The Role of Pancreatic Stone Protein (PSP) as a Biomarker of Pregnancy-Related Diseases.

Background: Pancreatic stone protein (PSP) is a biochemical serum marker that contains levels that are elevated in various inflammatory and infectious diseases. The role of PSP in the diagnosis of these diseases seems to be more important compared to clinically established biochemical serum markers in discriminating the severity of the same diseases. Standard values for PSP in pregnant women in relation to gestational age have been reported recently. Additionally, increased PSP levels have been observed to be associated with renal dysfunction in pregnant women. The aim of this study is to evaluate the diagnostic role of PSP in pregnancy-related diseases, such as pre-eclampsia (PE), hemolysis-elevated liver enzymes, and low platelet (HELLP) syndrome. In addition, the study aims to assess its diagnostic role in inflammation-triggered diseases as preterm premature rupture of membranes (PPROM) or COVID-19-positive pregnant women. Materials and Methods: In this single-centred prospective study performed at a tertiary university hospital between 2013 and 2021, we included 152 pregnant women who were diagnosed with either PE, HELLP syndrome, or PPROM. In December 2020, in the context of the COVID-19 pandemic, the Independent Ethics Committee (IEC) approved an amendment to the study protocol. Depending on the underlying disease, single or serial-serum PSP measurements were assessed. These PSP values were compared to PSP levels of women with normal pregnancies. Results: Pregnant women diagnosed with pre-eclampsia or HELLP syndrome had significantly increased PSP values (mean 9.8 ng/mL, SD 2.6) compared to healthy singleton pregnant women (mean 7.9 ng/mL, SD 2.6, p ≤ 0.001). There was no difference in serum PSP in pregnant women with PPROM compared to women with uncomplicated singleton pregnancies (mean in PPROM: 7.9 ng/mL; SD 2.9 versus mean in healthy pregnancies: 7.9 ng/mL; SD 2.6, p = 0.98). Furthermore, no difference in the PSP values in women with or without intra-amniotic infection was observed (infection: mean 7.9 ng/mL; SD 2.8 versus no infection: mean 7.8 ng/mL; SD 3, p = 0.85). The mean value of PSP in COVID-19-infected women during pregnancy (8.5 ng/mL, SD 2.3) was comparable to healthy singleton pregnancies (mean 7.9 ng/mL, SD 2.6), p = 0.24. Conclusions: The novel serum biomarker PSP is significantly upregulated in pregnant women with pre-eclampsia and HELLP syndrome. Our observations call for the further evaluation of PSP in randomized controlled clinical trials to demonstrate the actual role of PSP in pregnancy-related diseases and whether it may provide new approaches for the management and discrimination of the severity of these gestational conditions.

Success Rate and Long-Term Effects of Embolization of Pelvic Arteries for the Treatment of Postpartum Hemorrhage.

Introduction: Postpartum hemorrhage (PPH) is the leading cause of peripartal maternal mortality and accounts for 25% of all maternal deaths worldwide. The most common reasons of PPH are uterine atony, retained placenta, or placenta accreta spectrum. Treatment of PPH depends on the etiology and corresponds to a stepwise approach, which follows the German, Austrian and Swiss guideline for the diagnosis and therapy of PPH in Switzerland. In severe ongoing PPH, hysterectomy has been the ultima ratio for many decades. Nowadays, interventional embolization of the pelvic arteries (PAE) has become a popular alternative. Besides being a highly effective minimally invasive method, PAE avoids hysterectomy with consecutively reduced morbidity and mortality. However, data on the long-term effects of PAE on fertility and menstrual cycle are scarce. Methods: We performed a monocentric study consisting of a retro- and a prospective part including all women who had undergone a PAE between 2012 and 2016 at University Hospital Zurich. Descriptive characteristics of patients and efficacy of PAE defined as cessation of bleeding were analyzed retrospectively. In the prospective part, all patients were contacted for a follow-up questionnaire regarding menstruation and fertility after embolization. Results: Twenty patients with PAE were evaluated. Our data showed a success rate of PAE in 95% of patients with PPH; only 1 patient needed a second, then successful, PAE. No patient needed a hysterectomy or any other surgical intervention. In our study, an association between mode of delivery and identified etiology of PPH is observed. After spontaneous delivery (n = 6), the main reason of severe PPH was retained placenta (n = 4), while after cesarean section (n = 14), uterine atony was identified in most cases (n = 8). Regarding menstruation after embolization, all women reported regular menstruation after the breastfeeding period (100%). The majority reported a regular pattern with a shorter or similar duration (73%) and lower or similar intensity (64%). Dysmenorrhea decreased in 67% of patients. Four patients planned another pregnancy, of whom only one had become pregnant with assisted reproductive technology and ended up in a miscarriage. Discussion: Our study confirms the efficacy of PAE in PPH, thus obviating complex surgical interventions and associated morbidity. The success of PAE does not depend on the primary cause of PPH. Our results may encourage the prompt decision to perform PAE in the management of severe PPH in case of failure of conservative management and help physicians in the post-interventional counseling regarding menstruation patterns and fertility.

Serum Pancreatic Stone Protein Reference Values in Healthy Pregnant Women: A Prospective Cohort Study.

BACKGROUND: In non-pregnant populations, pancreatic stone protein (PSP) has been reported to have a higher diagnostic performance for identifying severe inflammatory and infectious disease than other established biomarkers. OBJECTIVE: To generate reference values for serum PSP in pregnancy and compare them to the values of the general healthy population. DESIGN: A prospective cohort study. SETTING: A single center. POPULATION: Healthy women with singleton and multiple pregnancies. METHODS: This is a prospective single-center cohort study. Between 2013 and 2021, samples of 5 mL peripheral blood were drawn from 440 healthy pregnant women. Therein, 393 cases were singletons and 47 were multiple pregnancies. Serum PSP levels were measured by specific enzyme-linked immunosorbent assay. The main outcome measures were serum PSP level (ng/mL) reference values in healthy pregnant women. RESULTS: The mean PSP reference values in women with singleton pregnancies were 7.9 ± 2.6 ng/mL (95% CI; 2.69-13.03 ng/mL). The PSP values in women with multiple pregnancies (9.17 ± 3.06 ng/mL (95% CI; 3.05-15.28 ng/mL)) were significantly higher (p = 0.001). The PSP values in the first trimester (6.94 ± 2.53 ng/mL) were lower compared to the second (7.42 ± 2.21 ng/mL) and third trimesters (8.33 ± 2.68 ng/mL, p = 0.0001). Subgroup analyses in singletons revealed no correlations between PSP values, maternal characteristics, and pre-existing medical conditions. CONCLUSION: The PSP values in healthy pregnant women (4-12 ng/mL) were in the range of the reference values of the general healthy population (8-16 ng/mL). This insight blazes a trail for further clinical studies on the use of PSP as a potential novel biomarker for the early detection of pregnancy-related diseases such as chorioamnionitis.

First trimester abortion protocols by facility type in Switzerland and potential barriers to accessing the service.

Simplified first-trimester abortion protocols are well established. However, data on the use of medical or surgical abortion protocols across Switzerland is lacking. We report protocol characteristics in abortion care for two different facility types, hospital vs private practices (office-based) in Switzerland. Furthermore, we investigate an association between protocol characteristics and the likelihood of following through with the abortion at the same facility. We also report abortion outcomes of an office-based cohort where doctors use simplified abortion protocols. This study consists of two parts. (i) Between April and July, 2019, we collected data regarding medical and surgical abortion protocols of institutions offering abortions, in a nationwide survey. We assessed whether the proportion of patients who followed through with the abortion (primary outcome) after first appointment was associated with predefined protocol characteristics, considered to complicate access to abortion services, using generalised estimating equations. (ii) We analysed abortion outcomes of six selected office-based facilities from January, 2008, to December, 2018, using simplified abortion protocols in accordance with the Worlds Health Organisation (WHO) guidelines. (i) We included a total of 39 institutions. Hospitals showed more protocol-based barriers to abortion access compared with office-based facilities. The odds of undergoing an abortion after the first appointment were increased using protocols with minimal barriers. Overall, office-based facilities applied higher gestational age limits, required fewer appointments, and administered mifepristone more often after the first visit than did hospitals. (ii) We included a total of 5274 patients with an incidence of complications requiring surgery of 2.5% in line with rates reported in published literature. Only a few hospitals provide abortion care with easy access to medical and surgical abortion, whereas most office-based facilities do. Access to abortion services is generally crucial, and should be provided in a single visit whenever clinically permissible.

The Impact of Prepartum Platelet Count on Postpartum Blood Loss and Its Association with Coagulation Factor XIII Activity.

Background: Postpartum hemorrhage is a leading cause of maternal morbidity and mortality worldwide. Contradictory information exists regarding the relevance of prepartum platelet count on postpartum hemorrhage. We have shown prepartum coagulation factor XIII to be associated with postpartum blood loss; however, little is known about the association of platelet count with factor XIII activity. Our objectives were, first, to evaluate the impact of prepartum platelet count on measured postpartum blood loss in the context of prepartum measurements of coagulation factors I, II, and XIII and, second, to evaluate the association of platelet count with coagulation factor XIII, both pre- and postpartum. Material and Methods: This is a secondary analysis of a prospective cohort study (PPH 1,300 study) which analyzed the impact of prepartum blood coagulation factors on postpartum blood loss in 1,300 women. Blood loss was quantified using a validated technique. The impact of prepartum platelet count on measured blood loss was assessed by continuous outcome logistic regression; the association of platelet count with factor XIII activity by Spearman rank correlation. Results: Prepartum platelet count was significantly associated with measured postpartum blood loss: every one unit (G/L) increase in prepartum thrombocytes was associated with an odds ratio of 1.002 (95% confidence interval, 1.001-1.004, p = 0.005) to keep blood loss below any given cut-off level. This means that the probability of postpartum hemorrhage decreases with increasing prepartum platelet levels. Moreover, a significant association of platelet count with factor XIII activity was shown (Spearman rank correlation coefficient for prepartum values 0.228, p < 0.001, and for postpartum values 0.293, p < 0.001). Discussion/Conclusion: The significant association of prepartum platelet count and postpartum blood loss as well as the association of platelet count with blood coagulation factor XIII activity support the likely role of platelets in preventing postpartum hemorrhage and support the new guidelines for the treatment of postpartum hemorrhage in Germany, Austria, and Switzerland, which calls for optimizing platelet counts peripartally in case of postpartum hemorrhage. A possible effect of platelets on the level of circulating factor XIII cannot be ruled out and should prompt further investigation.

Wearable sensors for prediction of intraamniotic infection in women with preterm premature rupture of membranes: a prospective proof of principle study.

PURPOSE: To evaluate the use of wearable sensors for prediction of intraamniotic infection in pregnant women with PPROM. MATERIALS AND METHODS: In a prospective proof of principle study, we included 50 patients diagnosed with PPROM at the University Hospital Zurich between November 2017 and May 2020. Patients were instructed to wear a bracelet during the night, which measures physiological parameters including wrist skin temperature, heart rate, heart rate variability, and breathing rate. A two-way repeated measures ANOVA was performed to evaluate the difference over time of both the wearable device measured parameters and standard clinical monitoring values, such as body temperature, pulse, leucocytes, and C-reactive protein, between women with and without intraamniotic infection. RESULTS: Altogether, 23 patients (46%) were diagnosed with intraamniotic infection. Regarding the physiological parameters measured with the bracelet, we observed a significant difference in breathing rate (19 vs 16 per min, P < .01) and heart rate (72 vs 67 beats per min, P = .03) in women with intraamniotic infection compared to those without during the 3 days prior to birth. In parallel to these changes standard clinical monitoring values were significantly different in the intraamniotic infection group compared to women without infection in the 3 days preceding birth. CONCLUSION: Our results suggest that wearable sensors are a promising, noninvasive, patient friendly approach to support the early detection of intraamniotic infection in women with PPROM. However, confirmation of our findings in larger studies is required before implementing this technique in standard clinical management.

Perinatal death by bile acid levels in intrahepatic cholestasis of pregnancy: a systematic review.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterized by the elevation of total bile acids (TBAs). The primary concern in women with ICP is the increased risk of stillbirth. ICP is generally considered as "mild" when TBA levels range from 10 to 39 µmol/L and "severe" with levels greater than 40 µmol/L, although levels of TBA ≥100 µmol/L have been also considered as a further threshold of severity. OBJECTIVE: To quantify the association between different severities of ICP (TBA 10-39, 40-99, and ≥100 µmol/L) and perinatal death. DATA SOURCES: Medline, Embase, Scopus, Web of Sciences, and ClinicalTrial.gov were searched from the inception of each database to February 2019. METHODS OF STUDY SELECTION: Randomized, cohort, case-control, or case series studies reporting maternal and perinatal outcomes on women with ICP by the three prespecified TBA levels (10-39, 40-99, and ≥100 µmol/L) were included. We excluded multiple gestations and trials which included an intervention. The analysis was performed with Pearson chi-square and Fisher's exact test as appropriate. Continuous outcomes were compared using metaregression with inverse variance weighting using reported sample sizes and standard deviations. Pairwise comparisons used a Bonferroni correction to control for multiple testing. TABULATION, INTEGRATION, AND RESULTS: Six articles including 1280 singleton pregnancies affected by ICP were included in the systematic review. Out of the 1280 singleton pregnancies affected by ICP included, 118 had ICP with TBA ≥100 µmol/L. Perinatal death was more common in women with TBA ≥100 µmol/L (0.4% for TBA 10-39 µmol/L versus 0.3% for TBA 40-99 µmol/L versus 6.8% for TBA ≥ 100 µmol/L, p < .0001). Of the 8 perinatal deaths in the TBA ≥100 µmol/L group, 3 occurred ≥34 weeks. TBA ≥100 µmol/L increased the risk of spontaneous preterm birth (PTB) (5.4% versus 8.6% versus 18.2% respectively, p < .0001) and iatrogenic PTB (10.8% versus 21.6% versus 35.8% respectively, p<.0001) as well as meconium-stained amniotic fluid (9.0% versus 18.4% versus 31.6% respectively, p < .0001). CONCLUSIONS: Maternal TBA ≥100 µmol/L is associated with a 6.8% incidence of perinatal death, most of which (5.9% overall) are stillbirths, while TBA <100 µmol/L are associated with an incidence of perinatal death of 0.3%. It may be reasonable to consider late preterm delivery (at about 35-36 weeks) in women with TBA ≥100 µmol/L.

Adverse effect of delayed pushing on postpartum blood loss in nulliparous women with epidural analgesia.

OBJECTIVE: To test for an association between blood loss and time until pushing (TUP) after full cervical dilation in nulliparous women with epidural analgesia. METHODS: A prospective cohort study was performed at the University Hospital of Zurich between October 2015 and November 2016. Included were 228 nulliparous women with singleton pregnancy, planned vaginal delivery after 36 completed weeks of gestation, epidural analgesia, and guided active pushing. TUP was defined as the interval between full cervical dilation and initiation of active pushing. The primary outcome measure was blood loss, assessed by the postpartum decrease in hemoglobin (ΔHb), estimated blood loss, and rate of ΔHb ≥30 g/L. Associations between TUP and primary and secondary maternal and neonatal delivery outcomes were assessed using Spearman correlation, Mann-Whitney U test, Kruskal-Wallis test, or Fisher exact test, as appropriate. RESULTS: Longer TUP correlated significantly with increased ΔHb (ρ=0.142, P=0.033) and higher rates of ΔHb ≥30 g/l (P=0.002). Composite adverse maternal and neonatal outcomes were unaffected. CONCLUSION: On the grounds of increased maternal blood loss, and in contrast to the current International Federation of Gynecology and Obstetrics (FIGO) guideline, delayed active pushing is not recommended in nulliparous women with epidural analgesia.

The impact of prepartum factor XIII activity on postpartum blood loss.

BACKGROUND: Postpartum hemorrhage (PPH), a major cause of maternal mortality, has several known risk factors but frequently occurs unexpectedly. PPH incidence and related maternal morbidity and mortality are rising worldwide. OBJECTIVE: To evaluate the impact of defined prepartum blood coagulation parameters on postpartum blood loss. METHODS: This single-center, prospective cohort study analyzed prepartum activities of coagulation factors II and XIII and fibrinogen levels in 1300 women. Blood samples were obtained at labor onset and analyzed only after the last patient had delivered, to prevent a potential treatment bias. Blood loss was quantified using a validated technique. The influence of coagulation factors on measured blood loss was assessed by continuous outcome logistic regression. RESULTS: Prepartum factor XIII activity strongly influenced measured blood loss: every one unit (%) increase in prepartum factor XIII was associated with an odds ratio of 1.011 (95% confidence interval, 1.006-1.015; P < .001) to keep blood loss below any given cut-off level. For illustration, this suggests that a 30% increase in factor XIII activity increases the odds of not suffering PPH (defined as blood loss ≥500 mL) by 38.9%. This effect remained significant after stratification for the delivery mode, when correcting for other risk factors, and was independent of the statistical model used. Factor II but not fibrinogen had a partially comparable, but much less pronounced, effect. CONCLUSION: In the largest population analyzed for the influence of prepartum coagulation factors on PPH to date, prepartum factor XIII activity had a strong impact on postpartum blood loss across every statistical model and clinical subgroup. Our hypothesis that early replenishment of factor XIII levels might constitute a new tool in the prevention and effective early treatment of PPH should be evaluated in future trials.

Induction of labor and postpartum blood loss.

BACKGROUND: To analyze blood loss after delivery in women with induction of labor compared to women with spontaneous onset of labor. METHODS: In this secondary analysis of a prospective cohort study investigating postpartum hemorrhage, 965 deliveries were analyzed including 380 women with induction of labor (39%) between 2015 and 2016. Primary outcome parameters were rate of postpartum hemorrhage, estimated blood loss and post-partum decrease in hemoglobin. RESULTS: Rates of postpartum hemorrhage and estimated blood loss were not significantly different in women with induction of labor. Women with induction of labor had a significantly reduced decrease in hemoglobin after delivery. In the multivariate linear regression analysis, induction of labor remained associated with reduced decrease in hemoglobin. Secondary maternal and neonatal outcomes were unaffected. CONCLUSIONS: Induction of labor is not associated with increased blood loss after delivery and should not be regarded as a risk factor for postpartum hemorrhage.

Validation of a quantitative system for real-time measurement of postpartum blood loss.

PURPOSE: Reliable real-time estimation of blood loss is crucial for the prompt management of postpartum hemorrhage (PPH), which is one of the major obstetric complications worldwide. Our study aims at the validation of feasibility and precision of measured blood loss (MBL) with a quantitative real-time measurement system during (1) vaginal delivery and (2) cesarean section by comparison with a hemoglobin-based formula for blood loss as an objective control. This is the first study to include a reasonable number of patients in an everyday clinical setting. METHODS: 921 patients were prospectively enrolled into this study (vaginal delivery: n = 461, cesarean delivery: n = 460) at a tertiary care hospital in Switzerland. Blood loss was measured by quantitative fluid collection bags. "Calculated blood loss" (CBL) was determined by modified Brecher`s formula based on the drop of hemoglobin after delivery. MBL based on our measurement system was compared to CBL by correlation analysis and stratified by the mode of delivery. RESULTS: During vaginal delivery, MBL as determined by our quantitative measurement system highly correlated with CBL (p < 0.001, r = 0.683). This was also true for patients with cesarean deliveries (p < 0.001, r = 0.402), however, in a less linear amount. In women with cesarean deliveries, objectively low blood loss tended to be rather overestimated, while objectively high blood loss was more likely underestimated. CONCLUSIONS: The technique of real-time measurement of postpartum blood loss after vaginal delivery as presented in this study is practicable, reliable and strongly correlated with the actual blood loss and, therefore, poses an actual improvement in the management of PPH.

Erroneously Suspected Ovarian Cancer in a 38-Year-Old Woman with Pelvic Inflammatory Disease and Chlamydia.

Chlamydia trachomatis is the most common bacterial cause of sexually transmitted disease and can cause pelvic inflammatory disease (PID), leading to severe outcomes such as ectopic pregnancy, infertility, or pelvic pain. We report a case of a 38-year-old patient with abdominal pain and dyspareunia. Clinical examination revealed diffuse abdominal tenderness. Vaginal and abdominal sonography showed substantial ascites and CA-125 level was elevated. Therefore, the attendant physician performed an abdominal CT scan for further diagnosis. Radiographically diffuse peritoneal enhancement, consistent with peritoneal carcinomatosis, 4-quadrant ascites, and slightly enlarged ovaries with solid and cystic structures were diagnosed, leading to the suspicion of ovarian cancer. In addition, the results of the cervical smear PCR for chlamydia were positive. Due to the positive chlamydia result, the suspicious CT scan, and the young age, we decided to perform a diagnostic laparoscopy as a first step. Intraoperatively, the ovaries were of normal aspect without any cancerous lesions. However, the ascites and the yellow-reddish jelly-like deposits were consistent with acute PID. Thus, chlamydia infection may simulate the presentation of ovarian cancer. Therefore, especially in young patients, we recommend careful scrutiny of every diagnosis of ovarian cancer even if its presentation seems to be typical.