Thrombosis during pregnancy: Risks, prevention, and treatment for mother and fetus--harvesting the power of omic technology, biomarkers and in vitro or in vivo models to facilitate the treatment of thrombosis

Maternal thromboembolism and a spectrum of placenta-mediated complications including the pre-eclampsia syndromes, fetal growth restriction, fetal loss, and abruption manifest a shared etiopathogenesis and predisposing risk factors. Furthermore, these maternal and fetal complications are often linked to subsequent maternal health consequences that comprise the metabolic syndrome, namely, thromboembolism, chronic hypertension, and type II diabetes. Traditionally, several lines of evidence have linked vasoconstriction, excessive thrombosis and inflammation, and impaired trophoblast invasion at the uteroplacental interface as hallmark features of the placental complications. "Omic" technologies and biomarker development have been largely based upon advances in vascular biology, improved understanding of the molecular basis and biochemical pathways responsible for the clinically relevant diseases, and increasingly robust large cohort and/or registry based studies. Advances in understanding of innate and adaptive immunity appear to play an important role in several pregnancy complications. Strategies aimed at improving prediction of these pregnancy complications are often incorporating hemodynamic blood flow data using non-invasive imaging technologies of the utero-placental and maternal circulations early in pregnancy. Some evidence suggests that a multiple marker approach will yield the best performing prediction tools, which may then in turn offer the possibility of early intervention to prevent or ameliorate these pregnancy complications. Prediction of maternal cardiovascular and non-cardiovascular consequences following pregnancy represents an important area of future research, which may have significant public health consequences not only for cardiovascular disease, but also for a variety of other disorders, such as autoimmune and neurodegenerative diseases.

Differential influence of maternal and fetal pregnancy factors on the in-vitro induction of human regulatory T cells: a preliminary study.

PROBLEM Given the important role of regulatory T cells (Treg) for successful pregnancy, the ability of soluble maternal and fetal pregnancy factors to induce human Treg was investigated. METHOD OF STUDY Peripheral blood mononuclear cells (PBMCs) or isolated CD4+CD25‒ cells were cultured in the presence of pooled second or third trimester pregnancy sera, steroid hormones or supernatants from placental explants, and the numbers and function of induced CD4+CD25+FOXP3+ Treg were analysed. RESULTS Third trimester pregnancy sera and supernatants of early placental explants, but not sex steroid hormones, induced an increase of Tregs from PBMCs. Early placental supernatant containing high levels of tumour necrosis factor-α, interferon-γ, interleukins -1, -6 and -17, soluble human leucocyte antigen-G, and transforming growth factor-β1, increased the proportion of Treg most effectively and was able to induce interleukin-10-secreting-Treg from CD4+CD25‒cells. CONCLUSIONS Compared with circulating maternal factors, placental- and fetal-derived factors appear to exert a more powerful effect on numerical changes of Treg, thereby supporting fetomaternal tolerance during human pregnancy.

Hypertension in pregnancy

PURPOSE OF REVIEW Hypertension in pregnancy contributes substantially to perinatal mortality and morbidity of both the mother and her child. High blood pressure is mainly responsible for this adverse outcome, in particular when associated with preeclampsia. Although preeclampsia is nowadays a well-known clinical-obstetrical entity, and screening for this complication has been part of routine care during pregnancy for nearly 100 years, its cause is still enigmatic. RECENT FINDINGS Profound changes of the demographic development of our society, the worldwide rising prevalence of obesity and metabolic disorders, and progress in reproductive medicine will inevitably modify the prevalence of many medical problems in pregnancy. Complications such as gestational diabetes mellitus, chronic hypertension, and preeclampsia will rise and an interdisciplinary approach is necessary to handle these women during pregnancy and also after delivery. Indeed, it is now well established that these women and their offspring born large or small-for-gestational age are at increased risk for severe cardiovascular and metabolic complications later in life. SUMMARY Knowledge of the pregnancy course is not only important for an obstetrician but also increasingly inevitable for the general practitioner. Recognition, classification, and adequate management of hypertensive pregnancy disorders and associated complications may considerably reduce perinatal death and morbidity.

Laparoscopic Ultrasound-Guided Repair of Uterine Scar Isthmocele Connected With the Extra-Amniotic Space in Early Pregnancy.

We present a video of an ultrasound-guided laparoscopic surgical management of a large uterine scar isthmocele connected with the extra-amniotic space in early pregnancy. A case of a pregnant patient who was diagnosed with a large isthmocele connected with the extra-amniotic space on routine ultrasound at 8 weeks of gestational age is presented. The uterine defect was successfully sutured laparoscopically under ultrasound guidance. The pregnancy continued uneventfully, and a healthy baby was delivered via cesarean section at 38 weeks gestational age.

The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease

Trying to conceive and being pregnant is an emotional period for those involved. In the majority of patients suffering from inflammatory bowel disease, maintenance therapy is required during pregnancy to control the disease, and disease control might necessitate introduction of new drugs during a vulnerable period. In this updated consensus on the reproduction and pregnancy in inflammatory bowel disease reproductive issues including fertility, the safety of drugs during pregnancy and lactation are discussed.

Thrombotic thrombocytopenic purpura during pregnancy versus imitator of preeclampsia.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is a severe disorder affecting the microcirculation of multiple organs due to a systemic endothelial cell injury secondary to a deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity. TTP is a rare complication of pregnancy with a poor prognosis and high fetal mortality, especially when it occurs during the first trimester. Recent data have supported that effective treatment of TTP is plasma therapy. Unfortunately a major problem remains in the delay in diagnosis due to confounding factors between other "imitators of preeclampsia." Rapid and readily available laboratory testing to quickly diagnose TTP is desperately needed to improve care and to save mother and future child life. CASE REPORT We describe a rare case of successful pregnancy after TTP manifestations occurring in the first trimester; most importantly, our experience represents the first case of atypical manifestation due to neurologic and kidney manifestations preceding laboratory assay alterations. RESULTS We treated a patient with plasma replacement of 30 mL/kg/day and daily plasmapheresis in combination with continuous infusion of fresh-frozen plasma 10 mL/kg/day. The response of clinical manifestation immediately improved. At 30 weeks, the patient had multiple episodes of high blood pressure and concomitant decrease of hemoglobin and platelet count, so a cesarean section was immediately performed. She delivered a healthy female baby. CONCLUSION Early diagnosis by ADAMTS13 activity, occasionally occurring before clinical manifestations, aided us in promptly administering commended and life-saving treatments.

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy.

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome.

Gestation-specific reference intervals for comprehensive spot urinary steroid hormone metabolite analysis in normal singleton pregnancy and 6 weeks postpartum

BACKGROUND: Normal pregnancy depends on pronounced adaptations in steroid hormone concentrations. Although in recent years, the understanding of these hormones in pregnancy has improved, the interpretation is hampered by insufficient reference values. Our aim was to establish gestation-specific reference intervals for spot urinary steroid hormone levels in normal singleton pregnancies and 6 weeks postpartum. METHODS: Cross-sectional multicentre observational study. Women recruited between 2008 and 2013 at 3 University Hospitals in Switzerland (Bern), Scotland (Glasgow) and Austria (Graz). Spot urine was collected from healthy women undergoing a normal pregnancy (age, 16-45 years; mean, 31 years) attending routine antenatal clinics at gestation weeks 11, 20, and 28 and approximately 6 weeks postpartum. Urine steroid hormone levels were analysed using gas-chromatography mass spectrometry. Creatinine was also measured by routine analysis and used for normalisation. RESULTS: From the results, a reference interval was calculated for each hormone metabolite at each trimester and 6 weeks postpartum. Changes in these concentrations between trimesters and postpartum were also observed for several steroid hormones and followed changes proposed for index steroid hormones. CONCLUSIONS: Normal gestation-specific reference values for spot urinary steroid hormones throughout pregnancy and early postpartum are now available to facilitate clinical management and research approaches to steroid hormone metabolism in pregnancy and the early postpartum period.

Certolizumab treatment during late pregnancy in patients with rheumatic diseases: Low drug levels in cord blood but possible risk for maternal infections. A case series of 13 patients

OBJECTIVE Due to reduction of immune-suppressive drugs, patients with rheumatic diseases can experience an increase in disease activity during pregnancy. In such cases, TNF-inhibitors may be prescribed. However, monoclonal antibodies with the Fc moiety are actively transported across the placenta, resulting in therapeutic drug levels in the newborn. As certolizumab (CZP) lacks the Fc moiety, it may bear a lower risk for the child. METHOD We report a case series of thirteen patients (5 with rheumatoid arthritis and 8 with spondyloarthritis) treated with CZP during late pregnancy to control disease activity. RESULT CZP measured in cord blood of eleven infants ranged between undetectable levels and 1μg/mL whereas the median CZP level of maternal plasma was 32.97μg/mL. Three women developed an infection during the third trimester, of whom one had a severe infection and one had an infection that resulted in a pre-term delivery. During the postpartum period, 6 patients remained on CZP while breastfeeding. CZP levels in the breast milk of two breastfeeding patients were undetectable. CONCLUSION The lack of the active transplacental transfer of CZP gives the possibility to treat inflammatory arthritis during late gestation without potential harm to the newborn. However, in pregnant women treated with TNF-inhibitors and prednisone, attention should be given to the increased susceptibility to infections, which might cause prematurity. CZP treatment can be continued while breastfeeding.

Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.

OBJECTIVE To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy.

Importance of cholesterol and cholesterol transporters in the placental trophoblast during pregnancy

Membrane transporters are essential during pregnancy, being a core component of the exchange of nutrients, gases, and metabolic products between the mother and the developing fetus. Important compounds to be transported include vitamins and minerals, amino acids, glucose, as well as cholesterol. Cholesterol transport across the plasma membrane is mediated mainly by members of the ATP-binding cassette (ABC) transporter family. Cholesterol is present in every cell of the body, where it helps maintain the integrity of cell membranes and also plays an important role in cell signaling events. Cholesterol also acts as a precursor for the biosynthesis of steroids that include sex hormones, glucocorticoids, mineralcorticoids, as well as bile acids and oxysterols. Cholesterol transport is therefore crucial for a host of different physiological processes. The following chapter addresses the involvement and importance of ABC transporters in these different processes. The critical role that ABC transporters Play for a successful pregnancy outcome is highlighted by pathological processes that result malfunction of cholesterol transport during pregnancy. Avenues of future research are also described, which may help to further delineate the function and mechanism of action of ABC transporters.

Adolescent Pregnancy Prevention in San Jose, Costa Rica : Assessment of an Educational Intervention

This thesis explores adolescent pregnancy in San Jose, Costa Rica and examines a school-based pregnancy prevention intervention. The relationships between school, gender and risk of adolescent pregnancy are also analyzed, and recommendations are made for effective pregnancy prevention programming. The Purral region of Guadalupe on the outskirts of San Jose, Costa Rica, suffers a higher rate of adolescent pregnancy compared to the rest of the country. In response to this problem, the International Health Central American Institute (IHCAI) implemented a sexual health education program in two local secondary schools in 2006. Very little information about the program is available. It is known that the program was initially evaluated through assessments of the participants’ knowledge before and after the educational sessions. There was no evaluation of the youth attitudes or behaviors, adolescent pregnancies, or long-term impact. The author worked with IHCAI in San Jose, Costa Rica to perform an assessment of the longer term effects of this sexual health education program. They developed a questionnaire to evaluate the knowledge, attitudes, and behaviors surrounding sexual health of youth in the Purral community. Researchers at IHCAI later used this survey to collect data from adolescents who had participated in the educational intervention and those who had not. This thesis analyzes the data collected by IHCAI to assess the effectiveness of the - 2 - educational intervention and the influence of other factors on the knowledge, attitudes, and behaviors of adolescents in the Purral region. The thesis begins with an overview of adolescent pregnancy, Costa Rica and the Purral region, and a description of the education intervention implemented by IHCAI. The research goal, logic model, and methods are then described. The results are reported, and the thesis then concludes with discussion of the results as well as study limitations and recommendations for future research and intervention. This thesis will be used to guide IHCAI’s continuation and expansion of adolescent pregnancy prevention programming.

A Study of the Teratogenic Potential of Oral Hormonal Pregnancy Tests in the White Rat

Submitted in partial fulfillment of the requirements for a Certificate in Orthodontics, Dept. of Orthodontics, University of Connecticut Health Center, 1976

African American female adolescents and antecedents of pregnancy

Although the pregnancy rate of teenage girls in the United States has decreased in recent years, African American female adolescents still have one of the highest teen pregnancy rates among girls in the United States. Previous studies report inconsistent relationships between adolescent pregnancy and self-esteem and parental communication, caring, and closeness. The purpose of this study was to assess relationships between pregnancy among African American female adolescents (7th to 12th grades) and self-esteem, communication levels and type of relationships with their parents. This study used data collected from The National Longitudinal Study of Adolescent Health (Add Health). Logistic regression analysis was used to determine if the independent variables of self-esteem, levels of parental caring and closeness and levels of communication with parents predicted the dependent variable of pregnancy. After controlling for age and levels of parental education, self-esteem was the only statistically significant variable that was associated with pregnancy. The findings of this study indicate that levels of self-esteem should be further investigated and that self-esteem may be an important factor when designing interventions to prevent adolescent pregnancy, particularly for African American females. ^

Contraceptive use in women by body mass index categories

The prevalence of obesity has increased sharply in the United States since the mid 1970's. Obese women who become pregnant are at increased risk of pregnancy complications for both mother and fetus. This study assessed whether women in higher body mass index (BMI) categories engage in the preventive behaviors of contraception more frequently than normal weight women. It also evaluated the type of contraception used by both obese and normal weight women. The study used cross-sectional data from 7 states participating in the Family Planning Module of the 2006 Behavioral Risk Factor Surveillance System (BRFSS). The Behavioral Risk Factor Surveillance System survey is an annual random digit dialed telephone survey of the non-institutionalized civilian population aged 18 years and older. The Family Planning Module was administered by Arizona, Kentucky, Minnesota, Missouri, Montana, Oregon, and Wisconsin. Of the 4,757 women who participated in the Family Planning Module, 2,244 (53.2%) were normal weight, 1,202 (25.6%) were overweight, and 1,072 (21.2%) were obese. The majority of these women 4,115 (86.2%) reported using some type of contraception to prevent pregnancy. Six hundred forty two women (13.8%) stated they did not use any type of contraception to prevent pregnancy. Within body mass index categories, 14% of normal weight women, 13% of overweight women, and 13.4% of obese women did not use any type of contraception. Neither the bivariate analysis nor the logistic regressions found body mass index categories to be statistically associated with contraceptive use. The relationship between body mass index categories and contraceptive method was found to be statistically significant. The predictive probability graph found that women at all levels of BMI have a lower probability of using barrier contraception methods as compared to procedural and hormonal methods. Hormonal contraception methods have the highest probability of use for women with a BMI of 15 to 25. In contrast, the probability of using procedural contraception methods is relatively flat and less than hormonal methods for BMI between 15 and 25. However, the probability of using procedural contraception increases dramatically with a BMI greater than 25. At a BMI greater than 42, women have a greater than 50% probability of using procedural contraception. Although a relationship between body mass index and contraception use was not found, contraception method was found to be associated with body mass index. The reasons why normal weight women prefer hormonal contraception while overweight/obese women are more likely to use procedural methods needs to be explored. By understanding the relationship between obesity and contraception, we can hopefully decrease unintended pregnancies and overall improve pregnancy related health outcomes. To determine if relationships between contraception use/type and body mass index exist, further research needs to be conducted on a national level. ^