BACKGROUND: Women who suffer an early pregnancy loss require specific clinical care, aftercare, and ongoing support. In the UK, the clinical management of early pregnancy complications, including loss is provided mainly through specialist Early Pregnancy Assessment Units. The COVID-19 pandemic fundamentally changed the way in which maternity and gynaecological care was delivered, as health systems moved to rapidly reconfigure and re-organise services, aiming to reduce the risk and spread of SARS-CoV-2 infection. PUDDLES is an international collaboration investigating the pandemic\'s impact on care for people who suffered a perinatal bereavement. Presented here are initial qualitative findings undertaken with UK-based women who suffered early pregnancy losses during the pandemic, about how they navigated the healthcare system and its restrictions, and how they were supported.
METHODS: In-keeping with a qualitative research design, in-depth semi-structured interviews were undertaken with an opportunity sample of women (N = 32) who suffered any early pregnancy loss during the COVID-19 pandemic. Data were analysed using a template analysis to understand women\'s access to services, care, and networks of support, during the pandemic following their pregnancy loss. The thematic template was based on findings from parents who had suffered a late-miscarriage, stillbirth, or neonatal death in the UK, during the pandemic.
RESULTS: All women had experienced reconfigured maternity and early pregnancy services. Data supported themes of: 1) COVID-19 Restrictions as Impractical & Impersonal; 2) Alone, with Only Staff to Support Them; 3) Reduction in Service Provision Leading to Perceived Devaluation in Care; and 4) Seeking Their Own Support. Results suggest access to early pregnancy loss services was reduced and pandemic-related restrictions were often impractical (i.e., restrictions added to burden of accessing or receiving care). Women often reported being isolated and, concerningly, aspects of early pregnancy loss services were reported as sub-optimal.
CONCLUSIONS: These findings provide important insight for the recovery and rebuilding of health services in the post-pandemic period and help us prepare for providing a higher standard of care in the future and through any other health system shocks. Conclusions made can inform future policy and planning to ensure best possible support for women who experience early pregnancy loss.

BACKGROUND: Methotrexate (MTX) is used in clinical practice as a medical treatment option in patients with early pregnancy complications like ectopic pregnancy.
OBJECTIVE: To review systemic MTX therapy use in the first trimester of pregnancy in our hospital and to examine subsequent clinical outcomes.
METHODS: Retrospective review of all women treated with systemic MTX in early pregnancy identified from electronic prescription records from 1 January 2018 to 31 December 2020 at Cork University Maternity Hospital, Ireland. Relevant data was transcribed from electronic health records.
RESULTS: Indications for treatment were tubal ectopic pregnancy (70%, n = 51), persistent pregnancy of unknown location (22%, n = 16) and caesarean scar pregnancy (7%, n = 5). Treatment was successful in 88% (n = 44) of tubal ectopic pregnancies with 73% (n = 37) and 14% (n = 7) of women receiving a single dose and repeated doses, respectively. Only 8% (n = 4) of tubal ectopic pregnancies required emergency surgery for subsequent tubal rupture. In 93% (n = 15) of cases of persistent pregnancy of unknown location, treatment was successful with one patient requiring uterine evacuation. Women with caesarean scar pregnancy were treated with combined MTX and uterine evacuation without complication.
CONCLUSIONS: The efficacy of medical treatment with systemic MTX for confirmed tubal ectopic pregnancy in our hospital is in line with national and international standards. Careful consideration should be given to treating caesarean scar pregnancy and persistent pregnancy of unknown location with systemic MTX. Systemic MTX use guided by clinicians specialised in early pregnancy complications and safe medication practices may improve treatment success and reduce adverse events.

Objective: To quantify proportions of loss to follow-up in patients presenting with a pregnancy of unknown location and explore patients\' perspectives on follow-up for pregnancy of unknown location. A pregnancy of unknown location is a scenario in which a patient has a positive pregnancy test but the pregnancy is not visualized on transvaginal ultrasound. Study Design: We conducted a retrospective cohort study of patients with pregnancy of unknown location who presented to an urban academic emergency department or complex family planning outpatient office. We sought to calculate the proportion of patients lost to follow-up, defined as inability to contact the patient within 2 weeks. We then conducted focus groups of patients diagnosed with a pregnancy of unknown location. We used thematic analysis to identify themes related to follow-up. Results: We reviewed 464 charts of patients diagnosed with pregnancy of unknown location. The median age in this cohort was 27 with most patients identifying as Black (80%, n = 370) and using public insurance (67%, n = 315). When looking at loss to follow-up rates, Black patients experienced loss to follow-up (20%, n = 72) more often than White patients (4%, n = 2; p = 0.003). Focus group participants had a mean age of 31.8+/-4.8, and the majority were of Black race (n = 16, 72.7%). Participants identified barriers to follow-up including the long duration of management, general inconvenience, and poor communication with their health care team. Participants felt a burden of responsibility to learn about their condition and to self-advocate for their follow-up and communication of results. Conclusions: These data indicate that Black patients are more likely to experience loss to follow-up compared with White patients during monitoring for pregnancy of unknown location. Patients identified many barriers to follow-up and felt that successful follow-up required substantial self-efficacy.

OBJECTIVE: The M6 prediction model stratifies the risk of development of ectopic pregnancy (EP) for women with pregnancy of unknown location (PUL) into low risk or high risk, using human chorionic gonadotrophin (hCG) and progesterone levels at the initial visit to a gynaecological emergency room and hCG level at 48 h. This study evaluated a second model, the M6NP model, which does not include the progesterone level at the initial visit. The main aim of this study was to validate the diagnostic accuracy of the M6NP model in a population of French women.
METHODS: Between January and December 2021, all women with an hCG measurement from the gynaecological emergency department of a teaching hospital were screened for inclusion in this study. Women with a pregnancy location determined before or at the second visit were excluded. The diagnostic test was based on logistic regression of the M6NP model, with classification into two groups: high risk of EP (≥5%) and low risk of EP (<5%). The reference test was the final outcome based on clinical, biological and sonographic results: failed PUL (FPUL), intrauterine pregnancy (IUP) or EP. Diagnostic performance for risk prediction of EP, and also IUP and FPUL, was calculated.
RESULTS: In total, 759 women with possible PUL were identified. After screening, 341 women with PUL were included in the main analysis. Of these, 186 (54.5%) were classified as low risk, including three (1.6%) with a final outcome of EP. The remaining 155 women with PUL were classified as high risk, of whom 60 (38.7%), 66 (42.8%) and 29 (18.7%) had a final outcome of FPUL, IUP and EP, respectively. Of the 32 women with PUL with a final outcome of EP, 29 (90.6%) were classified as high risk and three (9.4%) were classified as low risk. Therefore, the performance of the M6NP model to predict EP had a negative predictive value of 98.4%, a positive predictive value of 18.7%, sensitivity of 90.6% and specificity of 59.2%. If the prediction model had been used, it is estimated that 4.5 visits per patient could have been prevented.
CONCLUSIONS: The M6NP model could be used safely in the French population for risk stratification of PUL. Its use in clinical practice should result in a substantial reduction in the number of visits to a gynaecological emergency room.

Patients followed for a pregnancy of unknown location are generally followed by a team of clinicians through telephone calls, and their contraceptive needs at the time of pregnancy resolution may not be addressed.
This study aimed to assess contraceptive counseling and contraceptive uptake before and after a telephone-based intervention.
This was a retrospective pre-post study assessing pregnancy intendedness in patients with a pregnancy of unknown location and the proportion of patients who received contraceptive counseling and a contraceptive prescription before and after the initiation of a telephone-based intervention. We reviewed medical records 1 year before and 1 year after implementation of our intervention for demographic characteristics, pregnancy intendedness, pregnancy outcome, contraceptive counseling documentation, receipt of contraception, and repeat pregnancy within 6 months. We assessed the effects of an implementation strategy to address family planning needs once pregnancy was resolved by comparing the proportions of patients who were counseled and received contraception before and after our intervention was implemented. We performed logistic regression to identify associations between covariates and the outcomes of contraceptive counseling documentation and receipt of contraception.
Of the 220 patients in the combined cohort, the majority were Black (161/220, 73%) and ultimately had a resolved pregnancy of unknown location (162/220, 74%), and the proportion of pregnancies documented as unintended was 60% (132/220). Before our intervention, 27 of 100 (27%) patients received contraceptive counseling, compared with 94 of 120 (78%) patients after the intervention (odds ratio [OR] 9.77, 95% CI 5.26-18.16). Before the intervention, 17 of 90 (19%) patients who did not desire repeat pregnancy received contraception, compared with 32 of 86 (37%) patients after the intervention (OR 2.54, 95% CI 1.28-5.05). Our postintervention cohort had an increased odds of receiving contraceptive counseling (OR 9.77, 95% CI 5.26-18.16) and of receiving a contraceptive prescription (OR 2.54, 95% CI 1.28-5.05) compared with our preintervention cohort.
We found that over half of patients with a pregnancy of unknown location have an unintended pregnancy, and standardization of care through a telephone-based intervention improves contraceptive counseling and prescribing in patients with a resolved pregnancy of unknown location. This intervention could be used at any institution that follows patients with a pregnancy of unknown location remotely to improve care.

To compare days to diagnosis of pregnancy location for same-day medication abortion and same-day uterine aspiration with delayed treatment (expectant management) in patients with undesired pregnancy of unknown location (PUL).
We conducted a retrospective cohort study at a single Planned Parenthood health center in Minnesota. We reviewed electronic health records and included patients presenting for induced abortion diagnosed with PUL (positive high-sensitivity urine pregnancy test and no evidence of intrauterine or extrauterine pregnancy on transvaginal ultrasonography) without symptoms or ultrasonographic imaging concerning for ectopic pregnancy (low risk). The primary outcome was days to pregnancy location clinical diagnosis.
Of 19,151 abortion encounters in 2016-2019, 501 (2.6%) had a low-risk PUL. Participants chose delay-for-diagnosis before treatment (148, 29.5%), immediate treatment medication abortion (244, 48.7%), or immediate treatment uterine aspiration (109, 21.8%). Median days to diagnosis were significantly lower in the immediate treatment uterine aspiration group (2 days, IQR 1-3 days, p < 0.001) and similar for immediate treatment medication abortion (4 days, IQR 3-9 days, p = 0.304) compared with delay-for-diagnosis (3 days, IQR 2-10 days). Thirty-three low-risk participants (6.6%) were treated for ectopic pregnancy, but no difference in ectopic rate was detected among groups (p = 0.725). Participants in the delay-for-diagnosis group were more likely to be nonadherent with follow-up (p < 0.001). For participants who completed follow-up, abortion completion rate was lower for immediate treatment medication abortion (85.2%) compared with immediate treatment uterine aspiration (97.6%, p = 0.003).
For patients with undesired PUL, diagnosis of pregnancy location was fastest with immediate treatment uterine aspiration and similar for expectant management and immediate treatment medication abortion. Medication abortion efficacy may be reduced in treatment of undesired PUL.
For PUL patients desiring induced abortion, the option of proceeding at initial encounter may help improve access and patient satisfaction. Uterine aspiration for PUL may help diagnose pregnancy location more quickly.

BACKGROUND: There is no global agreement on how to best determine pregnancy of unknown location viability and location using biomarkers. Measurements of progesterone and β human chorionic gonadotropin (βhCG) are still used in clinical practice to exclude the possibility of a viable intrauterine pregnancy (VIUP). We evaluate the predictive value of progesterone, βhCG, and βhCG ratio cut-off levels to exclude a VIUP in women with a pregnancy of unknown location.
METHODS: This was a secondary analysis of prospective multicenter study data of consecutive women with a pregnancy of unknown location between January 2015 and 2017 collected from dedicated early pregnancy assessment units of eight hospitals. Single progesterone and serial βhCG measurements were taken. Women were followed up until final pregnancy outcome between 11 and 14 weeks of gestation was confirmed using transvaginal ultrasonography: (1) VIUP, (2) non-viable intrauterine pregnancy or failed pregnancy of unknown location, and (3) ectopic pregnancy or persisting pregnancy of unknown location. The predictive value of cut-off levels for ruling out VIUP were evaluated across a range of values likely to be encountered clinically for progesterone, βhCG, and βhCG ratio.
RESULTS: Data from 2507 of 3272 (76.6%) women were suitable for analysis. All had data for βhCG levels, 2248 (89.7%) had progesterone levels, and 1809 (72.2%) had βhCG ratio. The likelihood of viability falls with the progesterone level. Although the median progesterone level associated with viability was 59 nmol/L, VIUP were identified with levels as low as 5 nmol/L. No single βhCG cut-off reliably ruled out the presence of viability with certainty, even when the level was more than 3000 IU/L, there were 39/358 (11%) women who had a VIUP. The probability of viability decreases with the βhCG ratio. Although the median βhCG ratio associated with viability was 2.26, VIUP were identified with ratios as low as 1.02. A progesterone level below 2 nmol/L and βhCG ratio below 0.87 were unlikely to be associated with viability but were not definitive when considering multiple imputation.
CONCLUSIONS: Cut-off levels for βhCG, βhCG ratio, and progesterone are not safe to be used clinically to exclude viability in early pregnancy. Although βhCG ratio and progesterone have slightly better performance in comparison, single βhCG used in this manner is highly unreliable.

To validate externally five approaches to predict ectopic pregnancy (EP) in pregnancies of unknown location (PUL): the M6P and M6NP risk models, the two-step triage strategy (2ST, which incorporates M6P), the M4 risk model, and beta human chorionic gonadotropin ratio cut-offs (BhCG-RC).
Secondary analysis of a prospective cohort study.
Eight UK early pregnancy assessment units.
Women presenting with a PUL and BhCG >25 IU/l.
Women were managed using the 2ST protocol: PUL were classified as low risk of EP if presenting progesterone ≤2 nmol/l; the remaining cases returned 2 days later for triage based on M6P. EP risk ≥5% was used to classify PUL as high risk. Missing values were imputed, and predictions for the five approaches were calculated post hoc. We meta-analysed centre-specific results.
Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP.
Of 2899 eligible women, the primary analysis excluded 297 (10%) women who were lost to follow up. The area under the ROC curve for EP was 0.89 (95% CI 0.86-0.91) for M6P, 0.88 (0.86-0.90) for 2ST, 0.86 (0.83-0.88) for M6NP and 0.82 (0.78-0.85) for M4. Sensitivities for EP were 96% (M6P), 94% (2ST), 92% (N6NP), 80% (M4) and 58% (BhCG-RC); false-positive rates were 35%, 33%, 39%, 24% and 13%. M6P and 2ST had the best clinical utility and good overall calibration, with modest variability between centres.
2ST and M6P performed best for prediction and triage in PUL.
The M6 model, as part of a two-step triage strategy, is the best approach to characterise and triage PULs.

UNASSIGNED: The aim of this study was to evaluate the efficacy of methotrexate (MTX) in the treatment of ectopic pregnancies. We identified predictive factors of success or failure and compared our results with previous studies to make recommendations for its use.
UNASSIGNED: A cohort of 61 patients from a single center was retrospectively analyzed. Inclusion criteria were a diagnosis of ectopic pregnancy and treatment with a single-dose injection of MTX. The need to perform surgery despite MTX was defined as treatment failure while needing a second MTX injection was not.
UNASSIGNED: In our cohort, MTX demonstrated a success rate of 80%. This rate rose to 84% when patients with human Chorionic Gonadotropin (hCG ) > 5,000 IU/L were excluded. Twenty percent underwent surgery for pain, increased mass size and/or suboptimal hCG kinetics. Low hCG levels on days 0, 4 and 7 as well as the absence of pain, metrorrhagia and hemoperitoneum were predictive of success. MTX was also efficient in the treatment of persisting pregnancies of unknown location (PUL).
UNASSIGNED: Our results are consistent with previous studies and emphasize the fact that MTX is less effective above a certain level of hCG. We obtained a cut-off value of 2439 IU/L with a sensitivity of 66.7% and a specificity of 93.9%. MTX should not be used when hCG is higher than 5,000 IU/L and laparoscopic surgery should be performed. Our results bring additional data about the efficacy of MTX in the management of persisting pregnancies of unknown location.

The M6 risk-prediction model was published as part of a two-step protocol using an initial progesterone level of ≤ 2 nmol/L to identify probable failing pregnancies (Step 1) followed by the M6 model (Step 2). The M6 model has been shown to have good triage performance for stratifying women with a pregnancy of unknown location (PUL) as being at low or high risk of harboring an ectopic pregnancy (EP). This study validated the triage performance of the two-step protocol in clinical practice by evaluating the number of protocol-related adverse events and how effectively patients were triaged.
This was a prospective multicenter interventional study of 3272 women with a PUL, carried out between January 2015 and January 2017 in four district general hospitals and four university teaching hospitals in the UK. The final pregnancy outcome was defined as: a failed PUL (FPUL), an intrauterine pregnancy (IUP) or an EP (including persistent PUL (PPUL)). FPUL and IUP were grouped as low-risk and EP/PPUL as high-risk PUL. Serum progesterone and human chorionic gonadotropin (hCG) levels were measured at presentation in all patients. If the initial progesterone level was ≤ 2 nmol/L, patients were discharged and were asked to have a follow-up urine pregnancy test in 2 weeks to confirm a negative result. If the progesterone level was > 2 nmol/L or a measurement had not been taken, hCG level was measured again at 48 h and results were entered into the M6 model. Patients were managed according to the outcome predicted by the protocol. Those classified as \'low risk, probable FPUL\' were advised to perform a urine pregnancy test in 2 weeks and those classified as \'low risk, probable IUP\' were invited for a scan a week later. When a woman with a PUL was classified as high risk (i.e. risk of EP ≥ 5%) she was reviewed clinically within 48 h. One center used a progesterone cut-off of ≤ 10 nmol/L and its data were analyzed separately. If the recommended management protocol was not adhered to, this was recorded as a protocol deviation and classified as: unscheduled visit for clinician reason, unscheduled visit for patient reason or incorrect timing of blood test or ultrasound scan. The classifications outlined in the UK Good Clinical Practice (GCP) guidelines were used to evaluate the incidence of adverse events. Data were analyzed using descriptive statistics.
Of the 3272 women with a PUL, 2625 were included in the final analysis (317 met the exclusion criteria or were lost to follow-up, while 330 were evaluated using a progesterone cut-off of ≤ 10 nmol/L). Initial progesterone results were available for 2392 (91.1%) patients. In Step 1, 407 (15.5%) patients were classified as low risk (progesterone ≤ 2 nmol/L), of whom seven (1.7%) were ultimately diagnosed with an EP. In 279 of the remaining 2218 women with a PUL, the M6 model was not applied owing to protocol deviation or because the outcome was already known (usually on the basis of an ultrasound scan) before a second hCG reading was taken; of these patients, 30 were diagnosed with an EP. In Step 2, 1038 women with a PUL were classified as low risk, of whom eight (0.8%) had a final outcome of EP. Of 901 women classified as high risk at Step 2, 275 (30.5%) had an EP. Therefore, 275/320 (85.9%) EPs were correctly classified as high risk. Overall, 1445/2625 PUL (55.0%) were classified as low risk, of which 15 (1.0%) were EP. None of these cases resulted in a ruptured EP or significant clinical harm. Sixty-two women participating in the study had an adverse event, but no woman had a serious adverse event as defined in the UK GCP guidelines.
This study has shown that the two-step protocol incorporating the M6 model effectively triaged the majority of women with a PUL as being at low risk of an EP, minimizing the follow-up required for these patients after just two visits. There were few misclassified EPs and none of these women came to significant clinical harm or suffered a serious adverse clinical event. The two-step protocol incorporating the M6 model is an effective and clinically safe way of rationalizing the management of women with a PUL. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.