Abstract
Purpose
To identify predictors of complete miscarriage after expectant management or misoprostol treatment of non-viable early pregnancy in women with vaginal bleeding.
Methods
This was a planned secondary analysis of data from a published randomized controlled trial comparing expectant management with vaginal single dose of 800 µg misoprostol treatment of women with embryonic or anembryonic miscarriage. Predefined variables—serum-progesterone, serum-β-human chorionic gonadotropin, parity, previous vaginal deliveries, gestational age, clinical symptoms (bleeding and pain), mean diameter and shape of the gestational sac, crown-rump-length, type of miscarriage, and presence of blood flow in the intervillous space—were tested as predictors of treatment success (no gestational sac in the uterine cavity and maximum anterior–posterior intracavitary diameter was ≤ 15 mm as measured with transvaginal ultrasound on a sagittal view) in univariable and multivariable logistic regression.
Results
Variables from 174 women (83 expectant management versus 91 misoprostol) were analyzed for prediction of complete miscarriage at ≤ 17 days. In patients managed expectantly, the rate of complete miscarriage was 62.7% (32/51) in embryonic miscarriages versus 37.5% (12/32) in anembryonic miscarriages (P = 0.02). In multivariable logistic regression, the likelihood of success increased with increasing gestational age, increasing crown-rump-length and decreasing gestational sac diameter. Misoprostol treatment was successful in 80.0% (73/91). No variable predicted success of misoprostol treatment.
Conclusions
Complete miscarriage after expectant management is significantly more likely in embryonic miscarriage than in anembryonic miscarriage. Gestational age, crown-rump-length, and gestational sac diameter are independent predictors of success of expectant management. Predictors of treatment success may help counselling women with early miscarriage.
Keywords: First-trimester pregnancy, Misoprostol, Pregnancy complications, Logistic models prediction, Miscarriage
Introduction
Early miscarriage occurs in 10–15% of clinically recognized pregnancies [1–3]. Expectant or medical management are alternatives to surgical evacuation [4–6]. Randomized trials comparing medical treatment, most often misoprostol, with expectant management or placebo show substantial variation in success rates defined as complete miscarriage without surgical intervention [4–10]. The discrepancies are explained by differences in types of miscarriage included, symptomatology, definition of complete miscarriage and treatment success, and dose regimens of drugs. First-trimester miscarriages can be classified on ultrasound as (1) anembryonic, i.e., a gestational sac that is empty or with minimal embryonic debris without cardiac activity [11], (2) embryonic, i.e., a gestational sac with a visible embryo or fetus without cardiac pulsations [11], or as (3) incomplete miscarriage, i.e., no visible gestational sac but ultrasound signs of retained products of conception [12]. Incomplete miscarriages usually resolve spontaneously within a few weeks [12]. Expectant management of miscarriages with a retained gestational sac is less likely to be successful within a few weeks, especially in women with no vaginal bleeding [13]. Most studies investigating possible predictors of treatment success of medical treatment or expectant management include both incomplete miscarriages and embryonic or anembryonic miscarriages and/or both patients with and without vaginal bleeding [13–32]. This makes results difficult to generalize.
The aim of this work is to identify predictors of success of expectant management or misoprostol treatment in a well-defined group of patients, i.e., patients with embryonic or anembryonic miscarriage reporting vaginal bleeding.
Material and methods
This is a planned secondary analysis of prospectively collected data in a published randomized controlled trial comparing expectant management with vaginal single dose 800 µg misoprostol treatment of embryonic and anembryonic first-trimester miscarriage [6] (ClinicalTrials.gov ID: NCT01033903). The regional ethical review board, Lund University, Sweden, approved the trial (Dnr 83/2008), which was carried out in accordance with the code of ethics of the Declaration of Helsinki. The primary trial outcome was complete miscarriage ≤ 10 weeks. Secondary outcomes were complete miscarriage ≤ 17, ≤ 24 and ≤ 31 days. Complete miscarriage was defined as no gestational sac in the uterine cavity and maximum anterior–posterior diameter of the intracavitary contents ≤ 15 mm as measured with transvaginal ultrasound on a sagittal view. Trial details (including a CONSORT flow chart) have been published [6] and are briefly outlined below.
Women consulting the gynecological emergency clinic of Skåne University Hospital, Malmö, Sweden and reporting vaginal bleeding in early pregnancy were eligible for inclusion if hemodynamically stable. Women with heavy bleeding needing urgent surgical evacuation of the uterine cavity, as judged clinically, were not eligible. Inclusion criteria were: ≥ 18 years old, understanding written and spoken Swedish, hemoglobin concentration > 80 g/L, no contraindications to misoprostol treatment, fulfilling ultrasound criteria of anembryonic or embryonic miscarriage [11], and fetal crown-rump-length ≤ 33 mm. Because of new recommendations [33–35] our ultrasound criteria of non-viability were changed in 2014. Before 2014 the criteria were (1) intracavitary gestational sac with a diameter (mean of three orthogonal diameters) of > 16 mm with no embryonic pole [36] or (2) intracavitary gestational sac with an embryo with crown-rump-length ≥ 5 mm without cardiac pulsations [36], or (3) if the above criteria were not fulfilled, intracavitary gestational sac with or without an embryo showing no significant development at a repeat scan after 7 days [36]. After April 2014 our non-viability criteria were: (1) intracavitary gestational sac with a mean diameter ≥ 25 mm with no embryonic pole, or (2) intracavitary gestational sac with an embryo with crown-rump-length ≥ 7 mm without cardiac pulsations, or (3) if the above criteria were not fulfilled, no significant development at a repeat scan after 7 days [33, 34, 37, 38]. Women with incomplete miscarriage were not eligible. Women giving written consent were randomized into two parallel groups in an open-label 1:1 ratio to misoprostol treatment or expectant management. All patients were managed as outpatients.
The patients were examined clinically and with transvaginal ultrasound in the lithotomy position on the day of randomization. The trial clinician estimated bleeding and pain at speculum and clinical examination and placed 800 μg misoprostol in the posterior vaginal fornix of the patients allocated to medical treatment. The first follow-up was after 10 days. Subsequent follow-up visits were scheduled every 7 days until the miscarriage was complete (definition, see above). The patient was then discharged with no planned follow-up visits. If complete evacuation was not achieved on day 31, dilatation and evacuation was recommended. However, the participants could ask for dilatation and evacuation at any time for any reason during the trial.
At inclusion, information on demographic background data was collected from the woman and documented in research forms, and blood was drawn for analysis of hemoglobin, β-human chorionic gonadotropin (β-hCG), progesterone and blood type. hCG + β was measured with a sandwich immunoassay on a Cobas® instrument; Intact hCG + the β-subunit assay (Roche Diagnostics, Mannheim, Germany). Progesterone was measured with a competitive immunoassay on a Cobas® instrument; Progesterone III assay (Roche Diagnostics, Mannheim, Germany). On every follow-up visit clinical examination and transvaginal ultrasound were performed. Results were prospectively entered into research forms.
The ultrasound machine used was a Sequoia 512 ultrasound system (Siemens Medical Solutions Inc., Ultrasound Division, Mountain View, CA, USA) with a 4–8 MHz transducer. The shape of the gestational sac was assessed, the sac diameter and the crown-rump-length (if an embryo/fetus was present) were measured. The miscarriage was classified as embryonic or anembryonic. Assessment of blood flow in the presumed intervillous space was first made by looking for flickering areas within the chorion on grey-scale imaging. The color Doppler function was then switched on starting with standardized settings (space–time S2; edge zero; persistence two; color map V2; gate two; filter three; frequency 7 MHz; color Doppler gain 50; pulse repetition frequency corresponding to blood flow velocity 2.1 cm/s) which were adjusted to maximize detection of slow velocity blood flow without artifacts. A Doppler gate was placed where color Doppler signals were seen inside the chorion. By adjusting the position of the probe, arterial Doppler shift signals inside the chorion were searched for as previously described [39, 40]. Presence of blood flow in the presumed intervillous space as assessed on grey scale and color Doppler and of arterial Doppler shift signals in the presumed intervillous space was noted.
Women not showing up on a scheduled visit were included in this secondary analysis only if on a later visit the miscarriage was incomplete; the miscarriage was then classified as incomplete also on the missed visit. Women with a complete miscarriage on the first visit after the missed one were not included in the analysis, because we do not know, if the miscarriage was complete also on the missed visit.
We considered the following variables to be possibly related to treatment outcome and explored their ability to predict complete miscarriage ≤ 10 days and ≤ 17 days: serum/plasma levels of progesterone (nmol/L) and β-hCG (IU/L) at inclusion, gestational age (days) according to the last menstrual period (LMP), previous vaginal delivery (yes/no), parity (yes/no), bleeding at inclusion (moderate or heavy versus mild or none as assessed by the trial physician at speculum examination), pain at inclusion (yes/no), shape of the gestational sac (round or oval versus else), mean gestational sac diameter (mm), crown-rump-length (mm), type of miscarriage (embryonic or anembryonic), presence of blood flow in the presumed intervillous space according to grey scale and color Doppler ultrasound (yes/no), and presence of arterial Doppler shift signals in the presumed intervillous space (yes/no).
Statistical analysis was performed using SPSS Statistics, version 21 (IBM Corp., Armonk, NY, USA). It was done separately for the misoprostol group and the expectantly managed group and separately for treatment success ≤ 10 days and ≤ 17 days. The relation between the predefined predictor variables and treatment success was tested for statistical significance using univariable logistic regression with the likelihood ratio test. Two-tailed P values < 0.05 were considered statistically significant. Multivariable logistic regression was used to elucidate which variables were independently associated with treatment success and for building models to predict complete miscarriage. Because crown-rump-length and miscarriage type are related (in anembryonic miscarriages the crown-rump-length is zero), only one of these variables was included in the same multivariable analysis. We used different approaches for model building. In one, we included all predetermined variables (with a minimum of five individuals in each cell of a four-field table) in multivariable backward step-wise logistic regression analysis. In another, we started with including only variables with a P value < 0.20 in univariable analysis, and then we tested to add variables that we found clinically relevant.
Individual data for each patient were inserted into the regression models to calculate the probability of complete miscarriage for each patient and to plot receiver-operating characteristics curves. The area under the receiver-operating characteristic curve (AUC) and its 95% confidence interval (CI) were calculated. If the lower limit of the CI was > 0.5 the model was considered to have discriminatory ability. The larger the AUC the better the discriminative ability.
Results
Between September 2008 and December 2015 189 women were recruited into the trial. Ninety-five women were allocated to expectant management and 94 to misoprostol treatment. Twenty-one women (expectant group: 11; misoprostol group: 10) were recruited after the new ultrasound criteria of non-viability were adopted. After exclusions, our planned secondary analysis included 177 women (expectant group: 85; misoprostol group: 92). The reasons for exclusion were: withdrawal of consent (expectant group, n = 2), not fulfilling inclusion criteria (expectant group, n = 3), undergoing dilatation and evacuation before first follow-up at 10 days (expectant group, n = 5; misoprostol group, n = 2). For the analysis regarding prediction of complete miscarriage ≤ 17 days another three patients were excluded due to dilatation and evacuation on patient’s request (expectant group n = 1) or missed follow-up visit (expectant group n = 1, misoprostol group n = 1), the numbers analyzed for this outcome being 83 (expectant group) and 91 (misoprostol group).
Expectant management was successful ≤ 10 days in 45.8% (39/85) of the patients and ≤ 17 days in 53.0% (44/83). Variables associated with success of expectant management in univariable and multivariable analyses are shown in Tables 1, 2, 3, 4 and 5. Treatment success was more common in embryonic than anembryonic miscarriages: complete miscarriage ≤ 10 days 53.8% (28/52) versus 33.0% (11/33) (P = 0.06), complete miscarriage ≤ 17 days 62.7% (32/51) versus 37.5% (12/32) (P = 0.02). In multivariable analyses, the following variables were independently associated with treatment success: gestational age according to LMP (the higher the more likely successful treatment), mean gestational sac diameter (the smaller the more likely successful treatment) and crown-rump-length (the larger the more likely successful treatment). When we replaced crown-rump-length with type of miscarriage in the multivariable model, the odds of treatment success were approximately six times higher in embryonic than anembryonic miscarriages (Table 3). When s-β-hCG and s-progesterone were tested as predictors in multivariable analysis, either s-progesterone or s-β-hCG (not both) and crown-rump-length or miscarriage type were independently associated with complete miscarriage (Tables 4 and 5). The AUCs of the models ranged from 0.71 to 0.77.
Table 1.
Association between predefined possible predictors and success of expectant management of embryonic and anembryonic miscarriage ≤ 10 days (univariable logistic regression analysis); n = 85
| Variables tested as possible predictors | Success (n = 39) | Failure (n = 46) | P valuea | Odds ratio (95% CI) |
|---|---|---|---|---|
| Biochemical variables | ||||
| s-beta-human chorionic gonadotropin (IU/L)b | 2 missing | 0.01 | 0.956 (0.919–0.996)c | |
| Mean | 9387.6 ± 7690.1 | 17,744.8 ± 19,865.8 | ||
| Median | 7650.0 (107–26,585) | 9328.5 (1006–80,317) | ||
| s-Progesterone (nmol/L)b | 1 missing | 0.011 | 0.971 (0.942–1.000) | |
| Mean | 18.9 | 32.3 | ||
| Median | 18.0 (3–41) | 19.0 (4–190) | ||
| Clinical variables | ||||
| Gestational age according to last menstrual period | 2 missing | 3 missing | 0.053 | 1.040 (0.998–1.083) |
| Mean | 77.8 ± 11.1 | 72.9 ± 11.7 | ||
| Median | 76.0 (60–104) | 73.0 (42–94) | ||
| Vaginal delivery | ||||
| Yes | 20 (51.3) | 28 (60.9) | 0.374 | 0.677 (0.285–1.604) |
| No | 19 (48.7) | 18 (39.1) | ||
| Parity | ||||
| Parous | 24 (61.3) | 29 (63.0) | 0.887 | 0.938 (0.389–2.262) |
| Nulliparous | 15 (38.5) | 17 (37.0) | ||
| Bleeding at inclusiond | ||||
| Moderate/heavy | 8 (20.5) | 5 (10.9) | 0.218 | 2.116 (0.631–7.102) |
| None/mild | 31 (79.5) | 41 (89.1) | ||
| Pain at inclusion | ||||
| Yes | 12 (30.8) | 12 (26.1) | 0.633 | 1.259 (0.489–3.244) |
| No | 27 (69.2) | 34 (73.9) | ||
| Ultrasound variables | ||||
| Gestational sac | 0.624 | 0.788 (0.303–2.047) | ||
| Not round/oval | 10 (25.6) | 14 (30.4) | ||
| Round/oval | 29 (74.4) | 32 (69.6) | ||
| Gestational sac diameter (mm)e | 1 missing | 0.448 | 0.981 (0.933–1.031) | |
| Mean | 23.3 | 24.5 | ||
| Median | 21.0 (4.7–49.0) | 23.3 (10.7–41.0) | ||
| Crown-rump-length (mm) | 0.008 | 1.102 (1.020–1.191) | ||
| Mean | 7.5 ± 7.3 | 4.0 ± 4.9 | ||
| Median | 5.5 (0.0–26.0) | 3.1 (0.0–17.0) | ||
| Miscarriage type on ultrasound | ||||
| Embryonic | 28 (71.8) | 24 (52.2) | 0.063 | 2.333 (0.943–5.774) |
| Anembryonic | 11 (28.2) | 22 (47.8) | ||
| Crown-rump-length if embryonic miscarriage (mm) | n = 28 | n = 24 | 0.06 | 1.105 (0.988–1.235) |
| Mean | 10.5 ± 6.6 | 7.6 ± 4.3 | ||
| Median | 9.5 (3.0–26.0) | 5.5 (3.0–17.0) | ||
| Blood flow in presumed intervillous space according to | ||||
| Grey-scale ultrasound | 0.288 | 0.398 (0.069–2.299) | ||
| Yes | 35 (89.7) | 44 (95.7) | ||
| No | 4 (10.4) | 2 (4.3) | ||
| Color Doppler ultrasound | 1 missing | 0.109 | 0.327 (0.078–1.363) | |
| Yes | 32 (82.1) | 42 (93.3) | ||
| No | 7 (17.9) | 3 (6.7) | ||
| Spectral Doppler ultrasound (arterial blood flow) | 4 missing | 5 missing | 0.619 | 0.786 (0.304–2.032) |
| Yes | 22 (62.9) | 27 (65.9) | ||
| No | 13 (37.1) | 14 (34.1) | ||
Data are presented as n (%), mean ± SD or median (range)
CI confidence interval
aLikelihood ratio test
bAfter mid May 2013 beta-human chorionic gonadotropin and progesterone were analyzed in plasma not in serum, reference intervals are not affected
cOdds ratio is calculated for units of 1000
dBleeding as judged by the trial physician at speculum examination—all women reported vaginal bleeding
eMean of three orthogonal diameters
Table 2.
Association between predefined possible predictors and success of expectant management of embryonic and anembryonic miscarriage ≤ 17 days (univariable logistic regression analysis); n = 83
| Variables tested as possible predictors | Success (n = 44) | Failure (n = 39) | P valuea | Odds ratio (95% CI) |
|---|---|---|---|---|
| Biochemical variables | ||||
| s-beta-human chorionic gonadotropin (IU/L)b | 2 missing | 0.01 | 0.958 (0.922–0.995)c | |
| Mean | 9530.6 ± 7483.3 | 18,128.3 ± 21,019.9 | ||
| Median | 8308.0 (107–26,585) | 7990.0 (1006–80,317) | ||
| s-Progesterone (nmol/L)b | 1 missing | 0.003 | 0.965 (0.936–0.995) | |
| Mean | 18.5 ± 10.6 | 34.6 ± 38.2 | ||
| Median | 18.0 (3–41) | 20.5 (4–190) | ||
| Clinical variables | ||||
| Gestational age according to last menstrual period (days) | 2 missing | 3 missing | 0.04 | 1.042 (1.000–1.086) |
| Mean | 77.8 ± 10.7 | 72.4 ± 12.4 | ||
| Median | 78.0 (60–104) | 72.0 (42–94) | ||
| Vaginal delivery | ||||
| Yes | 25 (56.8) | 23 (59.0) | 0.843 | 0.915 (0.382–2.195) |
| No | 19 (43.2) | 16 (41.0) | ||
| Parity | ||||
| Yes | 29 (65.9) | 24 (61.5) | 0.679 | 1.208 (0.493–2.963) |
| No | 15 (34.1) | 15 (38.5) | ||
| Bleeding at inclusiond | ||||
| Moderate/heavy | 10 (22.7) | 3 (7.7) | 0.053 | 3.529 (0.894–13.927)e |
| None/mild | 34 (77.3) | 36 (92.3) | ||
| Pain at inclusion | ||||
| Yes | 13 (29.5) | 11 (28.2) | 0.893 | 1.067 (0.412–2.765) |
| No | 31 (70.5) | 28 (71.8) | ||
| Ultrasound variables | ||||
| Gestational sac | 0.925 | 0.955 (0.365–2.499) | ||
| Not round/oval | 12 (27.3) | 11 (28.2) | ||
| Round/oval | 32 (72.7) | 28 (71.8) | ||
| Gestational sac diameter (mm)f | 1 missing | 0.967 | 0.999 (0.950–1.050) | |
| Mean | 24.1 ± 9.5 | 24.1 ± 7.9 | ||
| Median | 21.4 (4.7–49.0) | 23.2 (10.7–41.0) | ||
| Crown-rump-length (mm) | ||||
| Mean | 7.5 ± 7.0 | 3.6 ± 4.9 | 0.004 | 1.119 (1.028–1.218) |
| Median | 5.6 (0.0–26.0) | 0.0 (0.0–17.0) | ||
| Miscarriage type on ultrasound | ||||
| Embryonic | 32 (72.7) | 19 (48.7) | 0.024 | 2.807 (1.126–6.998) |
| Anembryonic | 12 (27.3) | 20 (51.3) | ||
| Crown-rump-length if embryonic miscarriage (mm) | n = 32 | n = 19 | 0.069 | 1.109 (0.981–1.254) |
| Mean | 10.3 ± 6.2 | 7.4 ± 4.6 | ||
| Median | 9.5 (3.0–26.0) | 5.3 (3.0–17.0) | ||
| Blood flow in presumed intervillous space according to | ||||
| Grey-scale ultrasound | 0.105 | 0.205 (0.023–1.840) | ||
| Yes | 39 (88.6) | 38 (97.4) | ||
| No | 5 (11.4) | 1 (2.6) | ||
| Color Doppler ultrasound | 1 missing | 0.008 | 0.105 (0.013–0.873) | |
| Yes | 35 (79.5) | 37 (94.9) | ||
| No | 9 (20.5) | 1 (2.6) | ||
| Spectral Doppler ultrasound (arterial blood flow) | 4 missing | 4 missing | 0.125 | 0.468 (0.175–1.252) |
| Yes | 23 (57.5) | 25 (71.4) | ||
| No | 17 (42.5) | 10 (28.6) | ||
Data are presented as n (%), mean ± SD, median (range)
CI confidence interval
aLikelihood ratio test
bAfter mid May 2013 beta-human chorionic gonadotropin and progesterone were analyzed in plasma and not in serum, reference intervals are not affected
cOdds ratio is calculated for units of 1000
dBleeding as judged by the trial physician at speculum examination—all women reported vaginal bleeding
eWe consider this result unreliable, because only three patients in the failure group had heavy or moderate bleeding, the unreliable result is also reflected in the odds ratio
fMean of three orthogonal diameters
Table 3.
Results of multivariable logistic regression analysis showing variables independently associated with complete miscarriage ≤ 10 and ≤ 17 days in women with embryonic or anembryonic miscarriage managed expectantly
| Model with crown-rump-length | Model with miscarriage type | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | AUC | Constant | Coefficient | Odds ratio (95% CI) | P valuea | |
| Complete miscarriage ≤ 10 days (n = 79) | ||||||||||
| 0.764 | − 3.691 | 0.739 | − 5.058 | |||||||
| (0.659–0.869) | (0.628–0.850) | |||||||||
| Variables in model | ||||||||||
| Gestational age according to last menstrual period (OR for change in days) | 0.08 | 1.083 (1.023–1.146) | 0.003 | 0.083 | 1.087 (1.024–1.153) | 0.002 | ||||
| Mean sac diameter (OR for change in mm) | − 0.146 | 0.864 (0.788–0.948) | 0.001 | − 0.099 | 0.905 (0.838–0.978) | 0.007 | ||||
| CRL (OR for change in mm) | 0.202 | 1.224 (1.086–1.380) | 0 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.737 | 5.682 (1.724–18.730) | 0.002 | ||||
| Complete miscarriage ≤ 17 days (n = 79) | ||||||||||
| 0.763 | − 3.382 | 0.754 | − 4.783 | |||||||
| (0.658–0.869) | (0.645–0.863) | |||||||||
| Variables in model | ||||||||||
| Gestational age according to last menstrual period (OR for change in days) | 0.07 | 1.072 (1.015–1.133) | 0.008 | 0.076 | 1.079 (1.017–1.144) | 0.006 | ||||
| Mean sac diameter (OR for change in mm) | − 0.111 | 0.895 (0.818–0.979) | 0.01 | − 0.076 | 0.927 (0.858–1.001) | 0.046 | ||||
| CRL (OR for change in mm) | 0.194 | 1.214 (1.074–1.372) | 0 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.802 | 6.060 (1.837–19.992) | 0.001 | ||||
The probability of treatment success is calculated as [ez/(1 + ez) where e = 2.718 (base value of natural logarithm) and z is calculated as:
z = constant + (coefficient × gestational age according to last menstrual period in days + coefficient × crown-rump length in mm + coefficient × mean sac diameter in mm)
or
z = constant + (coefficient × gestational age according to last menstrual period in days + coefficient × type of miscarriage where anembryonic gestation is coded as 0 and fetal demise as 1 + coefficient × mean sac diameter in mm)
AUC area under receiver-operating characteristic curve, CI confidence interval, OR odds ratio, CRL crown-rump-length, NA not applicable
aLikelihood ratio test
Table 4.
Results of multivariable logistic regression analysis showing variables independently associated with complete miscarriage ≤ 10 and ≤ 17 days in women with embryonic or anembryonic miscarriage managed expectantly when s-β-hCG was included as a variable
| Model with crown-rump-length | Model with miscarriage type | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | |
| Complete miscarriage ≤ 10 days (n = 83) | ||||||||||
| 0.741 | − 0.212 | 0.714 | − 0.177 | |||||||
| (0.634–0.847) | (0.603–0.825) | |||||||||
| Variables in model | ||||||||||
| s-β-hCG (OR for change in units of 1000 IU/L) | − 0.044 | 0.957 (0.919–0.997) | 0.013 | − 0.052 | 0.949 (0.910–0.990) | 0.004 | ||||
| CRL (OR for change in mm) | 0.13 | 1.139 (1.036–1.252) | 0.002 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.177 | 3.243 (1.227–8.571) | 0.015 | ||||
| Complete miscarriage ≤ 17 days (n = 81) | ||||||||||
| 0.768 | − 0.024 | 0.735 | 0.008 | |||||||
| (0.664–0.872) | (0.623–0.846) | |||||||||
| Variables in model | ||||||||||
| s-β-hCG (OR for change in units of 1000 IU/L) | − 0.045 | 0.956 (0.918–0.995) | 0.01 | − 0.052 | 0.949 (0.910–0.989) | 0.003 | ||||
| CRL (OR for change in mm) | 0.169 | 1.185 (1.057–1.327) | 0 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.405 | 4.077 (1.505–11.046) | 0.004 | ||||
The probability of treatment success is calculated as [ez/(1 + ez) where e = 2.718 (base value of natural logarithm) and z is calculated as:
z = constant + (coefficient × s-beta-hCG in units of 1000 IU/L + coefficient × crown-rump length in mm)
or
z = constant + (coefficient × s-beta-hCG in units of 1000 IU/L + coefficient × type of miscarriage where anembryonic gestation is coded as 0 and fetal demise as 1)
s-β-hCG serum β-human chorionic gonadotropin, AUC area under receiver-operating characteristic curve, CI confidence interval, CRL crown-rump-length, OR odds ratio, NA not applicable
aLikelihood ratio test
Table 5.
Results of multivariable logistic regression analysis showing variables independently associated with complete miscarriage ≤ 10 days and ≤ 17 days in women with embryonic or anembryonic miscarriage managed expectantly when s-progesterone was included as a variable
| Model with crown-rump-length | Model with miscarriage type | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | |
| Complete miscarriage ≤ 10 days (n = 84) | ||||||||||
| 0.716 | − 0.077 | 0.711 | − 0.032 | |||||||
| (0.607–0.826) | (0.601–0.821) | |||||||||
| Variables in model | ||||||||||
| s-Progesterone (OR for change in nmol/L) | − 0.03 | 0.971 (0.945–0.997) | 0.006 | − 0.034 | 0.967 (0.938–0.996) | 0.004 | ||||
| CRL (OR for change in mm) | 0.126 | 1.135 (1.035–1.244) | 0.002 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.122 | 3.070 (1.182–7.978) | 0.018 | ||||
| Complete miscarriage ≤ 17 days (n = 82) | ||||||||||
| 0.765 | 0.263 | 0.749 | 0.284 | |||||||
| (0.662–0.867) | (0.642–0.857) | |||||||||
| Variables in model | ||||||||||
| s-Progesterone (OR for change in nmol/L) | − 0.037 | 0.964 (0.937–0.991) | 0.001 | − 0.041 | 0.960 (0.930–0.991) | 0.001 | ||||
| CRL (OR for change in mm) | 0.165 | 1.180 (1.056–1.318) | 0.001 | NA | NA | NA | ||||
| Type of miscarriage (embryonic or anembryonic) | NA | NA | NA | 1.408 | 4.086 (1.513–11.034) | 0.004 | ||||
The probability of treatment success is calculated as [ez/(1 + ez) where e = 2.718 (base value of natural logarithm) and z is calculated as:
z = constant + (coefficient × s-Progesterone in nmol/L + coefficient × crown-rump length in mm)
or
z = constant + (coefficient × s-Progesterone in nmol/L + coefficient × type of miscarriage where anembryonic gestation is coded as 0 and fetal demise as 1)
s-progesterone serum-progesterone, AUC area under receiver-operating characteristic curve, CI confidence interval, OR odds ratio, CRL crown-rump-length, NA not applicable
aLikelihood ratio test
In embryonic miscarriages, the higher the gestational age according to LMP, the larger the crown-rump-length and the smaller the mean gestational sac diameter the higher the likelihood of complete miscarriage ≤ 10 and ≤ 17 days (Table 6); and the lower the s-progesterone or s-β-hCG and the longer the crown-rump-length the higher the success rate (Table 7). The AUCs of the models ranged from 0.80 to 0.84. No variable was statistically significantly associated with complete miscarriage of anembryonic miscarriages when using expectant management (details available from the authors on request).
Table 6.
Results of multivariable logistic regression analysis showing variables independently associated with complete miscarriage ≤ 10 days and ≤ 17 days in women with embryonic miscarriage managed expectantly
| AUC (95% CI) | Constant | Coefficient | Odds ratio (95%) | P value | |
|---|---|---|---|---|---|
| Complete miscarriage ≤ 10 days (n = 48) | |||||
| 0.843 | − 5.397 | ||||
| (0.732–0.954) | |||||
| Variables in model | |||||
| Gestational age according to last menstrual period (OR for change in days) | 0.131 | 1.140 (1.024–1.268) | 0.005 | ||
| Mean sac diameter (OR for change in mm) | − 0.226 | 0.797 (0.693–0.918) | 0 | ||
| CRL (OR for change in mm) | 0.222 | 1.249 (1.036–1.505) | 0.007 | ||
| Complete miscarriage ≤ 17 days (n = 47) | |||||
| 0.802 | − 5.609 | ||||
| (0.657–0.948) | |||||
| Variables in model | |||||
| Gestational age according to last menstrual period (OR for change in days) | 0.129 | 1.137 (1.022–1.266) | 0.006 | ||
| Mean sac diameter (OR for change in mm) | − 0.177 | 0.838 (0.733–0.958) | 0.002 | ||
| CRL (OR for change in mm) | 0.17 | 1.186 (0.987–1.424) | 0.043 | ||
The probability of treatment success is calculated as [ez/(1 + ez) where e = 2.718 (base value of natural logarithm) and z is calculated as:
z = constant + (coefficient × gestational age according to last menstrual period in days + coefficient × mean sac diameter in mm + coefficient × crown-rump length in mm)
AUC area under receiver-operating characteristic curve, CI confidence interval, OR odds ratio, CRL crown-rump-length
aLikelihood ratio test
Table 7.
Results of multivariable logistic regression analysis showing variables independently associated with complete miscarriage ≤ 10 days and ≤ 17 days in women with embryonic miscarriage managed expectantly when s-β-hCG or s-progesterone were included as variables
| Model with s-hCG | Model with s-progesterone | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | AUC (95% CI) | Constant | Coefficient | Odds ratio (95% CI) | P valuea | ||
| Complete miscarriage ≤ 10 days (n = 49) | (n = 50) | ||||||||||
| 0.821 | 0.834 | ||||||||||
| (0.707–0.936) | 2.857 | (0.726–0.943) | − 0.032 | ||||||||
| Variables in model | |||||||||||
| s-β-hCG (OR for change in units of 1000 IU/L) | − 0.066 | 0.936 (0.866–1.011) | 0.035 | NA | NA | NA | |||||
| s-Progesterone (OR for change in nmol/L) | NA | NA | NA | − 0.038 | 0.963 (0.920–1.008) | 0.006 | |||||
| Mean sac diameter (OR for change in mm) | − 0.145 | 0.865 (0.775–0.966) | 0.004 | − 0.159 | 0.853 (0.761–0.957) | 0.002 | |||||
| CRL (OR for change in mm) | 0.254 | 1.289 (1.052–1.581) | 0.003 | 0.289 | 1.335 (1.074–1.659) | 0.001 | |||||
| Complete miscarriage ≤ 17 days (n = 49) | (n = 49) | ||||||||||
| 0.796 | 0.824 | ||||||||||
| (0.654–0.938) | 0.348 | (0.704–0.943) | 3.072 | ||||||||
| Variables in model | |||||||||||
| s-β-hCG (OR for change in units of 1000 IU/L) | − 0.061 | 0.941 (0.889–0.996) | 0.008 | NA | NA | NA | |||||
| s-Progesterone (OR for change in nmol/L) | NA | NA | NA | − 0.043 | 0.958 (0.918–1.000) | 0.001 | |||||
| Mean sac diameter (OR for change in mm) | NA | NA | NA | − 0.114 | 0.893 (0.797–1.000) | 0.036 | |||||
| CRL (OR for change in mm) | 0.152 | 1.165 (0.973–1.395) | 0.049 | 0.27 | 1.311 (1.037–1.656) | 0.006 | |||||
The probability of treatment success is calculated as [ez/(1 + ez) where e = 2.718 (base value of natural logarithm) and z is calculated as:
z = constant + (coefficient × s-beta-hCG in units of 1000 IU/L + coefficient × mean sac diameter in mm + coefficient × crown-rump length in mm)
or
z = constant + (coefficient × s-progesterone in nmol/L + coefficient × mean sac diameter in mm + coefficient × crown-rump length in mm)
s-β-hCG serum beta-human chorionic gonadotropin, s-progesterone serum-progesterone, AUC area under receiver-operating characteristic curve, CI confidence interval, OR odds ratio, CRL crown-rump length, NA not applicable
aLikelihood ratio test
Misoprostol treatment was successful ≤ 10 days in 67% (62/92) of patients and ≤ 17 days in 80% (73/91). No variable predicted success of misoprostol treatment either in embryonic or anembryonic miscarriages. (Details available from the authors on request).
Comments
In patients managed expectantly the likelihood of spontaneous complete miscarriage ≤ 10 or ≤ 17 days was twice as high in embryonic as in anembryonic miscarriages. The likelihood of complete miscarriage increased with increasing gestational age according to LMP, increasing crown-rump-length and decreasing gestational sac diameter; and the larger the crown-rump-length and the lower the s-β-hCG or s-progesterone level the higher the likelihood of treatment success. No variable predicted treatment outcome in the misoprostol group.
The strength of our study is the well-defined study population. We included only embryonic and anembryonic miscarriages and only women reporting vaginal bleeding. Our results are generalizable to such women. It is a limitation that we changed our definitions of non-viable pregnancy at the end of the recruitment period because of new research results and guidelines [33–35, 37, 38, 41–43]. However, it is unlikely that this had any major impact on our results. Our definition of successful treatment, also used by others [7, 8, 19, 27, 44], may also be criticized [45–48]. Absence of a gestational sac and/or cessation of vaginal bleeding may be better definitions [49]. It is a weakness that our prediction models have not been validated in a new study sample. In our trial, we did not find any association between presence of blood flow or pulsatile flow in the intervillous space and treatment success. However, we did not make any attempts to quantify blood flow, for example using three-dimensional ultrasound and calculating vascular indices. This may be seen as a limitation.
The results of other studies exploring possible predictors of complete miscarriage with expectant management are very heterogenous (Table 8) [13–22, 25, 30]. This is probably explained by differences in study populations (types of miscarriage, symptomatology), definitions of complete miscarriage and treatment success, and variables tested as predictors. However, more than one study reported that the lower the s-β-hCG and s-progesterone values the higher the likelihood of success of expectant management [16, 18, 19, 21] and that success rate is higher in incomplete miscarriages than in embryonic or anembryonic miscarriages [15–17]. Only two studies are reasonably similar to ours with regard to inclusion criteria and definition of treatment success [18, 21]. Schwärzler et al. found that pulsatile flow in the presumed intervillous space was a predictor of successful treatment [21]. We could not confirm this, perhaps because examination of blood flow in the intervillous space in early pregnancy requires skill, carefulness and time. Therefore, it is unlikely to be useful in busy emergency departments or early pregnancy units. Memtsa et al. reported that the older the patient and the lower the s-progesterone level the higher the likelihood of complete miscarriage < 7 days [18]. We did not test patient age as a predictor, because we found it unlikely to be related to the time to complete evacuation of the uterine cavity.
Table 8.
Published studies exploring possible predictors of outcome of expectant management or medical treatment of early miscarriage
| First author, year | Rate of success | Inclusion criteria (type of miscarriage, symptoms) | Definition of successful treatment | Variables tested as predictors | Variables predictive of success in univariable analysisb | Variables predictive of success in multivariable analysisb |
|---|---|---|---|---|---|---|
| Study type | ||||||
| Number of patients | ||||||
| Expectant management | ||||||
| Acharya 2002 [14] | 54% (46/86) | Embryonic (59%), anembryonic (41%); bleeding or not bleeding is not stated | Complete miscarriage within 4 weeks (no heavy bleeding and AP diameter of uterine contents < 15 mm) | Maternal age, menstrual age, parity, abortion, CRL, mean sac diameter, gestational sac volume | Menstrual age (+) | Not performed |
| Prospective observational | ||||||
| N = 86 | ||||||
| Jurkovic 1998 [13] | 25% (21/85) | Embryonic, anembryonic; both bleeding and no bleeding | Absence of vaginal bleeding and no evidence of RPOC on TVS (no cut off in mm); no time limit | Not clearly stated: Maternal age, parity, number of previous miscarriages, menstrual age, vaginal bleeding, mean gestational sac diameter | Mean gestational sac diameter? (−), menstrual age (−) | Not performed |
| Prospective observational | ||||||
| N = 85 | ||||||
| Elson 2005 [16] | 69% (37/54) | Missed miscarriages (embryonic or anembryonic—41%); incomplete miscarriages (no gestational sac—59%); bleeding and mild lower abdominal pain | Complete miscarriage, i.e., bleeding settled and negative urine pregnancy test without D&E, no time limit; median time to resolution 7 days | s-β-hCG, s-progesterone, 17-hydroxy-progesterone, inhibin A, inhibin pro α-C RI, insulin growth factor-binding protein-1 (all in serum) Maternal age, menstrual age, bleeding yes or no, mean diameter of uterine contents, type of miscarriage | (Decision tree analysis) Diameter of RPOC (−), s-β-hCG (−), s-progesterone (−), inhibin A (−), inhibin pro α-C RI (−), type of miscarriage, i.e., incomplete (+) and non-viable pregnancy (−) | Not performed |
| Observational | ||||||
| N = 54 | ||||||
| Luise 2002 [30] | 2 weeks: 83% (184/221); 4 weeks: 91% (201/221) | Incomplete miscarriage < 13 weeks (heterogeneous irregular tissue with or without gestational sac not compatible with missed miscarriage or anembryonic pregnancy); probably all patients had bleeding | Complete miscarriage without D&E within 4 weeks (< 15 mm endometrial thickness and no bleeding or pain) | Presence of gestational sac (yes or no), endometrial thickness | No variable predicted the outcome of expectant management. Trend towards a decrease in proportion of success with increasing endometrial thickness | Not performed |
| Prospective observational | ||||||
| N = 221 | ||||||
| Luise 2002 [17] | 81% (367/451) | First-trimester miscarriage: Incomplete miscarriage (heterogeneous tissue with or without gestational sac with no cut off in mm), embryonic and anembryonic; probably all patients had bleeding | Complete miscarriage (endometrial thickness < 15 mm and absence of bleeding) ≤ 4 weeks | Type of miscarriage | P values not presented, Type of miscarriage: Incomplete (+ +), fetal demise (+), anembryonic pregnancy (−) | Not performed |
| Prospective observational | ||||||
| N = 451 | ||||||
| Casikar 2013 [22] | 77% (161/210) | Incomplete, embryonic and anembryonic; both symptomatic and asymptomatic (bleeding and/or pain) | Cessation of vaginal bleeding and the absence of RPOC (not defined) on TVS ≤ 2 weeks | Bleeding (“none”, “without clots”, “with clots”), pain (yes/no) | Presence of bleeding was significantly predictive of success in incomplete miscarriage. Pain was not predictive | Not performed |
| Prospective observational | ||||||
| N = 210 | ||||||
| Casikar 2012 [25] | 85% (134/158) | Incomplete (no gestational sac, hyperechoic material in the uterine cavity, no cut off in mm); both bleeding and no bleeding | Complete miscarriage within 2 weeks i.e., cessation of bleeding and the absence of RPOC (not defined, no cut off) on TVS | Maternal age, parity, number of vaginal deliveries, number of cesarean sections, previous miscarriages, previous termination of pregnancies, menstrual age, bleeding (yes or no), endometrial thickness, RPOC volume, power Doppler color score, color Doppler signals detectable (yes or no) | Vaginal bleeding (+), absence of color Doppler signals in RPOC (+) | Not performed |
| Prospective observational | ||||||
| N = 158 | ||||||
| Nielsen 1996 [19] | 79% (81/103) | Inevitable (not defined) or incomplete miscarriage < 13 weeks with intrauterine tissue and blood clots; AP diameter 15–50 mm on TVS; clinical signs of miscarriage (bleeding) | Complete miscarriage (AP diameter of uterine contents ≤ 15 mm) on TVS ≤ 3 days | α-fetoprotein, 17β-estradiol, CA125, 17α-hydroxyprogesterone, s-β-hCG, s-progesterone, daily change in s-β-hCG (all in serum) Patient age, menstrual age, parity, previous miscarriages, previous medical terminations, duration of bleeding, volume of intrauterine contents, diameter of intrauterine contents | Volume of intrauterine contents (−), diameter of intrauterine contents (−), 17β-estradiol (−), CA125 (+), 17α-hydroxyprogesterone (−), s-β-hCG (−), s-progesterone (−), daily change in s-β-hCG (+) | s-progesterone (−) daily hCG-change (+) CA125 (+) α-fetoprotein (−) intrauterine contents diameter (−) A model with only s-β-hCG, s-progesterone and intrauterine diameter was also tested (P values not presented) |
| Retrospective (randomized in earlier study) | ||||||
| N = 103 | ||||||
| Schwartzler 1999 [21] | 1 week: 54% (46/85); 4 weeks: 84% (71/85) | Embryonic and anembryonic pregnancies; vaginal bleeding and/or pain | Endometrial cavity thickness < 10 mm and negative urinary pregnancy test within 7 days | Age, parity, previous miscarriage, menstrual age, gestational sac diameter, diameter of intrauterine contents, s-β-hCG, s-progesterone, Hb, PI, RI, PSV in uterine arteries and spiral arteries, presence of blood flow in presumed intervillous space (PI, RI, PSV in intervillous space) | Presence of blood flow in the intervillous space was more common in success group, p value not reported | s-progesterone (−) and s-β-hCG (−); Doppler results were not included in multivariable analysis |
| Prospective observational | ||||||
| N = 85 | ||||||
| Wieringa-de Waard 2003 [20] | 51% (95/188) | Early miscarriage < 16 weeks (embryonic and anembryonic) and incomplete miscarriage (uterine contents > 15 mm AP diameter on TVS); both bleeding and no bleeding | Uterine contents < 15 mm AP diameter on TVS. Time limit not stated (several weeks) | Maternal age, parity, menstrual age, gestational sac (yes or no), gestational sac diameter, bleeding before inclusion (days), pain before inclusion (days), previous miscarriage, previous termination of pregnancy Included in multivariable: Gestational sac on TVS (yes or no), course and amount of bleeding, abdominal pain (yes or no) | Only women with bleeding analyzed (n = 142): Results not reported | Only women with bleeding analyzed (n = 142): Increasing bleeding after inclusion (+) |
| Combined randomized and non-randomized (expectant vs. D&E) | ||||||
| N = 188 | ||||||
| Memtsa 2017 [18] | 64/83 (77%) | Missed miscarriage in first trimester (embryonic or anembryonic) Bleeding and/or pain | Urinary pregnancy test negative and bleeding ceased ≤ 7 days without D&E (time not clearly stated) | s-β-hCG, s-PAPP-A, s-hs-CRP, s-progesterone, Maternal age, menstrual age, ethnicity, BMI, smoker (yes or no), parity, pain (yes or no), amount of bleeding, gestational sac diameter, gestational sac volume | Maternal age (+),s- progesterone (−), s- PAPP-A (−) | Maternal age (+) and s-progesterone (−) |
| Prospective observational | ||||||
| N = 83 | ||||||
| Casikar 2013 [15] | Training set: 74% (137/186); test set: 77% (97/126) | First-trimester miscarriages: Incomplete (65%) (heterogenous RPOC but no cut off in mm), embryonic (20%), anembryonic (15%); both bleeding and no bleeding | Complete resolution ≤ 2 weeks: cessation of vaginal bleeding and the absence of RPOC (no cut off) on TVS | Maternal age, menstrual age, previous vaginal delivery, previous cesarean section, previous miscarriage, previous termination of pregnancy, subtype of miscarriage, smoker (yes or no), amount of vaginal bleeding, endometrial thickness (only if incomplete miscarriage), RPOC volume (only if incomplete miscarriage), abdominal pain (yes or no) | Training set: maternal age (−), menstrual age (−), previous miscarriage (−), bleeding (+), symptoms (+), type of miscarriage, i.e., incomplete (+), embryonic and anembryonic(−) | Type of miscarriage, i.e., incomplete (+), embryonic and anembryonic (−), maternal age (−), vaginal bleeding (+) |
| Prospective observational | ||||||
| N = 312; 186 (training set) + 126 (test set) | ||||||
| Medical management | ||||||
| Schreiber 2015 [32] | 52% (49/95) | First-trimester pregnancy failure (embryonic, anembryonic); both bleeding and no bleeding | Complete expulsion of products of conception (≤ 30 mm AP diameter on TVS) ≤ 3 days | Maternal age, ethnicity, BMI, previous miscarriage, parity, miscarriage type, duration of bleeding, abdominal pain within last 24 h (yes or no), vaginal bleeding within last 24 h (yes or no), gestational sac mean diameter, s-Activin A, s-ADAM-12, s-human placental lactogen, s-glycodelin, s-progesterone, s-estradiol, s-β-hCG | Parity (−) Hispanic ethnicity (−) s-ADAM-12 (−) | Hispanic ethnicity (−), parity (−), s- β-hCG ≥ 4000 (+), s-ADAM-12 ≥ 2500 (+) |
| Retrospective sub-analysis of a randomized controlled multicenter trial. Misoprostol 800 µg per vaginam; single dose | ||||||
| N = 95 | ||||||
| Creinin 2006 [26] | 84% (410/485) (single or repeated dose) | Anembryonic (36%), embryonic (58%), incomplete (endometrial lining > 30 mm) and inevitable (gestational sac and open cervical os and vaginal bleeding) (6%) | Complete miscarriage (≤ 30 mm AP diameter on TVS) without D&E ≤ 30 days (D&E on day 8 if still RPOC) | Abdominal pain within last 24 h (yes or no), vaginal bleeding within last 24 h (yes or no), Rh-type, type of miscarriage, parity, fever/chills during last week (yes or no), status of cervical os (closed or open), blood in vagina, maternal age, race, menstrual age, number of previous pregnancies, planned pregnancy (yes or no), s-β-hCG, Hb, number of previous miscarriages, height, weight, social and cultural variables, and more | Abdominal pain within last 24 h (+), vaginal bleeding within last 24 h (+), Rh-negative blood type (+), type of pregnancy failure, i.e., incomplete/inevitable (+ +), embryonic (+), anembryonic (−), no people younger than 18 years in the household (+) | Single-dose success: Vaginal bleeding within last 24 h (+) and nulliparity (+), Overall success: Localized abdominal pain within last 24 h (+), vaginal bleeding within last 24 h (+), Rh-negative blood type (+), nulliparity (+) |
| Planned substudy of multicenter randomized trial. Misoprostol 800 µg per vaginam; single dose per vaginam; or, if needed (gestational sac or endometrial lining > 30 mm) a second dose after 3 days | ||||||
| N = 485 | ||||||
| Odeh 2010 [31] | 40% (32/81) (one or two doses) | Anembryonic gestation (16%), embryonic (84%) < 12 weeks according to ultrasound examination; probably no bleeding | Endometrial lining < 30 mm on TVS within 12–24 h | Maternal age, menstrual age, previous delivery, previous abortions, previous pregnancies, CRL, gestational sac volume, s-β-hCG | Previous deliveries (−), s-β-hCG (−) | Not performed |
| Retrospective cohort. Misoprostol 800 µg per vaginam | ||||||
| N = 81 | ||||||
| Agostini 2005 [23] | 65% (180/276) | Anembryonic (gestational sac < 75 mm) or embryonic(CRL < 50 mm); both bleeding or no bleeding | Complete expulsion of pregnancy products (endometrial thickness < 15 mm) within 24 h | Maternal age, menstrual age, previous pregnancies, parity, previous vaginal deliveries, previous spontaneous abortions, CRL, mean gestational sac diameter | Previous pregnancies (−), parity (−), previous vaginal deliveries (−) | Parity: para ≤ 1 (+), para ≥ 2 (−) |
| Prospective observational Misoprostol 800 µg per vaginam | ||||||
| N = 276 | ||||||
| Lavecchia 2015 [28] | No D&E: 80% (155/199) No unplanned return to emergency department (URED): 69% (137/199) | Emergency department prescription for medical management and pregnancy arrest < 8 weeks according to ultrasound: missed abortion (33%), anembryonic gestation (28%), incomplete abortion (39%); no definitions of miscarriage types; at least some patients had bleeding | No D&E and no URED, observation time not stated | Maternal age, parity, previous cesarean delivery, previous abortions, type of miscarriage, menstrual age | Menstrual age ≤ 8 weeks (+), menstrual age > 8 weeks (−) | Menstrual age (−) |
| Retrospective cohort Different and not defined misoprostol regimes | ||||||
| N = 199 | ||||||
| Lavecchia 2016 [29] | No D&E 80% (182/227) No unplanned return to the emergency department (URED): 70% (159/227) | Emergency department prescription for medical management and pregnancy arrest < 8 weeks according to ultrasound examination: missed abortion (38%), anembryonic (28%), incomplete (34%); no definitions of miscarriage types; at least some patients had bleeding | No D&E and no URED, observation time not stated The aim was to identify predictors of failure | Uterine cavity sonographic measurements, maternal age, gestational age, previous abortions, previous cesarean delivery, parity | Uterine cavity diameter (−) (for no D&E and no URED), uterine cavity volume (−) (for no URED), uterine cavity length (−) (for no URED) | Uterine cavity diameter > 15 mm was an independent risk factor for the need of D&E and URED |
| Secondary analysis of retrospective observational cohort Different not defined misoprostol regimes | ||||||
| N = 227 | ||||||
| Jung In Kim 2017 [27] | 94% (209/222) | Miscarriage (embryonic and anembryonic) ≤ 11 weeks; both bleeding and no bleeding | Complete expulsion of the conceptus (not defined) without D&E ≤ 24 h | Maternal age, menstrual age, parity, previous cesarean delivery, previous vaginal delivery, previous curettage, type of miscarriage, mean gestational sac diameter, CRL, uterine myoma (yes/no), uterine adenomyosis (yes/no), s-β-hCG | Previous vaginal delivery (no patient in the failure group had a previous vaginal delivery), s-β-hCG (−) | s-β-hCG > 40,000 was significantly associated with failed medical management ≤ 24 h |
| Retrospective cohort 1–3 doses of Misoprostol 800 µg per vaginam; | ||||||
| N = 228 | ||||||
| Banerjee 2013 [24] | 77% (40/52) | Embryonic or anembryonic < 12 weeks, no active bleeding | Complete miscarriage (not defined) ≤ 72 h | Maternal age, menstrual age, parity, s-progesterone | s-progesterone (+) | Mifepristone + misoprostol was less effective if s-progesterone was < 10 nmol/L |
| Prospective observational Mifepristone and misoprostol | ||||||
| N = 53 | ||||||
AP diameter, anterior–posterior diameter of intrauterine contents on transvaginal ultrasound BMI body mass index, CRL crown-rump length, RPOC retained products of conception, TVS transvaginal ultrasound, D&E dilatation and evacuation, hCG human chorionic gonadotropin, Hb hemoglobin, PI pulsatility index, RI resistance index, PSV peak systolic velocity, PAPP-A pregnancy associated plasma protein-A, hs-CRP high sensitivity C-reactive protein, URED unplanned return to emergency department
aThe table is not based on a systematic literature search
b(+) the higher the value of the variable tested the higher the success rate of miscarriage management, alternatively if the variable was present the likelihood of success increased; (−) the higher the value of the variable tested the lower the success rate of miscarriage management, alternatively if the variable was present the likelihood of success decreased
Our results seem plausible from a pathophysiological perspective. Higher concentrations of s-β-hCG and s-progesterone probably reflect better functioning corpus luteum and trophoblast and are compatible with earlier stages of miscarriage explaining longer time to complete miscarriage. The relation between gestational age according to LMP, crown-rump-length and gestational sac diameter may reflect the time since the embryo died. The apoptotic process may be faster for the gestational sac than for the embryo. This could be an explanation for a smaller gestational sac being a predictor of treatment success. Long time between embryonic death and start of bleeding may also indicate resistance to expulsion. In some anembryonic miscarriages, the absence of an embryo might be explained by the embryo having been resorbed after having been dead for a long time.
The likely reason why we did not find any predictor of successful misoprostol treatment is that misoprostol is very effective in most patients. Results of other studies investigating predictors of successful misoprostol treatment are extremely variable (Table 8) [23, 24, 26–29, 31, 32] and no study is directly comparable to ours. The variable results are probably explained by differences in patient selection, definition of treatment success and predictor variables tested.
Some women prefer expectant management to medical intervention [17, 49] and knowledge about prognostic factors is important for being able to provide them with realistic expectations of treatment success. Our prediction models are helpful in this respect but need to be prospectively validated. A simple blood test predicting successful outcome without treatment would be clinically valuable and therefore a goal of future research. Serum-progesterone or serum-hCG results may not always be available at the time of patient counselling. Therefore, they may be less clinically useful as predictors than clinical and ultrasound information available bedside.
Acknowledgements
Open access funding provided by Lund University. This study was funded by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement, and by another Swedish governmental grant (Landstingsfinansierad Regional Forskning).
Author contributions
AF: data collection, data analysis, manuscript writing/editing. LJ: data collection, data analysis, manuscript editing. PS: project development, data analysis, manuscript editing. LV: project development, data analysis, manuscript writing/editing.
Funding
The study sponsors had no role in the collection, analysis or interpretation of data or in the writing of the manuscript.
Compliance with ethical standards
Conflict of interest
None of the authors have any conflict of interest.
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the regional ethical review board, Lund University, Sweden (Dnr 83/2008).
Consent to participate
Written and oral informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Hemminki E. Treatment of miscarriage: current practice and rationale. Obstet Gynecol. 1998;91:247–253. doi: 10.1016/s0029-7844(97)00606-6. [DOI] [PubMed] [Google Scholar]
- 2.Ellish NJ, Saboda K, O'Connor J, Nasca PC, Stanek EJ, Boyle C. A prospective study of early pregnancy loss. Hum Reprod. 1996;11:406–412. doi: 10.1093/humrep/11.2.406. [DOI] [PubMed] [Google Scholar]
- 3.Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ. 1989;299:541–545. doi: 10.1136/bmj.299.6698.541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Nielsen S, Hahlin M, Platz-Christensen J. Randomised trial comparing expectant with medical management for first trimester miscarriages. BJOG. 1999;106:804–807. doi: 10.1111/j.1471-0528.1999.tb08401.x. [DOI] [PubMed] [Google Scholar]
- 5.Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial) BMJ. 2006;332:1235–1240. doi: 10.1136/bmj.38828.593125.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Fernlund A, Jokubkiene L, Sladkevicius P, Valentin L. Misoprostol treatment vs expectant management in women with early non-viable pregnancy and vaginal bleeding: a pragmatic randomized controlled trial. Ultrasound Obstet Gynecol. 2018;51:24–32. doi: 10.1002/uog.18940. [DOI] [PubMed] [Google Scholar]
- 7.Bagratee JS, Khullar V, Regan L, Moodley J, Kagoro H. A randomized controlled trial comparing medical and expectant management of first trimester miscarriage. Hum Reprod. 2004;19:266–271. doi: 10.1093/humrep/deh049. [DOI] [PubMed] [Google Scholar]
- 8.Blohm F, Fridén BE, Milsom I, Platz-Christensen JJ, Nielsen S. A randomised double blind trial comparing misoprostol or placebo in the management of early miscarriage. BJOG. 2005;112:1090–1095. doi: 10.1111/j.1471-0528.2005.00632.x. [DOI] [PubMed] [Google Scholar]
- 9.Wood SL, Brain PH. Medical management of missed abortion: a randomized clinical trial. Obstet Gynecol. 2002;99:563–566. doi: 10.1016/s0029-7844(01)01765-3. [DOI] [PubMed] [Google Scholar]
- 10.Lister MS, Shaffer LET, Bell JG, Lutter KQ, Moorma KH. Randomized, double-blind, placebo-controlled trial of vaginal misoprostol for management of early pregnancy failures. Am J Obstet Gynecol. 2005;193:1338–1343. doi: 10.1016/j.ajog.2005.05.010. [DOI] [PubMed] [Google Scholar]
- 11.Kolte AM, Bernardi LA, Christiansen OB, Quenby S, Farquharson RG, Goddjin M, Stephenson MD. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod. 2015;30:495–498. doi: 10.1093/humrep/deu299. [DOI] [PubMed] [Google Scholar]
- 12.Kim C, Barnard S, Neilson JP, Hickey M, Vazquez JC, Dou L. Medical treatments for incomplete miscarriage. Cochrane Database Syst Rev. 2017;1:Cd07223. doi: 10.1002/14651858.CD007223.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Jurkovic D, Ross JA, Nicolaides KH. Expectant management of missed miscarriage. BJOG. 1998;105:670–671. doi: 10.1111/j.1471-0528.1998.tb10184.x. [DOI] [PubMed] [Google Scholar]
- 14.Acharya G, Morgan H. Does gestational sac volume predict the outcome of missed miscarriage managed expectantly? J Clin Ultrasound. 2002;30:526–531. doi: 10.1002/jcu.10107. [DOI] [PubMed] [Google Scholar]
- 15.Casikar I, Lu C, Reid S, Condous G. Prediction of successful expectant management of first trimester miscarriage: development and validation of a new mathematical model. Aust N Z J Obstet Gynaecol. 2013;53:58–63. doi: 10.1111/ajo.12053. [DOI] [PubMed] [Google Scholar]
- 16.Elson J, Tailor A, Salim R, Hillaby K, Dew T, Jurkovic D. Expectant management of miscarriage–prediction of outcome using ultrasound and novel biochemical markers. Hum Reprod. 2005;20:2330–2333. doi: 10.1093/humrep/dei038. [DOI] [PubMed] [Google Scholar]
- 17.Luise C, Jermy K, May C, Costello G, Collins WP, Bourne TH. Outcome of expectant management of spontaneous first trimester miscarriage: observational study. BMJ. 2002;324:873–875. doi: 10.1136/bmj.324.7342.873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Memtsa M, Jauniaux E, Gulbis B, Nyrhinen NC, Jurkovic D. Maternal serum markers in predicting successful outcome in expectant management of missed miscarriage. Reprod Biomed Online. 2017;34:98–103. doi: 10.1016/j.rbmo.2016.09.004. [DOI] [PubMed] [Google Scholar]
- 19.Nielsen S, Hahlin M, Odén A. Using a logistic model to identify women with first-trimester spontaneous abortion suitable for expectant management. BJOG. 1996;103:1230–1235. doi: 10.1111/j.1471-0528.1996.tb09634.x. [DOI] [PubMed] [Google Scholar]
- 20.Wieringa-de Waard M, Ankum WM, Bonsel GJ, Vos J, Biewenga P, Bindels PJ. The natural course of spontaneous miscarriage: analysis of signs and symptoms in 188 expectantly managed women. Brit J Gen Practice. 2003;53:704–708. [PMC free article] [PubMed] [Google Scholar]
- 21.Schwarzler P, Holden D, Nielsen S, Hahlin M, Sladkevicius P, Bourne TH. The conservative management of first trimester miscarriages and the use of colour Doppler sonography for patient selection. Hum Reprod. 1999;14:1341–1345. doi: 10.1093/humrep/14.5.1341. [DOI] [PubMed] [Google Scholar]
- 22.Casikar I, Lu C, Reid S, Condous G. Does symptomatology at presentation correlate with successful expectant management of first trimester miscarriage: a prospective observational study. Aust N Z J Obstet Gynaecol. 2013;53:178–183. doi: 10.1111/ajo.12068. [DOI] [PubMed] [Google Scholar]
- 23.Agostini A, Ronda I, Capelle M, Romain F, Bretelle F, Blanc B. Influence of clinical and ultrasound factors on the efficacy of misoprostol in first trimester pregnancy failure. Fertil Steril. 2005;84:1030–1032. doi: 10.1016/j.fertnstert.2005.04.032. [DOI] [PubMed] [Google Scholar]
- 24.Banerjee AK, Emembolu JO, Habiba M. The association between serum progesterone and outcome of medical management of early fetal demise: a pilot study. J Obstet Gynaecol. 2013;33:384–386. doi: 10.3109/01443615.2013.769943. [DOI] [PubMed] [Google Scholar]
- 25.Casikar I, Lu C, Oates J, Bignardi T, Alhamdan D, Condous G. The use of power Doppler colour scoring to predict successful expectant management in women with an incomplete miscarriage. Hum Reprod. 2012;27:669–675. doi: 10.1093/humrep/der433. [DOI] [PubMed] [Google Scholar]
- 26.Creinin MD, Huang X, Westhoff C, Barnhart K, Gilles JM, Zhang J. Factors related to successful misoprostol treatment for early pregnancy failure. Obstet Gynecol. 2006;107:901–907. doi: 10.1097/01.AOG.0000206737.68709.3e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Kim JI, Park IY, Yim JM, Cheon JY, Yun HG, Kwon JY. Serum beta-hCG concentration is a predictive factor for successful early medical abortion with vaginal misoprostol within 24 hours. Obstet Gynecol Sci. 2017;60:427–432. doi: 10.5468/ogs.2017.60.5.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Lavecchia M, Abenhaim HA. Effect of menstrual age on failure of medical management in women with early pregnancy loss. J Obstet Gynaecol Can. 2015;37:617–623. doi: 10.1016/S1701-2163(15)30199-7. [DOI] [PubMed] [Google Scholar]
- 29.Lavecchia M, Klam S, Abenhaim HA. Effect of uterine cavity sonographic measurements on medical management failure in women with early pregnancy loss. J Ultrasound Med. 2016;35:1705–1710. doi: 10.7863/ultra.15.09063. [DOI] [PubMed] [Google Scholar]
- 30.Luise C, Jermy K, Collins WP, Bourne TH. Expectant management of incomplete, spontaneous first-trimester miscarriage: outcome according to initial ultrasound criteria and value of follow-up visits. Ultrasound Obstet Gynecol. 2002;19:580–582. doi: 10.1046/j.1469-0705.2002.00662.x. [DOI] [PubMed] [Google Scholar]
- 31.Odeh M, Tendler R, Kais M, Maximovsky O, Ophir E, Bornstein J. Early pregnancy failure: factors affecting successful medical treatment. Isr Med Assoc J. 2010;12:325–328. [PubMed] [Google Scholar]
- 32.Schreiber CA, Ratcliffe SJ, Quinley KE, Miller C, Sammel MD. Serum biomarkers may help predict successful misoprostol management of early pregnancy failure. Reprod Biology. 2015;15:79–85. doi: 10.1016/j.repbio.2015.02.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Abdallah Y, Daemen A, Guha S, Syed S, Naji O, Pexsters A, et al. Gestational sac and embryonic growth are not useful as criteria to define miscarriage: a multicenter observational study. Ultrasound Obstet Gynecol. 2011;38:503–509. doi: 10.1002/uog.10075. [DOI] [PubMed] [Google Scholar]
- 34.Abdallah Y, Daemen A, Kirk E, Pexsters A, Naji O, Stalder C, et al. Limitations of current definitions of miscarriage using mean gestational sac diameter and crown-rump length measurements: a multicenter observational study. Ultrasound Obstet Gynecol. 2011;38:497–502. doi: 10.1002/uog.10109. [DOI] [PubMed] [Google Scholar]
- 35.Jeve Y, Rana R, Bhide A, Thangaratinam S. Accuracy of first-trimester ultrasound in the diagnosis of early embryonic demise: a systematic review. Ultrasound Obstet Gynecol. 2011;38:489–496. doi: 10.1002/uog.10108. [DOI] [PubMed] [Google Scholar]
- 36.Levi CS, Lyons EA, Lindsay DJ. Ultrasound in the first trimester of pregnancy. Radiol Clin North Am. 1990;28:19–38. [PubMed] [Google Scholar]
- 37.National Guideline C: ACR Appropriateness Criteria® first trimester bleeding. https://www.guideline.gov/summaries/summary/43883. Accessed 24 Apr 2017
- 38.National Institute of care and excellence: ectopic pregnancy and miscarriage: diagnosis and initial management. https://www.nice.org.uk/guidance/cg154. Accessed 24 Apr 2017 [PubMed]
- 39.Valentin L, Sladkevicius P, Laurini R, Soderberg H, Marsal K. Uteroplacental and luteal circulation in normal first-trimester pregnancies: Doppler ultrasonographic and morphologic study. Am J Obstet Gynecol. 1996;174:768–775. doi: 10.1016/s0002-9378(96)70462-3. [DOI] [PubMed] [Google Scholar]
- 40.Valentin L, Sladkevicius P, Laurini R, Soderberg H, Olofsson P, Marsal K. Effect of a prostaglandin E1 analogue (gemeprost) on uterine and luteal circulation in normal first trimester pregnancies. A Doppler velocimetry study. Eur J Obstet Gynecol Reprod Biol. 1995;59:25–34. doi: 10.1016/0028-2243(94)02027-c. [DOI] [PubMed] [Google Scholar]
- 41.Practice Bulletin No 150: early pregnancy loss. Obstet Gynaecol. 2015;125:1258–1267. doi: 10.1097/01.AOG.0000465191.27155.25. [DOI] [PubMed] [Google Scholar]
- 42.Australasian Society for Ultrasound in Medicine: guidelines for the performance of first trimester ultrasound. https://www.asum.com.au/files/public/SoP/D11-Guidelines-for-the-Performance-of-First-Trimester-Ultrasound.pdf. Accessed 22 Aug 2017
- 43.Morin L, Cargill YM, Glanc P. Ultrasound Evaluation of First Trimester Complications of Pregnancy. J Obstet Gynaecol Can. 2016;38:982–988. doi: 10.1016/j.jogc.2016.06.001. [DOI] [PubMed] [Google Scholar]
- 44.Nielsen S, Hahlin M. Expectant management of first-trimester spontaneous abortion. Lancet. 1995;345:84–86. doi: 10.1016/s0140-6736(95)90060-8. [DOI] [PubMed] [Google Scholar]
- 45.Chen BA, Creinin MD. Medical management of early pregnancy failure: efficacy. Semin Reprod Med. 2008;26:411–422. doi: 10.1055/s-0028-1087107. [DOI] [PubMed] [Google Scholar]
- 46.Creinin MD, Harwood B, Guido RS, Fox MC, Zhang J. Endometrial thickness after misoprostol use for early pregnancy failure. Int J Gynaecol Obstet. 2004;86:22–26. doi: 10.1016/j.ijgo.2004.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Reeves MF, Lohr PA, Harwood BJ, Creinin MD. Ultrasonographic endometrial thickness after medical and surgical management of early pregnancy failure. Obstet Gynecol. 2008;111:106–112. doi: 10.1097/01.AOG.0000296655.26362.6d. [DOI] [PubMed] [Google Scholar]
- 48.Sawyer E, Ofuasia E, Ofili-Yebovi D, Helmy S, Gonzalez J, Jurkovic D. The value of measuring endometrial thickness and volume on transvaginal ultrasound scan for the diagnosis of incomplete miscarriage. Ultrasound Obstet Gynecol. 2007;29:205–209. doi: 10.1002/uog.3914. [DOI] [PubMed] [Google Scholar]
- 49.Wieringa-de Waard M, Bindels PJ, Vos J, Bonsel GJ, Stalmeier PF, Ankum WM. Patient preferences for expectant management vs. surgical evacuation in first-trimester uncomplicated miscarriage. J Clin Epidemiol. 2004;57:167–173. doi: 10.1016/j.jclinepi.2003.07.004. [DOI] [PubMed] [Google Scholar]