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Objectives: Ectopic pregnancy (EP) is a major high‐risk outcome following a pregnancy of unknown location (PUL) classification. Biochemical markers are used to triage PUL as high vs low risk to guide appropriate follow‐up. The M6 model is currently the best risk‐prediction model. We aimed to update the M6 model and evaluate whether performance can be improved by including clinical factors. Methods: This prospective cohort study recruited consecutive PUL between January 2015 and January 2017 at eight units (Phase 1), with two centers continuing recruitment between January 2017 and March 2021 (Phase 2). Serum samples were collected routinely and sent for β‐human chorionic gonadotropin (β‐hCG) and progesterone measurement. Clinical factors recorded were maternal age, pain score, bleeding score and history of EP. Based on transvaginal ultrasonography and/or biochemical confirmation during follow‐up, PUL were classified subsequently as failed PUL (FPUL), intrauterine pregnancy (IUP) or EP (including persistent PUL (PPUL)). The M6 models with (M6P) and without (M6NP) progesterone were refitted and extended with clinical factors. Model validation was performed using internal–external cross‐validation (IECV) (Phase 1) and temporal external validation (EV) (Phase 2). Missing values were handled using multiple imputation. Results: Overall, 5473 PUL were recruited over both phases. A total of 709 PUL were excluded because maternal age was < 16 years or initial β‐hCG was ≤ 25 IU/L, leaving 4764 (87%) PUL for analysis (2894 in Phase 1 and 1870 in Phase 2). For the refitted M6P model, the area under the receiver‐operating‐characteristics curve (AUC) for EP/PPUL vs IUP/FPUL was 0.89 for IECV and 0.84–0.88 for EV, with respective sensitivities of 94% and 92–93%. For the refitted M6NP model, the AUCs were 0.85 for IECV and 0.82–0.86 for EV, with respective sensitivities of 92% and 93–94%. Calibration performance was good overall, but with heterogeneity between centers. Net Benefit confirmed clinical utility. The change in AUC when M6P was extended to include maternal age, bleeding score and history of EP was between −0.02 and 0.01, depending on center and phase. The corresponding change in AUC when M6NP was extended was between −0.01 and 0.03. At the 5% threshold to define high risk of EP/PPUL, extending M6P altered sensitivity by −0.02 to −0.01, specificity by 0.03 to 0.04 and Net Benefit by −0.005 to 0.006. Extending M6NP altered sensitivity by −0.03 to −0.01, specificity by 0.05 to 0.07 and Net Benefit by −0.005 to 0.006. Conclusions: The updated M6 model offers accurate diagnostic performance, with excellent sensitivity for EP. Adding clinical factors to the model improved performance in some centers, especially when progesterone levels were not suitable or unavailable. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: 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). Design: Secondary analysis of a prospective cohort study. Setting: Eight UK early pregnancy assessment units. Population: Women presenting with a PUL and BhCG >25 IU/l. Methods: 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. Main outcome measures: Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP. Results: 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. Conclusions: 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. The M6 model, as part of a two‐step triage strategy, is the best approach to characterise and triage PULs. [ABSTRACT FROM AUTHOR]

Risk prediction models utilising hCG and progesterone are effective tools to manage pregnancy of unknown location (PUL). Sensitivity was 0.94 (M6P) and 0.92 (M6NP), specificity was 0.62 (M6P) and 0.55 (M6NP) and negative predictive value (NPV) was 0.99 (M6P) and 0.98 (M6NP). [Extracted from the article]

An abstract of the article "A multicentre trial on the performance and complications of a two-step triage protocol based on initial serum progesterone and serial serum hCG to manage pregnancy of unknown location (PUL)," by S. Bobdiwala and colleagues is presented.

Objectives: To investigate prognostic factors for anxiety, depression and post-traumatic stress (PTS) symptoms 1 month after early pregnancy loss (EPL)., Design: A prospective cohort study. Consecutive women were recruited, and demographic and clinical data were collected. Surveys containing the Hospital Anxiety and Depression Scale (HADS) and Post-traumatic Stress Diagnostic Scale (PDS) were emailed 1 month after a loss. Univariable logistic regression was performed to link factors with caseness of anxiety, depression or PTS according to screening measures., Setting: Early pregnancy units of three central London hospitals., Participants: 737/1116 eligible women with an EPL were recruited. 492 responded to HADS and 487 to PDS., Primary and Secondary Outcome Measures: Primary outcome is the area under the curve (AUC) to predict any psychological morbidity (defined as moderate/severe anxiety or depression, or meeting screening criteria for PTS) for each variable. Further outcomes are explained variation (R 2 ) and p value for any morbidity, and AUC, explained variation, and p value for each morbidity separately., Results: Women who had a past diagnosis of a psychiatric condition were more likely to meet criteria for anxiety, depression or PTS (75% for current diagnosis vs 55% for past vs 30% for no diagnosis; AUC 0.61; R 2 8.4%; p<0.0001), as were those with previous pregnancy loss (48% vs 30%; AUC 0.59; R 2 4.3%; p<0.0001). Most of the assessed factors did not demonstrate potential utility in predicting psychological distress, including gestational age, overnight admission, time taken for diagnosis, pre-existing children and the diagnosis itself (miscarriage vs ectopic vs other) (AUCs≤0.54; R 2 ≤0.9%)., Conclusions: Women with a history of mental health problems, or those with previous losses, may be at higher risk of psychological illness 1 month after pregnancy loss. However, prognostic ability was poor overall. All women should be considered at risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: 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., Material and 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., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: 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)., Design: Secondary analysis of a prospective cohort study., Setting: Eight UK early pregnancy assessment units., Population: Women presenting with a PUL and BhCG >25 IU/l., Methods: 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., Main Outcome Measures: Discrimination, calibration and clinical utility (decision curve analysis) for predicting EP., Results: 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., Conclusions: 2ST and M6P performed best for prediction and triage in PUL., Tweetable Abstract: The M6 model, as part of a two-step triage strategy, is the best approach to characterise and triage PULs., (© 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objectives: To assess if there is any association between hyperemesis gravidarum (HG), psychological morbidity and infant bonding and to quantify any psychosocial consequences of HG., Design: Two-point prospective case-control, multicentre survey study with antenatal and postnatal data collection., Setting: Three London hospitals., Participants: Pregnant women at ≤12 completed weeks gestation recruited consecutively over 2 years. Women with HG were recruited at the time of admission; controls recruited from a low risk antenatal clinic. 106 women were recruited to the case group and 108 to the control. Response rates at antenatal data collection were 87% and 85% in the case and control groups, respectively. Postnatally, the response rate was 90% in both groups., Primary and Secondary Outcome Measures: Primary outcomes were psychological morbidity in the antenatal and postnatal periods, infant bonding in the postnatal period and psychosocial implications of HG. Secondary outcomes were the effects of severity and longevity of HG and assessment of correlation between Edinburgh Postnatal Depression Scale scores and maternal-to-infant bonding scores., Results: Antenatally, 49% of cases had probable depression compared with 6% of controls (OR 14.4 (5.29 to 39.44)). Postnatally, 29% of cases had probable depression versus 7% of controls (OR 5.2 (1.65 to 17.21)). There was no direct association between HG and infant bonding. 53% of women in the HG group reported needing four or more weeks of sick leave compared with 2% in the control group (OR 60.5 (95% CI 8.4 to 2535.6))., Conclusions: Long-lasting psychological morbidity associated with HG was evident. Significantly more women in the case group sought help for mental health symptoms in the antenatal period, however very few were diagnosed with or treated for depression in pregnancy or referred to specialist perinatal mental health services. HG did not directly affect infant bonding. Women in the case group required long periods off work, highlighting the socioeconomic impact of HG., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Early pregnancy losses are common, but their psychologic sequelae are often overlooked. Previous studies have established links between miscarriage and early symptoms of anxiety and depression. However, the incidence of posttraumatic stress symptoms and the psychologic response specifically to ectopic pregnancies have not been investigated., Objective: The purpose of this study was to investigate levels of posttraumatic stress, depression, and anxiety in women in the 9 months after early pregnancy loss, with a focus on miscarriage and ectopic pregnancy. Morbidity at 1 month was compared with a control group in healthy pregnancy., Study Design: This was a prospective cohort study. Consecutive women were recruited from the early pregnancy and antenatal clinics at 3 London hospitals and received emailed surveys that contained standardized psychologic assessments that included the Hospital Anxiety and Depression Scale and Posttraumatic stress Diagnostic Scale, at 1, 3, and 9 months after loss. Control subjects were assessed after a dating scan. We assessed the proportion of participants who met the screening criteria for posttraumatic stress and moderate/severe anxiety or depression. We used logistic regression to calculate adjusted odds ratios., Results: Seven hundred thirty-seven of 1098 women (67%) with early pregnancy loss (including 537 miscarriages and 116 ectopic pregnancies) and 171 of 187 control subjects (91%) agreed to participate. Four hundred ninety-two of the women with losses (67%) completed the Hospital Anxiety and Depression Scale after 1 month; 426 women (58%) completed it after 3 months, and 338 women (46%) completed it after 9 months. Eighty-seven control subjects (51%) participated. Criteria for posttraumatic stress were met in 29% of women with early pregnancy loss after 1 month and in 18% after 9 months (odds ratio per month, 0.80; 95% confidence interval, 0.72-0.89). Moderate/severe anxiety was reported in 24% after 1 month and in 17% after 9 months (odds ratio per month, 0.69; 95% confidence interval, 0.50-0.94). Moderate/severe depression was reported in 11% of the women after 1 month and 6% of the women after 9 months (odds ratio per month, 0.87; 95% confidence interval, 0.53-1.44). After miscarriage, proportions after 9 months were 16% for posttraumatic stress, 17% for anxiety, and 5% for depression. Corresponding figures after ectopic pregnancy were 21%, 23%, and 11%, respectively. In contrast, among control women with viable pregnancies, 13% reported moderate-to-severe anxiety (odds ratio loss at 1 month vs controls: 2.14; 95% confidence interval, 1.14-4.36), and 2% reported moderate-to-severe depression (odds ratio loss at 1 month vs control subjects: 3.88; 95% confidence interval, 1.27-19.2)., Conclusion: Women experience high levels of posttraumatic stress, anxiety, and depression after early pregnancy loss. Distress declines over time but remains at clinically important levels at 9 months., (Copyright © 2019. Published by Elsevier Inc.)

Background: Early pregnancy loss (EPL) is a common event, with scope for long-term personal and societal impact. There are three decades worth of published evidence of profound psychological sequelae in a significant proportion of women. However, the wide variety of outcomes, screening instruments, assessment timings and geographical locations makes it challenging to form a coherent picture of the morbidity within the whole group and its subgroups., Objective and Rationale: This review aims to investigate three questions. (1) What is the evidence for depression, anxiety and post-traumatic stress disorder (PTSD) following a miscarriage or an ectopic pregnancy in women and/or their partners? (2) What is the intensity and duration of these conditions, and how do they compare to those without losses? (3) Which patients have been found to be at highest risk of psychopathology? Answers to these questions are salient not only in day-to-day clinical interactions with those experiencing EPL, whose psychological needs may not be prioritized, but should also form the basis for tailoring healthcare policy in terms of screening for and treating the associated psychological morbidity., Search Methods: The following databases were searched, from the start of each database up to July 2017: MEDLINE (Ovid interface, 1948 onwards), Embase classic + Embase (Ovid interface, 1947 onwards), and PsychINFO (Ovid interface, 1806 onwards). Search strategies were developed using medical subject headings (MeSH). The concepts of psychological morbidity (anxiety, depression or PTSD) and pregnancy loss (miscarriage or ectopic pregnancy) were first expanded with the Boolean operator 'or', then linked together using 'and'. Included studies were of prospective cohort design, including women or men following EPL (with the majority to have experienced losses before 24 weeks gestation), and reporting standardized psychometric measures for anxiety, depression and post-traumatic stress disorder. The timing of follow-up had to be specified and standardized across participants. Manuscript quality and risk of bias was assessed using the Newcastle-Ottawa Scale., Outcomes: We found evidence of significant depression and anxiety in the first month following EPL in women. Partners were also shown to display depression and anxiety, albeit to a generally lower level. There is also evidence of post-traumatic stress symptoms relating to the EPL in three studies., Wider Implications: In view of their high frequency, EPLs can significantly contribute to the overall burden of psychopathology within a population. Recognition of this impact is important, so that severely affected individuals may be screened and treated appropriately. Further research to establish risk factors to promptly identify and treat these patients, and to optimize their management, is crucial.

Objective: To determine whether ambulatory (outpatient (OP)) treatment of severe nausea and vomiting of pregnancy (NVP) is as effective as inpatient (IP) care., Design: Non-blinded randomised control trial (RCT) with patient preference arm., Setting: Two multicentre teaching hospitals in London., Participants: Women less than 20 weeks' pregnant with severe NVP and associated ketonuria (>1+)., Methods: Women who agreed to the RCT were randomised via web-based application to either ambulatory or IP treatment. Women who declined randomisation underwent the treatment of their choice in the patient preference trial (PPT) arm. Treatment protocols, data collection and follow-up were the same for all participants., Main Outcome Measures: Primary outcome was reduction in Pregnancy Unique Quantification of Emesis (PUQE) score 48 hours after starting treatment. Secondary outcome measures were duration of treatment, improvement in symptom scores and ketonuria at 48 hours, reattendances within 7 days of discharge and comparison of symptoms at 7 days postdischarge., Results: 152/174 eligible women agreed to participate with 77/152 (51%) recruited to the RCT and 75/152 (49%) to the PPT.Patients were initially compared in four groups (randomised IP, randomised OP, non-randomised IP and non-randomised OP). Comprehensive cohort analysis of participants in the randomised group (RCT) and non-randomised group (PPT) did not demonstrate any differences in patient demographics or baseline clinical characteristics. Pooled analysis of IP versus OP groups showed no difference in reduction in PUQE score at 48 hours (p=0.86). There was no difference in change in eating score (p=0.69), drinking score (p=0.77), well-being rating (p=0.64) or reduction in ketonuria (p=0.47) at 48 hours, with no difference in duration of index treatment episode (p=0.83) or reattendances within 7 days (p=0.52)., Conclusions: Ambulatory management is an effective direct alternative to IP management of severe NVP. The trial also demonstrated that many women requiring treatment for severe NVP have strong preferences regarding treatment setting, which may need to be considered by care providers, especially given the psychological impact of severe NVP., Trial Registration Number: http://www.isrctn.com/ISRCTN24659467 (March 2014)., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Psychological illness occurring in association with hyperemesis gravidarum (HG) has been widely reported., Objective: To determine if there is a higher incidence of psychological morbidity in women with HG compared with women without significant nausea and vomiting in pregnancy., Search Strategy: PubMed, MEDLINE, Embase and PsychINFO were searched up to September 2015., Selection Criteria: Articles referring to psychological morbidity in relation to HG. For meta-analysis case-control studies using numerical scales to compare psychological symptoms., Data Collection and Analysis: Articles were independently assessed for inclusion by two reviewers and methodology was appraised using the Newcastle Ottawa Scale. Comparison was made using the standard mean difference (SMD) in symptom scale scores., Main Results: In all, 59 articles were included in the systematic review, 12 of these were used in the meta-analysis. Meta-analysis of depression scale scores demonstrated a very large effect with statistically significantly higher depression scale scores in women with HG (SMD 1.22; 95% CI 0.80-1.64; P ≤ 0.01) compared with controls. Meta-analysis of anxiety scores demonstrated a large effect with statistically significantly higher anxiety disorder scale scores in women with HG (SMD 0.86; 95% CI 0.53-1.19; P ≤ 0.01). In both analyses significant heterogeneity was identified (depression and HG I 2  = 94%, P ≤ 0.01; anxiety and HG I 2  = 84%, P = 0.02)., Conclusions: Our systematic review and meta-analysis have shown a significantly increased frequency of depression and anxiety in women with HG. The findings should prompt service development for women with HG that includes provision of psychological care and support., Tweetable Abstract: Meta-analysis demonstrates an increase in #PsychologicalMorbidity in women with #HyperemesisGravidarum., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Objectives: This is a pilot study to investigate the type and severity of emotional distress in women after early pregnancy loss (EPL), compared with a control group with ongoing pregnancies. The secondary aim was to assess whether miscarriage or ectopic pregnancy impacted differently on the type and severity of psychological morbidity., Design: This was a prospective survey study. Consecutive women were recruited between January 2012 and July 2013. We emailed women a link to a survey 1, 3 and 9 months after a diagnosis of EPL, and 1 month after the diagnosis of a viable ongoing pregnancy., Setting: The Early Pregnancy Assessment Unit (EPAU) of a central London teaching hospital., Participants: We recruited 186 women. 128 had a diagnosis of EPL, and 58 of ongoing pregnancies. 11 withdrew consent, and 11 provided an illegible or invalid email address., Main Outcome Measures: Post-traumatic stress disorder (PTSD) was measured using the Post-traumatic Diagnostic Scale (PDS), and anxiety and depression using the Hospital Anxiety and Depression Scale (HADS)., Results: Response rates were 69/114 at 1 month and 44/68 at 3 months in the EPL group, and 20/50 in controls. Psychological morbidity was higher in the EPL group with 28% meeting the criteria for probable PTSD, 32% for anxiety and 16% for depression at 1 month and 38%, 20% and 5%, respectively, at 3 months. In the control group, no women met criteria for PTSD and 10% met criteria for anxiety and depression. There was little difference in type or severity of distress following ectopic pregnancy or miscarriage., Conclusions: We have shown a large number of women having experienced a miscarriage or ectopic pregnancy fulfil the diagnostic criteria for probable PTSD. Many suffer from moderate-to-severe anxiety, and a lesser number depression. Psychological morbidity, and in particular PTSD symptoms, persists at least 3 months following pregnancy loss., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)