Is Icatibant Safe for the Treatment of Hereditary Angioedema During Pregnancy?

PURPOSE OF REVIEW: Hereditary angioedema (HAE) is a disorder affecting bradykinin regulation presenting as recurrent cutaneous or mucosal swelling. Treatment options include plasma-derived or human-recombinant C1-inhibitor, icatibant, or ecallantide. Due to the lack of knowledge and experience on the topic, the treatment of choice in pregnancy is plasma-derived C1-inhibitor, and reporting any new experience is recommended. This review presents current guidelines for HAE treatment with a focus on pregnancy and reviews all experience with icatibant use during pregnancy. RECENT FINDINGS: Our experience of treating a pregnant nC1-INH HAE patient with icatibant is presented, with no adverse effects or abnormalities, to add to the growing knowledge of icatibant use during pregnancy. Considering the limited number of attacks that our patient usually experiences, which continued at more or less the same frequency during pregnancy, we feel icatibant to be a safe choice for on-demand HAE treatment during pregnancy for such cases.

The contribution of twins conceived by in vitro fertilization to preterm birth rate: observations from a quarter of century.

Objective Little information exists related to the contribution of assisted reproductive technology (ART) twins to the preterm and very preterm birth rate. We sought to examine this contribution over a period of more than two decades in a tertiary perinatal center. Methods We identified all preterm births from 1993 to 2017, born at <37 or <32 weeks' gestation, by mode of conception [in vitro fertilization (IVF) vs. non-IVF pregnancies]. We generated trend lines of the annual change of the dependent variable (% preterm birth). Results We evaluated 74,299 births, including 3934 (5.3%) preterm births at <37 and 826 (1.1%) at <32 weeks' gestation. In this period, 1019 (1.4%) twin pairs were born including 475 (46.6%) and 80 (7.8%) at <37 and <32 weeks, respectively. There were 213 (5.4%) IVF pregnancies among the preterm births at <37 weeks, including 88 (41.3%) twins. Fifteen (1.8%) births of all IVF gestations were at <32 weeks, and all were twins. Whereas the annual rate of spontaneous twins did not change, a significant increase over time exists for IVF twins (P < 0.05, R2 = 0.6). We demonstrated an increase in IVF twin births at <37 weeks but not for spontaneously conceived twins. Whereas the twin birth rate at <32 weeks did not change over time, all preterm births at <32 weeks following IVF were twins. Conclusions The risk of twins after ART increasingly contributes to preterm births at <37 weeks and ART twins are at significant risk for preterm births at <32 weeks.

Factor X Deficiency Management for Elective Cesarean Delivery in a Pregnant Patient.

BACKGROUND Congenital factor X deficiency is a rare inherited coagulopathy. Pregnancies in women with this disorder are often associated with adverse outcomes, including miscarriage, premature labor, and hemorrhage during pregnancy and in the peripartum period. The literature on this disorder is sparse and shows a limited number of successful pregnancies in women with factor X deficiency. CASE REPORT In this report, we present the case of a successful pregnancy and term delivery by elective cesarean section in a 39-year-old primigravida with congenital factor X deficiency. Medical management followed the recommendations of an interdisciplinary team comprising specialists in obstetrics, anesthesia, transfusion medicine, hematology, and neonatology. This high-risk pregnancy was successfully brought to term, and a healthy male neonate was delivered by elective cesarean section at 39 weeks' gestation. The patient's factor X deficiency (0.19 kIU/L) was treated using 4 units of solvent-detergent-treated fresh frozen plasma (SD-FFP) 1 h before the cesarean section, leading to hemostatic levels of factor X and an uneventful intraoperative course. Postoperatively, the patient's factor X levels were controlled daily and corrected using SD-FFP as needed, with no clinically significant blood loss. CONCLUSIONS SD-FFP can be used to manage congenital factor X deficiency in the peripartum period and maintain perioperative blood loss within normal limits.

Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. OBJECTIVES: To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. SELECTION CRITERIA: Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. DATA COLLECTION AND ANALYSIS: We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. MAIN RESULTS: Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 µmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. AUTHORS' CONCLUSIONS: The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.

Prenatal selenium status, neonatal cerebellum measures and child neurodevelopment at the age of 18 months.

OBJECTIVES: The aim of this study was to evaluate the association of maternal blood selenium (Se) levels and cord blood Se levels with neonatal cerebellum measures and child neurodevelopment at the age of 18 months. Moreover, to investigate whether the neonatal cerebellum measures could be used as a potential biomarker for selenium homeostasis during pregnancy. STUDY GROUP AND METHODS: The study population consisted of 205 mother-child pairs from Croatian Mother and Child Cohort. Maternal blood and cord blood were obtained at delivery and selenium level was analyzed by Inductively Coupled Plasma Mass Spectrometry. Cranial ultrasonography examination was performed on 49 newborns - cerebellum length and width have been measured. Neurodevelopmental assessment of cognitive, language and motor skills were conducted on 154 children, using The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), at the age of 18 months. RESULTS: The mean levels of selenium in maternal blood and cord blood were 92.6 ng/g and 97.0 ng/g, respectively. Maternal blood selenium levels were moderately and negatively correlated (r = -0.372; p = 0.008) with cerebellum length, while cord blood selenium levels were positively correlated with cerebellum width (r = 0.613; p = 0.007) among female children group. Maternal blood selenium levels were weakly and positively correlated (r = 0.176; p = 0.029) with child's cognitive abilities. CONCLUSION: To the best of our knowledge, our study is the first one investigating the association between neonatal brain measures and selenium levels in mother-child pairs. Our results indicate that prenatal selenium intake correlated with cerebellum length and width measured by cranial ultrasonography. Hence, cerebellum may be used as a potential biomarker and a target "organ" for early detection of possible adverse effects of prenatal status to various micronutrients.

Effect of gender on growth-restricted fetuses born preterm.

Objective To assess the effect of fetal gender in small-for-gestational age (SGA) neonates with birth weight less than the fifth percentile by gestational age. Methods We compared male and female SGA neonates for maternal and neonatal outcomes in the following gestational age subgroups: at <32 + 6, 33 + 0-36 + 6 and at ≥37 + 0 weeks of gestation. Results We examined 159, 154 and 2363 SGA neonates born at <32 + 6, 33 + 0 to 36 + 6 and ≥37 weeks of pregnancy, respectively, whose birth weight was below the fifth percentile for gestational age and who met our inclusion criteria. Overall, there were no significant differences between the mothers of males and females, except that there were more males at term and the incidence of nulliparas was greater among the mothers of males. In terms of outcomes, males had a similar incidence of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) and admissions to intensive care. Interestingly, low Apgar scores were more common in preterm females born at 33-37 weeks and vice versa in births over 37 weeks. Conclusion Our data do not support an advantage of either gender in preterm birth of infants who are most likely growth restricted.

Liver Disease During Pregnancy: A Challenging Clinical Issue.

One of the least studied topics in the field of obstetrics is liver disease during pregnancy, which creates a challenge for both gynecologists and hepatologists. Approximately 3% of pregnant women are affected by some form of liver disease during pregnancy. Some of these conditions can be fatal for both the mother and child. In addition, 3 types of liver disease need to be differentiated during pregnancy. One type is liver disease directly related to pregnancy, which can occur at a specific time during pregnancy. Another type is liver disease not related to pregnancy, which can occur at any time, such as viral- or drug-induced hepatitis. Furthermore, pregnancy can occur in women with pre-existing liver disease. It is essential that the clinicians are familiar with this disorder so they can respond promptly and appropriately in all of these situations, especially when emergency delivery is needed and must not be postponed.

Crohn's disease in women.

This article provides an overview of the obstetric and gynecological manifestations of Crohn's disease (CD). High incidence of the new onset of the disease in young women in their reproductive years demands special concern from physicians involved in their treatment. Pregnant women with CD are considered high-risk patients, regardless of disease activity index, due to associated complications. Predominately described complications are premature birth, low birth weight, and congenital anomalies. To minimize the risk for adverse pregnancy/birth outcomes, it is recommended that remission be achieved before conception. Treatment of CD in pregnant women is similar to that among the nonpregnant population, and there is no valid reason to terminate it, since most of the drugs are proven to be safe. Women with CD who wish to conceive or are already pregnant need to be properly advised according to the newest guidelines on the subject, given by the European Crohn's and Colitis Organization. Gynecological manifestations are another special feature of CD. They are important in that they may facilitate early recognition of the underlying disease, which usually stays unrecognized for years before intestinal manifestation; in this way, the underlying manifestations are often mistreated.

Lamellar body count as a diagnostic test in predicting neonatal respiratory distress syndrome.

AIM: To determine the lamellar body count (LBC) cutoff value for fetal lung maturity and to evaluate the clinical usefulness of LBC in predicting the severity of neonatal respiratory distress syndrome (RDS). METHODS: A prospective study was conducted from 2002 until 2010. LBC was estimated in uncentrifugated amniotic fluid samples using Cell-Dyn 1800 analyzer. Amniotic fluid samples were obtained by amniocentesis or by puncturing embryonic membranes during cesarean section. The presence of mild, moderate, and severe RDS was assessed by neonatologist. RESULTS: A total of 313 patients with singleton pregnancies (24-41 weeks) were included in the study and 294 met the inclusion criteria. RDS was diagnosed in 28 neonates - mild in 8, moderate in 10, and severe in 10. In premature neonates (<37 gestational weeks), significant differences in LBC were only found between the subgroup without RDS and the group with moderate and the group with severe RDS (P<0.001). In all neonates, significant differences were found between neonates without RDS and neonates with RDS. Using LBC cutoff value of ≥20,000/µL, sensitivity, specificity, and positive and negative predictive values of LBC in determining mature fetal lungs were 96%, 88%, 45.6%, and 99.5%, respectively. CONCLUSION: This study suggests that LBC cutoff value of ≥20,000/µL can predict pulmonary maturity and reduce the risk of neonatal respiratory distress syndrome.

The influence of pre-eclampsia on fetal lung maturity.

OBJECTIVE: To use amniotic fluid (AF) lamellar body count (LBC) to assess the influence of pre-eclampsia and associated pathologic conditions on fetal lung maturity (FLM). METHODS: A prospective study was conducted to analyze 378 AF samples containing 5 mL of AF from 306 singleton pregnancies at 26-39 weeks. Stratified by gestational age groups, pregnancies were categorized as follows: pre-eclampsia (n=25); intrauterine growth restriction (IUGR) (n=74); pre-eclampsia and IUGR (n=63); and control (n=144). Amniotic fluid LBC in each group was estimated and medians were compared for defined gestational age periods. Statistical analyses were performed via non-parametric tests. RESULTS: Between 31 and 33 weeks, significantly lower median LBCs were found in the pre-eclampsia group than in the IUGR group (P=0.022) and in pregnancies with both entities (P=0.031). Between 34 and 36 weeks, there were significantly lower median LBCs in the pre-eclampsia and the pre-eclampsia/IUGR groups than in the IUGR group (P=0.026 and P=0.004, respectively), as well as in the pre-eclampsia/IUGR group compared with the control group (P=0.04). CONCLUSION: Significantly lower LBCs in pre-eclamptic pregnancies between 31 and 36 weeks of gestation indicate delayed FLM associated with pre-eclampsia.

Acute pancreatitis during pregnancy.

Acute pancreatitis in pregnancy is a rare condition estimated to occur in 1 per 1000 to 1 per 12,000 pregnancies. The most frequent etiology in pregnancy is biliary, followed by hyperlipidemia and/or alcohol abuse. Abdominal ultrasound and endoscopic ultrasound are ideal imaging techniques for diagnosing disease because they have no radiation risk. Computed tomography, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography should be used with caution. Treatment could be conservative or surgical, and standard algorithms are slightly modified in pregnant women. In the last decades the outcome of acute pancreatitis in pregnancy is much better, and perinatal mortality is less than 5%.

Molecular analysis in diagnostic procedure of hearing impairment in newborns.

AIM: To determine the proportion of newborns diagnosed with hearing impairment through the hearing impairment screening program in newborns, and the frequency of 35delG/GJB2 mutation as a cause of hearing impairment. The results of the study imply the integration of the mutation analysis in the neonatal screening program. METHODS: Evoked otoacustic emission (E-OAE) screening program was performed among 6019 newborns at the Department of Obstetrics and Gynaecology, Rijeka University Hospital Center, between October 2002 and December 2004. Newborns diagnosed with hearing impairment were re-examined after three weeks and if abnormal responses persisted, the diagnosis was evaluated by auditory brainstem evoked response (ABER) testing. Children with confirmed diagnosis were examined by allele-specific polymerase chain reaction to identify the presence of 35delG/GJB2 mutation. RESULTS: After the first and second stage of screening, 86 newborns were suspect of having hearing impairment. ABER confirmed the diagnosis of hearing impairment in 14 children. Molecular analysis revealed 35delG/GJB2 mutation in 2 of 8 children analyzed. The mutation was homozygous in one, and heterozygous in the other child. CONCLUSION: Neonatal hearing impairment screening is useful for early diagnosis of hearing impairment. It should be complemented with the 35delG/GJB2 mutation analysis, because the identification of the mutation and the etiologic diagnosis might improve the medical treatment and genetic counselling of patients and families with hearing impairment.