Laboratory of the Quanzhou First Hospital, Tengzhou Central People’s Hospital and Jincheng People’s Hospital according to the standard protocols.

Detection of AEA level

Plasma AEA was extracted and performed as previously described [ 15 ]. Briefly, 4 mL blood was collected in EDTA tube and placed on ice. After centrifugation at 1200 g/30 min at 22 °C, 2 mL of plasma was transferred to a glass Kimble scintillation vial (Fisher Scientific, Loughborough, UK) and added 2.5 pmol of deuterium-labelled AEA (AEA-d8; Cayman Chemicals, Ann Arbor, MI, USA). Plasma proteins were mixed with an equal volume of ice-cold acetone followed by centrifugation at 1200 g/10 min at 22 °C. Then the supernatant was transferred to a clean Kimble vial and used in the subsequent steps according to the instructions. The reconstituted mixture was performed by the ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) as described [ 16 ].

Predictive models construction

Six machine learning tools were established to predict the threatened miscarriage, including logistic regression (LR) model, random forest (RF) model, extreme gradient boosting (XGboost) model, k-nearest neighbors classifier (KNN) model, multilayer perceptron (MLP) neural network model and support vector machine (SVM) model and combined AEA, P4 and β-hCG by Python (v.3.7.0). All models were chosen default parameters. The patients were randomly allocated into training set. In the training set, k-fold cross-validation (k = 5) was used. K-fold is a common cross validation approach as described [ 17 ]. For each model, the evaluation indicators used were the confusion matrix, area under the receiver operating characteristic (ROC) curve (AUC), accuracy and precision.

Statistical analysis

Continuous variables are presented as the median with interquartile range ( IQR) because of the non-Gaussian distributions of our data [ 18 ]. Continuous variables between the two groups were compared using a nonparametric Mann–Whitney test by GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA, USA). Six machine learning models (KNN, LR, SVM, RF, MLP and XGboost) were performed and evaluated by Python (v.3.7.0). The diagnostic values of the 6 models were assessed by ROC analysis. Correlations among threatened miscarriage, inevitable miscarriage, AEA, P4 and β-hCG were analyzed by Pearson correlation analysis using the “psych” package [ 19 ] of R studio [ 20 ] in R software [ 21 ]. A P < 0 . 05 was considered statistically significant.

Comparison of AEA, P4, β-hCG and clinical data between women with healthy pregnancies and threatened miscarriages

A total of 215 pregnant women were recruited, including 119 healthy pregnant women (normal pregnancy group) and 96 pregnant women with threatened miscarriages (threatened miscarriage group). The median concentration with IQR of AEA was significantly lower in the normal pregnancy group than that in the threatened miscarriage group, which is 0.62 (0.30-1.21) nM vs. 1.21 (0.72-1.83) nM. Meanwhile, the median concentration with IQR of P4 was significantly higher in the normal pregnancy group than that in the threatened miscarriage group, which is 21.92 (17.48-27.83) ng/mL vs. 19.53 (13.28-24.21) ng/mL. However, there were no noticeable differences in the age, body mass index (BMI), gestational age and β-hCG between the two groups (Table 1 ).

Comparison of AEA, P4, β-hCG and clinical data between women with ongoing pregnancies and inevitable miscarriages

Among 96 threatened miscarriages, 58 samples were ongoing pregnancies (ongoing pregnancy group) and 38 samples were inevitable miscarriages (inevitable miscarriage group). There were no significant differences in the age, BMI, AEA and β-hCG between the two groups (Table 2 ). Only the median concentration with IQR of P4 was significantly lower in the ongoing pregnancy group than that in the inevitable miscarriage group, which is 15.91 (10.27-21.01) ng/mL vs. 20.59 (15.21-24.58) ng/mL.

Correlation analysis among AEA, P4, β-hCG and threatened miscarriage

Pearson correlation analysis was performed to evaluate the correlations among AEA, P4, β-hCG and threatened miscarriage. AEA is strongly positively correlated with threatened miscarriage ( r = 0.38, p < 0.0001), while P4 is negatively correlated with threatened miscarriage ( r = − 0.23, p < 0.001). Interestingly, AEA and P4 are negatively correlated with each other ( r = − 0.18, p < 0.01). However, β-hCG has no significant correlation with other factors (Fig. 1 ). It suggests that AEA and P4 are associated with threatened miscarriage.

Correlations analysis among AEA, P4, β-hCG and threatened miscarriage. ** p < 0.01, and *** p < 0.0001

Correlation analysis among AEA, P4, β-hCG and inevitable miscarriage

Among 96 threatened miscarriage, 58 samples were ongoing pregnancies and 38 samples were inevitable miscarriages. Thus, we analyzed the correlation among AEA, P4, β-hCG tested in these patients. However, only P4 is significantly negatively correlated with the inevitable miscarriage ( r = − 0.29, p < 0.01) (Fig. 2 ). It suggests that P4 is also associated with inevitable miscarriage.

Correlations analysis among AEA, P4, β-hCG and inevitable miscarriage. ** p < 0.01

Comparison six predictive models

Furthermore, we constructed six machine learning models combing AEA, P4 and β-hCG to predict the threatened miscarriage risk. Among 6 models, LR model obtained the highest AUC value 0.75 (Fig. 3 ), and showed the highest accuracy (0.65) and precision (0.70) (Table 3 ). Moreover, both SVM and MLP models had same AUC value 0.70, and the accuracy and precision were above 0.61 and 0.60, respectively. However, KNN had the lowest AUC (0.61), accuracy (0.60) and precision (0.57). The results indicated AEA, P4 and β-hCG could predict threatened miscarriage using machine learning tools.

Construction 6 models to predict threatened miscarriage. The figure shows the average ROC curves of the 6 models. The mean AUC values with standard deviations of the different prediction models are shown in the box

In order to further analyze whether combing AEA, P4 and β-hCG could predict the risk of inevitable miscarriage, 58 samples with ongoing pregnancies and 38 samples with inevitable miscarriages were enrolled in 6 predictive models. However, all models showed poor prediction ability and the AUC values were lower than 0.70. Among 6 models, LR model still obtained the highest AUC value 0.67 (Fig. S 1 ), and the accuracy (0.61) and precision were 0.61 and 0.74, respectively (Table S 1 ). It suggests that the prediction ability of machine learning tools combing the level of AEA, P4 and β-hCG were better in threatened miscarriage risk than that in inevitable miscarriage.

Threatened miscarriage is a very common problem during pregnancy and is faced with therapeutic challenges. In the present study, we used three hormones P4, AEA and β-hCG to predict threatened miscarriage in early pregnancy in order to avoid the inevitable miscarriage and help doctors to provide the active treatments for women with threatened miscarriage in the early stage.

There are various miscarriage-inducing risk factors. For example, the age of parents, female with BMI > 25 kg/m 2 , the ethnicity of black female, as well as smoking and high alcohol consumption are associated with the risk of miscarriage [ 1 ]. The association between air pollutions and miscarriage are also reported [ 22 ]. In addition, chromosomal abnormalities are found in approximately 60% of miscarried tissues [ 23 ]. In the present study, we recruited 119 healthy pregnant women and 96 samples with threatened miscarriages including 58 cases with ongoing pregnancies and 38 cases with inevitable miscarriages. However, there is no significant difference in ages and BMI between the normal pregnancy and threatened miscarriage groups, as well as between the ongoing pregnancy and inevitable miscarriage groups. Small sample size, perhaps, is one of the reasons behind this, so it is urgent to enlarge the cohort to illustrate this issue in the near future.

Besides that, the concentration of AEA was significant higher in the threatened miscarriage group than that in the normal pregnancy group, which is consistent with a previous study that AEA was higher in the non-viable pregnancy group than in the viable pregnancy group [ 18 ]. Meanwhile, β-hCG level has no significant difference between the two groups in this study, which is also similar to the previous study [ 18 ]. Furthermore, we detected the correlations among AEA, P4 and β-hCG in all participates. P4 and AEA showed a significant negative correlation with each other. A previous study has shown that the P4 enhanced the FAAH activity in lymphocytes through the transcription factor Ikaros, thus causing the AEA decreased [ 24 ]. In addition, we found that AEA was positively correlated with the threatened miscarriage, although there is no study reported yet.

With the development of artificial intelligence (AI), AI techniques like machine learning tools have been increasingly used in disease diagnosis and prediction [ 25 , 26 ]. As nonlinear, fault tolerant, real-time operating AI tools, machine learning algorithms are designed to fit a set of observation by selecting the best model from a set of alternatives, and they are suitable for complex applications [ 27 ]. Ma et al. has shown that KNN, LR and XGboost models were suitable for predicting the risk of Chronic obstructive pulmonary disease [ 28 ]. Xiao et al. has established and developed LR, XGboost and Elastic Net online tools to predict chronic kidney disease progression [ 29 ].

In the present study, we used 6 machine learning tools combing AEA, P4 and β-hCG to predict the risk of threatened miscarriage. The results showed that LR, SVM and MLP models all preformed a good AUC value 0.70. According to Luo and colleagues’ research, if the model AUC is greater than 0.70, the model has high accuracy [ 30 ]. However, when applying the machine learning models constructed with AEA, P4 and β-hCG to predict the risk of inevitable miscarriage, the prediction ability are poor. Hence, machine learning combing AEA, P4 and β-hCG showed good predictive power in predicting threatened miscarriage.

There are several limitations in this study. First, the total sample size was small and unbalanced for many groups. Second, we only detect the AEA, P4 and β-hCG in the first time trimester, but not in the second and third time trimester, so we cannot compare three hormones concentrations among three stages. Third, six predictive models were used only in the training set but not in the validation set. Thus, it is urgent for us to enlarge cohorts for validation in the near future.

In the present study, AEA was positively correlated with the threatened miscarriage while P4 was negatively correlated with both the threatened miscarriage and the inevitable miscarriage. Furthermore, LR model combined AEA, P4 and β-hCG showed the best performance to predict the threatened miscarriage risk. Although many studies are investigating machine learning tools with novel biomarkers as promising approaches to predict disease, in some cases, the absence of a reliable reference standard may limit the reliability of these models. In addition, establishing accurate and reliable labels for data might require more extensive follow-up. Thus, we need to validate our result in larger samples from multiple centers before the models can be applied in the clinic for predicating threatened miscarriage.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Endocannabinoid anandamide
Progesterone

β-human chorionic gonadotrophin

Area under the receiver operating characteristic curve

N-acyl phosphatidylethanolamine phospholipase D

Fatty acid amide hydrolase

Logistic regression

Random forest

k-nearest neighbors classifier

Multilayer perceptron

Support vector machine

Body mass index

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This work was financially supported by Translational Medicine Collaborative Innovation Center Foundation from Shanghai Jiao Tong University School of Medicine, Shanghai Cooperative Innovation Center (No: TM291729).

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Jingying Huang, Ping Lv and Yunzhi Lian contributed equally to this work.

Authors and Affiliations

Department of Gynaecology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, China

Jingying Huang

Department of Obstetrics, Jincheng People’s Hospital, Jincheng, 048000, Shanxi, China

Department of Clinical Laboratory, Jincheng People’s Hospital, Jincheng, 048000, Shanxi, China

Yunzhi Lian

Department of Medical Image, Tengzhou Central People’s Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China

Meihua Zhang

Department of Pharmacy, Tengzhou Central People’s Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China

Department of Thyroid &Mammary, Tengzhou Central People’s Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China

Shanghai Biotecan Pharmaceuticals Co., Ltd, No. 180 Zhangheng Road, Shanghai, 201204, China

Yingxia Pan, Jiangman Zhao, Yue Xu & Hui Tang

Shanghai Biotecan Medical Diagnostics Co., Ltd, Shanghai, 201204, China

Department of Gynaecology, Tengzhou Central People’s Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China

Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, China

Zhishan Zhang

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JYH, PL and YZL designed the study. MHZ, XG and SHL collected samples and performed the experiments. YXP, JYH and PL analyzed the data. HT, NL and ZSZ wrote the manuscript. HT, JYH YXP, JMZ, YX and ZSZ revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hui Tang , Nan Li or Zhishan Zhang .

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Additional file 1: fig. s1..

Construction 6 models to predict inevitable miscarriage. The figure shows the average ROC curves of the 6 models. The mean AUC values with standard deviations of the different prediction models are shown in the box.

Additional file 2: Table S1.

The performance of accuracy and precision in six models to predict inevitable miscarriage.

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Huang, J., Lv, P., Lian, Y. et al. Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study. BMC Pregnancy Childbirth 22 , 697 (2022). https://doi.org/10.1186/s12884-022-05025-y

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Threatened miscarriage

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ERIN HENDRIKS, MD, HONOR MACNAUGHTON, MD, AND MARICELA CASTILLO MACKENZIE, MD

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Related letter: Progestin Therapy Not Likely to Be Harmful in Women with First Trimester Bleeding

Patient information: See related handout on bleeding in early pregnancy , written by the authors of this article.

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Approximately one-fourth of pregnant women will experience bleeding in the first trimester. The differential diagnosis includes threatened abortion, early pregnancy loss, and ectopic pregnancy. Pain and heavy bleeding are associated with an increased risk of early pregnancy loss. Treatment of threatened abortion is expectant management. Bed rest does not improve outcomes, and there is insufficient evidence supporting the use of progestins. Trends in quantitative β subunit of human chorionic gonadotropin (β-hCG) levels provide useful information when distinguishing normal from abnormal early pregnancy. The discriminatory level (1,500 to 3,000 mIU per mL) is the β-hCG level above which an intrauterine pregnancy should be visible on transvaginal ultrasonography. Failure to detect an intrauterine pregnancy, combined with β-hCG levels higher than the discriminatory level, should raise concern for early pregnancy loss or ectopic pregnancy. Ultrasound findings diagnostic of early pregnancy loss include a mean gestational sac diameter of 25 mm or greater with no embryo and no fetal cardiac activity when the crown-rump length is 7 mm or more. Treatment options for early pregnancy loss include expectant management, medical management with mifepristone and misoprostol, or uterine aspiration. The incidence of ectopic pregnancy is 1% to 2% in the United States and accounts for 6% of all maternal deaths. Established criteria should be used to determine treatment options for ectopic pregnancy, including expectant management, medical management with methotrexate, or surgical intervention.

Approximately 25% of pregnant women experience bleeding before 12 weeks' gestation. 1 , 2 The differential diagnosis includes nonobstetric causes, bleeding in a viable intrauterine pregnancy, early pregnancy loss, and ectopic pregnancy. Physical examination findings, laboratory testing, and ultrasonography can be used to diagnose the cause of first trimester bleeding and provide appropriate management. A glossary of terms used in this article is available in Table 1 . 3 – 6

WHAT IS NEW ON THIS TOPIC

A meta-analysis evaluating the accuracy of a single progesterone test to predict pregnancy outcomes for women with first trimester bleeding showed that a progesterone level less than 6 ng per mL (19.1 nmol per L) reliably excluded viable pregnancy, with a negative predictive value of 99%.

Guidelines for ultrasound diagnosis of early pregnancy loss have been established to decrease the likelihood of false diagnosis and of intervening in a desired viable pregnancy.

Oral mifepristone (Mifeprex), 200 mg, followed 24 hours later by misoprostol, 800 mcg vaginally, is the most effective regimen for medical management of early pregnancy loss and, when available, should be recommended over misoprostol alone.

History and Physical Examination

Vaginal bleeding in early pregnancy requires prompt attention. A review of the menstrual history and prior ultrasonography can help establish gestational dating and determine whether the pregnancy location is known. Patients should be asked about pain and the amount of bleeding. Bleeding equal to or heavier than a menstrual period and bleeding accompanied by pain are associated with an increased risk of early pregnancy loss. 2 , 7 Patients should be assessed for signs and symptoms of hypovolemia. Vital signs indicating hemodynamic instability or peritoneal signs on physical examination require emergent evaluation. A speculum examination can help identify nonobstetric causes of bleeding, such as vaginitis, cervicitis, or a cervical polyp. If products of conception are visible on speculum examination, the diagnosis of incomplete abortion can be made and treatment offered. Further evaluation is needed unless a definitive nonobstetric cause of bleeding is found or products of conception are seen ( Figure 1 ) . 8

Laboratory Testing

Β-human chorionic gonadotropin.

The β subunit of human chorionic gonadotropin (β-hCG) can be detected in the plasma of a pregnant woman as early as eight days after ovulation. 9 Quantitative β-hCG levels can provide useful information in early pregnancy. The rate of β-hCG increase is less rapid as the level increases. For symptomatic women with a viable intrauterine pregnancy, initial β-hCG levels of less than 1,500 mIU per mL, 1,500 to 3,000 mIU per mL, or more than 3,000 mIU per mL will increase over 48 hours by at least 49%, 40%, or 33%, respectively. 10 A slower rate of increase suggests early pregnancy loss or ectopic pregnancy. By approximately 10 weeks' gestation, the β-hCG level typically plateaus or decreases, after which serial ultrasonography is the preferred diagnostic tool. 11

Rh factor testing should be performed if Rh status is not known at the time of presentation. Rh o (D) immune globulin (Rhogam) is indicated within 72 hours for all Rh-negative patients with abdominal trauma or ectopic pregnancy, and in those who undergo uterine aspiration. Rh o (D) immune globulin can also be administered within 72 hours of early pregnancy loss, especially later in the first trimester, although the risk of alloimmunization is estimated to be 1.5% to 2% in this setting. 12 There is insufficient evidence for or against the use of Rh o (D) immune globulin in Rh-negative patients who present with threatened abortion. A 50- or 120-mcg dose is recommended before 12 weeks' gestation, although 300 mcg can be administered if lower doses are not available. 3 After 12 weeks, a 300-mcg dose should be given. 12

PROGESTERONE

Measurement of serum progesterone may be useful in distinguishing between an early viable or nonviable pregnancy, especially in the setting of inconclusive ultrasonography. A meta-analysis evaluating the accuracy of a single progesterone test to predict pregnancy outcome in women with first trimester bleeding showed that a level less than 6 ng per mL (19.1 nmol per L) reliably excludes viable pregnancy, with a negative predictive value of 99%. 13 A low progesterone level cannot distinguish intrauterine pregnancy from ectopic pregnancy. 13

A baseline hemoglobin level should be documented for all women with bleeding during pregnancy. All patients should be instructed to seek care if they have symptoms of anemia or heavy bleeding, quantified as soaking through more than two sanitary pads per hour for two consecutive hours. 3

Ultrasonography

The embryologic events of early pregnancy occur in a predictable, stepwise fashion. Deviations from this established pattern should raise suspicion for early pregnancy loss or ectopic pregnancy ( Table 2 ). 4 , 5 Guidelines have been established for ultrasound diagnosis of early pregnancy loss to decrease the risk of false diagnosis and intervention in a desired viable intrauterine pregnancy.

DISCRIMINATORY LEVEL

The discriminatory level is the β-hCG level above which an intrauterine pregnancy is expected to be seen on transvaginal ultrasonography. 14 When combined with β-hCG levels greater than the discriminatory level, ultrasonography that does not show an intrauterine pregnancy should raise concern for early pregnancy loss or ectopic pregnancy. The discriminatory level varies with the type of ultrasound machine used, the sonographer, and the number of gestations. A recent study found a 99% probability that an intrauterine gestational sac will be detected at a β-hCG level of 3,510 mIU per mL. 14 Currently, a discriminatory level of 1,500 to 3,000 mIU per mL is typically used. 10 , 15 However, ultrasonography can be diagnostically useful in symptomatic women at any β-hCG level. Signs of ectopic pregnancy (e.g., adnexal mass, fluid in the cul-de-sac) can be seen on ultrasonography well below the discriminatory level.

Pregnancy of Unknown Location

Pregnancy of unknown location describes the scenario in which a pregnancy test is positive, but neither intrauterine nor ectopic pregnancy is shown on ultrasonography. In stable patients, close monitoring of symptoms, serial quantitative β-hCG testing, and ultrasonography are recommended 4 ( Figure 2 8 , 10 , 14 , 15 ) . Pregnancy of unknown location can be diagnostically challenging because the increase in β-hCG level can be similar among women with an early viable pregnancy, ectopic pregnancy, or early pregnancy loss. 10 Because pregnancy of unknown location does not exclude ectopic pregnancy, and because rupture of ectopic pregnancy can occur at any β-hCG level, serial measurements should be obtained until a definitive diagnosis is made or until the level is undetectable. 16 Patients should be counseled about warning signs of ectopic pregnancy, including shoulder pain, pelvic pain, and dizziness.

Threatened Abortion

The diagnosis of threatened abortion should be made in patients with bleeding and an ultrasound-confirmed viable intrauterine pregnancy. The rate of early pregnancy loss is approximately 11% after a live fetus has been detected on ultrasonography. 17 The risk of early pregnancy loss is increased when subchorionic hemorrhage ( Figure 3 6 ) and bleeding are present. When an intrauterine pregnancy is detected on ultrasonography but viability is uncertain, repeat ultrasonography should be performed in seven to 10 days to confirm viability. 3 , 5 In these cases, a normal increase in the β-hCG level or a normal progesterone level can be reassuring.

Threatened abortion should be managed expectantly. There is insufficient evidence to support the use of progestin for the prevention of early pregnancy loss. 3 , 18 Bed rest does not improve outcomes and may cause psychological harm in patients with subsequent early pregnancy loss. 19 Patients should be reassured that nothing they did caused the bleeding.

Early Pregnancy Loss

Expectant management, medical management, and uterine aspiration are safe and effective treatments for early pregnancy loss. Patient satisfaction, mental health outcomes, infection rates, and future fertility are similar between these treatments. 20 – 22 Mental health outcomes are better when patients are included in the decision-making process, and shared decision making should guide management. 23

EXPECTANT MANAGEMENT

Watchful waiting is recommended as first-line treatment for patients with incomplete abortion; more than 90% of these patients will complete the process spontaneously within four weeks. 24 Watchful waiting is less effective in patients with an anembryonic gestation or embryonic demise, with completion rates at one month of 66% and 76%, respectively. 24 Patients who choose expectant management over uterine aspiration experience more days of bleeding, longer time to completion, and higher rates of unplanned surgical intervention. 20 , 21 Serious complications are rare, and patients who opt for expectant management should be informed that it is safe to wait as long as they wish as long as there are no signs of infection or hemorrhage. Patients may switch to medical management or uterine aspiration at any time.

MEDICAL MANAGEMENT

A Cochrane review found that medical management with misoprostol (Cytotec) in women with incomplete abortion does not improve rates of completed abortion or decrease the need for unplanned surgical procedures compared with expectant management. 22 In contrast, medical management is more effective than expectant management for the treatment of anembryonic gestation or embryonic demise. 25 The most effective regimen for medical management is 200 mg of oral mifepristone (Mifeprex) followed 24 hours later by 800 mcg of vaginally administered misoprostol. 26 Success rates at two days with this regimen are 84% vs. 67% in those treated with misoprostol alone. Many regimens for using misoprostol alone have been studied, and none has been proven optimal. 22 One common regimen is 800 mcg vaginally, with a repeat dose in 24 to 48 hours if the first dose is unsuccessful. 27 Besides the expected cramping and vaginal bleeding, common adverse effects include nausea and diarrhea. 22

UTERINE ASPIRATION

Uterine aspiration is the preferred procedure for surgical management of early pregnancy loss. Compared with sharp curettage, vacuum aspiration is associated with decreased pain, shorter procedure duration, and less blood loss. 28 Office-based uterine aspiration is safe, less expensive, and often more convenient than treatment in the operating room. 29 , 30 Choices about analgesia during the aspiration procedure should be made with the patient's input.

Completed early pregnancy loss should be confirmed by one of the following: visualization of products of conception on examination or after uterine aspiration; ultrasonography showing the absence of an intrauterine pregnancy after previous ultrasonography documenting an intrauterine pregnancy; or a decrease in β-hCG levels by at least 50% at two days or 87% at seven days. 31 Once completion is confirmed, the β-hCG level does not need to be followed to zero, except in women with pregnancy of unknown location, or if gestational trophoblastic disease is being considered because of abnormal uterine bleeding or symptoms of malignancy. 32

Patients who wish to use contraception after early pregnancy loss can start immediately. All women who may conceive should be counseled to take folic acid. It is safe to try to conceive again immediately; those who attempt to conceive within the first three months after early pregnancy loss have higher rates of pregnancy and live birth compared with those who wait longer. 33 , 34 Although a Cochrane review found insufficient evidence that psychological support after pregnancy loss improves well-being, the decision to refer for counseling should be made on an individual basis. 35

Ectopic Pregnancy

The incidence of ectopic pregnancy is 1% to 2% in the United States. 36 Ruptured ectopic pregnancies account for 6% of all maternal deaths, with a higher rate in black patients. 36 Risk factors include pelvic inflammatory disease, previous tubal surgery, previous ectopic pregnancy, and in utero exposure to diethylstilbestrol. 37 Criteria for surgical, medical, or expectant management are described in Table 3 . 6 , 15 , 38 , 39

SURGICAL MANAGEMENT

Surgical management is indicated for patients with contraindications to medical treatment or failed medical treatment, and for patients who are hemodynamically unstable. Ruptured ectopic pregnancy is associated with peritoneal signs and requires emergency surgery, although most patients present with bleeding or pain before rupture. 39

Surgical treatment options include salpingectomy or salpingostomy, which are appropriate if the location of the pregnancy is the fallopian tube, but not if there is a less common location. Salpingostomy is preferred for patients who wish to preserve fertility; however, it may result in inadequate evacuation of products of conception and a recurrence of symptoms. Laparoscopy is the preferred surgical approach. Laparotomy is reserved for patients who are hemodynamically unstable. A Cochrane review found no difference in success rates between laparoscopic salpingostomy and medical treatment with systemic methotrexate, as well as no differences in tubal patency or subsequent fertility rates. 40

Medical management is safe and effective in carefully selected patients. There are different treatment protocols, but the single-dose regimen is most common. 15 This includes an intramuscular injection of 50 mg of methotrexate per m 2 , followed by close monitoring of symptoms and measurement of β-hCG levels four and seven days after injection. β-hCG levels should decrease by at least 15% from days 4 to 7; once this occurs, levels should be monitored weekly until undetectable, which may take five to seven weeks. Treatment failure is assumed if the β-hCG level plateaus or increases from days 4 to 7. In this case, a repeat dose of methotrexate may be given, although surgery may be required if the patient is symptomatic.

Patients undergoing expectant management must receive extensive counseling on the risk of tubal rupture and the importance of close surveillance. β-hCG levels should be obtained every 48 hours to confirm that they are decreasing, then weekly until they reach zero. No specific range of decrease is considered normal as long as the patient is asymptomatic and the decrease continues. 39 Surgical management is indicated if the patient experiences increased abdominal pain or if β-hCG levels increase. 38

Patients with previous ectopic pregnancy have higher rates of ectopic pregnancy and early pregnancy loss in subsequent pregnancies. However, those who have a viable intrauterine pregnancy after an ectopic pregnancy have similar reproductive outcomes compared with patients who have not had a previous ectopic pregnancy. 41 β-hCG levels in patients with ectopic pregnancy should be followed to zero, after which no further workup is indicated. 15

This article updates a previous article on this topic by Deutchman, et al . 6

Data Sources: An evidence summary generated from Essential Evidence Plus was reviewed and relevant studies referenced. Additionally, a PubMed search was completed in Clinical Queries using the following key terms: first trimester bleeding, threatened abortion, miscarriage, ectopic pregnancy, and discriminatory zone. The search included meta-analyses, randomized controlled trials, clinical trials, guidelines, and reviews. Also searched were the Cochrane database, the Agency for Health-care Research and Quality, DynaMed, and the National Guideline Clearinghouse. Search dates: August 3, 2017, to October 21, 2018.

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Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study

Affiliations.

1 Department of Gynaecology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, China.
2 Department of Obstetrics, Jincheng People's Hospital, Jincheng, 048000, Shanxi, China.
3 Department of Clinical Laboratory, Jincheng People's Hospital, Jincheng, 048000, Shanxi, China.
4 Department of Medical Image, Tengzhou Central People's Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China.
5 Department of Pharmacy, Tengzhou Central People's Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China.
6 Department of Thyroid &Mammary, Tengzhou Central People's Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China.
7 Shanghai Biotecan Pharmaceuticals Co., Ltd, No. 180 Zhangheng Road, Shanghai, 201204, China.
8 Shanghai Biotecan Medical Diagnostics Co., Ltd, Shanghai, 201204, China.
9 Shanghai Biotecan Pharmaceuticals Co., Ltd, No. 180 Zhangheng Road, Shanghai, 201204, China. [email protected].
10 Shanghai Biotecan Medical Diagnostics Co., Ltd, Shanghai, 201204, China. [email protected].
11 Department of Gynaecology, Tengzhou Central People's Hospital Affiliated to Jining Medical University, Tengzhou, 277500, Shandong, China. [email protected].
12 Department of Clinical Laboratory, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, Fujian, China. [email protected].
PMID: 36085038
PMCID: PMC9461209
DOI: 10.1186/s12884-022-05025-y

Background: Endocannabinoid anandamide (AEA), progesterone (P4) and β-human chorionic gonadotrophin (β-hCG) are associated with the threatened miscarriage in the early stage. However, no study has investigated whether combing these three hormones could predict threatened miscarriage. Thus, we aim to establish machine learning models utilizing these three hormones to predict threatened miscarriage risk.

Methods: This is a multicentre, observational, case-control study involving 215 pregnant women. We recruited 119 normal pregnant women and 96 threatened miscarriage pregnant women including 58 women with ongoing pregnancy and 38 women with inevitable miscarriage. P4 and β-hCG levels were detected by chemiluminescence immunoassay assay. The level of AEA was tested by ultra-high-performance liquid chromatography-tandem mass spectrometry. Six predictive machine learning models were established and evaluated by the confusion matrix, area under the receiver operating characteristic (ROC) curve (AUC), accuracy and precision.

Results: The median concentration of AEA was significantly lower in the healthy pregnant women group than that in the threatened miscarriage group, while the median concentration of P4 was significantly higher in the normal pregnancy group than that in the threatened miscarriage group. Only the median level of P4 was significantly lower in the inevitable miscarriage group than that in the ongoing pregnancy group. Moreover, AEA is strongly positively correlated with threatened miscarriage, while P4 is negatively correlated with both threatened miscarriage and inevitable miscarriage. Interestingly, AEA and P4 are negatively correlated with each other. Among six models, logistic regression (LR), support vector machine (SVM) and multilayer perceptron (MLP) models obtained the AUC values of 0.75, 0.70 and 0.70, respectively; and their accuracy and precision were all above 0.60. Among these three models, the LR model showed the highest accuracy (0.65) and precision (0.70) to predict threatened miscarriage.

Conclusions: The LR model showed the highest overall predictive power, thus machine learning combined with the level of AEA, P4 and β-hCG might be a new approach to predict the threatened miscarriage risk in the near feature.

Keywords: Endocannabinoid anandamide; Progesterone; Threatened miscarriage; β-Human chorionic gonadotrophin.

Publication types

Multicenter Study
Observational Study
Abortion, Spontaneous*
Abortion, Threatened* / diagnosis
Case-Control Studies
Chorionic Gonadotropin, beta Subunit, Human
Machine Learning
Pregnancy Trimester, First
Progesterone

IMAGES

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How to Identify a Possible Miscarriage
[PDF] Evidence-based interventions of threatened miscarriage
(PDF) Threatened miscarriage in general practice: Diagnostic value of
Miscarriage
(PDF) Evidence-based interventions of threatened miscarriage

COMMENTS

Human Ethics
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Pregnancy loss, also referred to as miscarriage or spontaneous abortion, is generally defined as a nonviable intrauterine pregnancy up to 20 weeks of gestation. Early pregnancy loss, which occurs in the first trimester (ie, up to 12+6 weeks gestation), is the most common type. Individuals experiencing pregnancy loss are evaluated for conditions ...
Threatened Miscarriage: Causes, Symptoms & Treatment
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History . Older women are at increased risk of miscarriage in the general population. w3 A prospective study on women with threatened abortion reported that women older than 34 years had an odds ratio of 2.3 for miscarriage, however, the 95% confidence interval was wide (0.76 to 7.10), and the contribution of maternal age in regression analysis was not significant (P = 0.13). 4 Having had ...
(PDF) The Influence of Threatened Miscarriage on ...
Methods: A retrospective case -controlled study was performed on 89 women with threatened miscarriage (study group) at Maternity and Children Hospital Buraidah, KSA from January 2010 to December ...
Stress, anxiety, intolerance of uncertainty, and psychological well
The aim of this study was to examine the stress, anxiety, intolerance of uncertainty, and psychological well-being of pregnant women with and without threatened miscarriage. This is a case-control study.
Early Pregnancy Loss
Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study . Hum Reprod 2002 ; 17 : 446 - 51 . (Level II-2) ... Uterine muscle relaxant drugs for threatened miscarriage . Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002857. DOI: 10.1002/14651858.CD002857.pub2 . ...
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Aim: Aim of the study was to evaluate the late-pregnancy and perinatal outcomes of patients with threatened miscarriage in the first trimester. Methods: An observational cohort study was performed on 81 pregnant women. Subjects were divided into two groups: 1) no bleeding; 2) threatened miscarriage. Patients were followed up until delivery and each materno-fetal complication was registered.
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To estimate the miscarriage rate in a cohort of pregnant women and the final outcome of pregnancy. Two year prospective community study. Women registered with four semirural practices at one ...
Construction of machine learning tools to predict threatened
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Threatened miscarriage: evaluation and management

Introduction

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Sonographic evaluation

Maternal serum markers

Progesterone

Other regimens

Rh prophylaxis

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Threatened miscarriage: evaluation and management

Stefania Papatheodorou

George Makrydimas

Sources and selection

Sonographic evaluation

Maternal serum markers

Progesterone

Other regimens

Rh prophylaxis

Conclusions

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Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study

Conclusions

Materials and methods

Detection of serum β-hCG and P4 levels

Detection of AEA level

Predictive models construction

Statistical analysis

Comparison of AEA, P4, β-hCG and clinical data between women with healthy pregnancies and threatened miscarriages

Comparison of AEA, P4, β-hCG and clinical data between women with ongoing pregnancies and inevitable miscarriages

Correlation analysis among AEA, P4, β-hCG and threatened miscarriage

Correlation analysis among AEA, P4, β-hCG and inevitable miscarriage

Comparison six predictive models

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BMC Pregnancy and Childbirth

WHAT IS NEW ON THIS TOPIC

History and Physical Examination

Laboratory Testing

PROGESTERONE

Ultrasonography

DISCRIMINATORY LEVEL

Pregnancy of Unknown Location

Threatened Abortion

Early Pregnancy Loss

EXPECTANT MANAGEMENT

MEDICAL MANAGEMENT

UTERINE ASPIRATION

Ectopic Pregnancy

SURGICAL MANAGEMENT

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Construction of machine learning tools to predict threatened miscarriage in the first trimester based on AEA, progesterone and β-hCG in China: a multicentre, observational, case-control study

Publication types

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