Belimumab use during pregnancy: Interim results of the belimumab pregnancy registry.

BACKGROUND: Belimumab is approved for active, autoantibody-positive systemic lupus erythematosus (SLE) and lupus nephritis, but limited data exist regarding its use in pregnancy. The Belimumab Pregnancy Registry (BPR, GSK Study BEL114256; NCT01532310) was created to evaluate pregnancy and infant outcomes following belimumab exposure. METHODS: Individuals with SLE exposed to belimumab from 4 months before and/or during pregnancy can enroll into the BPR. The primary outcome is major birth defects; secondary outcomes include miscarriages, stillbirths, elective termination, pre-term birth, neonatal death, small for gestational age, and adverse infant outcomes during the first year of life. Belimumab exposure timing, concomitant medications, and other potential confounding factors are also collected. Data up to March 8, 2021, are reported descriptively. RESULTS: From an expected sample size target of 500 prospective pregnancies with a known outcome, only 55 were enrolled in the study. Among these, two pregnancy losses and 53 pregnancies with a live birth outcome were reported. Ten of the 53 live birth pregnancies resulted in a major birth defect. Ten pregnancies were enrolled after the pregnancy outcome occurred and were examined retrospectively (four live births with no defects, four miscarriages, and two elective terminations). There was no indication or pattern of birth defects associated with belimumab. CONCLUSIONS: Low recruitment numbers for the BPR and incomplete information limit the conclusions regarding belimumab exposure during pregnancy. There was no pattern or common mechanism of birth defects associated with belimumab within the BPR data.

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Effectiveness of an algorithm-based approach to the utilization of plerixafor in patients undergoing chemotherapy-based stem cell mobilization.

Autologous stem cell transplantation remains a mainstay of therapy for diseases such as multiple myeloma and relapsed lymphoma. The use of plerixafor has been shown to augment the ability to collect adequate stem cells, but the optimal use of this agent when used with chemotherapy is not yet clear. We utilized an algorithm-based approach with the addition of plerixafor to 54 patients undergoing chemomobilization with reduced-dose etoposide who had a less than optimal preapheresis CD34(+) cell count. We used a CD34(+) precount of 20 cells/µL as a threshold to initiate stem cell apheresis. Ninety-four percent of patients were successfully collected and proceeded to transplantation. Fourteen of 51 (28%) patients who successfully collected required plerixafor to augment stem cell yield. Of the patients who successfully collected, 94% (89% of the entire population) were able to collect in 2 or fewer days. Compared with previous data from our institution, the rate of patients collecting > 4 × 10(6) CD34(+) cells/kg in a single collection was increased from 39% to 69%. The safety profile of this approach was acceptable. The use of this algorithm-based method to determine when and whether to add plerixafor to chemomobilization was shown to be a successful and cost-effective approach to stem cell collection.

Lopinavir/ritonavir in pregnancy.

OBJECTIVE: The Antiretroviral Pregnancy Registry was established in 1989 to collect data on birth defects after pregnancy exposures to antiretroviral therapy. Using Registry data, this study estimates the birth defect risk after pregnancy exposures to lopinavir/ritonavir. METHODS: The analysis population includes all prospective lopinavir/ritonavir-exposed pregnancies enrolled in the Registry from September 2000 through July 2007. Birth defect prevalence after pregnancy exposure is compared with rates from a population-based surveillance system, and first-trimester exposures are compared with combined second/third-trimester exposures. RESULTS: Among 955 live births prenatally exposed to lopinavir/ritonavir, 23 cases with birth defects were reported [2.4%, 95% confidence interval (CI) = 1.5 to 3.6). Among 267 live births with first-trimester exposures, 5 had birth defects (1.9%, 95% CI = 0.6 to 4.3). These rates are similar to the population-based comparator rate of 2.67% and the rate in infants with second/third-trimester exposures (2.6%, 95% CI = 1.6 to 4.1). No pattern of birth defects suggestive of a common etiology was seen. CONCLUSIONS: The prevalence of birth defects among infants prenatally exposed to lopinavir/ritonavir is not significantly different from internal or external comparison groups. These data provide reassuring information to patients and clinicians about the safety of lopinavir/ritonavir in the treatment of HIV-positive pregnant women.

The antiretrovirals in pregnancy registry: a fifteenth anniversary celebration.

UNLABELLED: The year 2007 marks the fifteenth anniversary year of the founding of a landmark effort in drug safety risk management, the formation of the first monitoring effort of an antiretroviral (ARV) drug in pregnancy which has become the Antiretrovirals in Pregnancy Registry, the APR. This multicompany, multi-national voluntary collaborative registry monitors pregnancy exposure to a class of highly important drugs for any indication of an increase in the postexposure incidence of birth defects in the offspring of these pregnancies. To recognize the anniversary, the Steering Committee of the APR has commissioned this review of the contributions and lessons learned over the past decade and a half and, in the spirit of continuous process improvement, has committed to apply these lessons for the next fifteen years. This retrospective examines the antecedents to this registry and the context in which the APR was formed; the early efforts to establish technical and organizational procedures and policies; the evolving experiences with enrollment and follow-up, patient and participant protections, information management and oversight; public and regulatory dissemination; and of course, the accomplishments and lessons learned. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to explain the value of a drug registry in determining safety risk management; summarize that the Antiretroviral (ARV) drugs in Pregnancy Registry (APR) is a very successful multinational, multicompany collaborative effort that has been in place for 15 years; and state that it has been an ideal public interest effort dealing with the devastating pandemic of human immunodeficiency viral disease.

Assessing the risk of birth defects associated with antiretroviral exposure during pregnancy.

OBJECTIVE: The purpose of this study was to examine teratogenic risk of antiretroviral (ARV) drugs. STUDY DESIGN: The Antiretroviral Pregnancy Registry (APR) monitors prenatal exposures to ARV drugs and pregnancy outcome through a prospective exposure-registration cohort. Statistical inference uses exact methods for binomial proportions. RESULTS: Through July 2003, APR has monitored 3583 live births exposed to ARV. Among 1391 first trimester exposures, there were 38 birth defects, prevalence of 2.7% (95% CI 1.9-3.7), not significantly higher than the CDC's population surveillance rate, 3.1 per 100 live births (95% CI 3.1-3.2). For lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine, sufficient numbers of live births (>200) following first-trimester exposures have been monitored to allow detection of a 2-fold increase in risk of birth defects overall; no increases have been detected. CONCLUSION: APR data demonstrate no increase in prevalence of birth defects overall or among women exposed to lamivudine, nelfinavir, nevirapine, stavudine, and zidovudine.

Clinical review procedures for the Antiretroviral Pregnancy Registry.

The Antiretroviral Pregnancy Registry (APR) is an international pregnancy exposure registry designed to monitor prenatal antiretroviral medication exposures and detect any potential increase in the risk of major birth defects. The APR process imitates that of the Metropolitan Atlanta Congenital Defects Program (MACDP) modified to account for the differences in surveillance systems. The APR case definition attempts to separate prenatal and postnatal medication exposure, includes cases with multiple conditional defects only and collects cases diagnosed at later ages. Possible temporal association between defect pathogenesis and antiretroviral medication exposure includes a way to identify cases with known etiology--such as familial genetic conditions--and those with currently ambiguous pathogenesis--like hemangiomata and club feet. The APR also accounts for confounding factors like maternal alcohol use. Some defect reports automatically generate questions back to the reporter asking for more information. The APR incorporates procedures for managing and recording some of the more inconsistently reported malformations, such as microcephaly.

Assessing teratogenicity of antiretroviral drugs: monitoring and analysis plan of the Antiretroviral Pregnancy Registry.

This paper describes the Antiretroviral Pregnancy Registry's (APR) monitoring and analysis plan. APR is overseen by a committee of experts in obstetrics, pediatrics, teratology, infectious diseases, epidemiology and biostatistics from academia, government and the pharmaceutical industry. APR uses a prospective exposure-registration cohort design. Clinicians voluntarily register pregnant women with prenatal exposures to any antiretroviral therapy and provide fetal/neonatal outcomes. A birth defect is any birth outcome > or = 20 weeks gestation with a structural or chromosomal abnormality as determined by a geneticist. The prevalence is calculated by dividing the number of defects by the total number of live births and is compared to the prevalence in the CDC's population-based surveillance system. Additionally, first trimester exposures, in which organogenesis occurs, are compared with second/third trimester exposures. Statistical inference is based on exact methods for binomial proportions. Overall, a cohort of 200 exposed newborns is required to detect a doubling of risk, with 80% power and a Type I error rate of 5%. APR uses the Rule of Three: immediate review occurs once three specific defects are reported for a specific exposure. The likelihood of finding three specific defects in a cohort of < or = 600 by chance alone is less than 5% for all but the most common defects. To enhance the assurance of prompt, responsible, and appropriate action in the event of a potential signal, APR employs the strategy of 'threshold'. The threshold for action is determined by the extent of certainty about the cases, driven by statistical considerations and tempered by the specifics of the cases.

Risk of birth defects associated with nelfinavir exposure during pregnancy.

OBJECTIVE: The objective of this study was to examine the human teratogenic risk of the protease inhibitor, nelfinavir mesylate, used to treat human immunodeficiency virus. METHODS: This study used a subset of data from the Antiretroviral Pregnancy Registry, which was designed to monitor prenatal exposures to antiretroviral therapy and detect a potential increase in the risk of birth defects. The registry uses a prospective exposure-registration cohort design. All records of pregnant women exposed to nelfinavir, used alone or in combination, were extracted and analyzed. The prevalence of birth defects was compared with the Centers for Disease Control and Prevention's (CDC) population-based surveillance system. RESULTS: Through July 2002, the registry had monitored 915 live births exposed to nelfinavir. Among 301 first-trimester exposures, there were 9 birth defects, for a prevalence of 3% (95% confidence interval 1.4, 5.6). This rate is not significantly different from the CDC's system, which had a prevalence of 3.1 per 100 live births (95% confidence interval 3.1, 3.2; P =.99). There was no consistent pattern among reported birth defects. CONCLUSION: Adequate numbers of first-trimester exposures to nelfinavir have been monitored to detect a 2-fold increase in the prevalence of overall birth defects. No such increases have been detected when compared with the CDC rate. However, the numbers are not sufficient to detect any increased rate of specific defects. Although nelfinavir should only be used in pregnancy if the benefits outweigh the potential risks, the findings from this study should provide some assurance. LEVEL OF EVIDENCE: III

Prognostic indices in breast cancer are related to race.

African-American (AA) women have a higher mortality from breast cancer than Caucasians (C). This may be attributed to stage of disease at presentation, but specific prognostic factors are not well identified. We sought to identify prognostic factors in our database of early-stage (stage I and II) breast cancer from 1990 to 1999. There were 153 tumors in 150 AA women and 773 tumors in 760 C women. Prognostic factors are listed according to race with relative risk (RR) and 95 per cent confidence intervals. AA women presented significantly more often than C women under the age of 50 years (RR = 1.8) with palpable disease (RR = 1.3), higher-grade tumors (RR = 1.5), more estrogen receptor-negative disease (RR = 1.7), more progesterone receptor-negative disease (RR = 1.4), higher proliferation indices (RR = 1.9), and more lymph node-positive disease (RR = 1.6). Many of these adverse prognostic features persisted in "good" prognostic groups, i.e., those women over the age of 50 years with tumors <20 mm and having node-negative disease. We conclude that prognostic factors are related to race with AA women presenting at an earlier age and more often with palpable disease. More importantly AA women presented significantly more often with higher-grade tumors, hormone receptor-negative tumors, higher proliferation indices, and node-positive disease. These findings may explain a higher breast cancer mortality in AA women.

National estimates of mortality rates for radical pancreaticoduodenectomy in 25,000 patients.

BACKGROUND: Recent publications suggest an inverse relationship between mortality rates in the Whipple procedure for periampullary cancer and hospital volume/teaching status. METHODS: The Nationwide Inpatient Sample database from 1988 to 1995, containing 24926 patients undergoing pancreatectomy for periampullary cancer, was used. RESULTS: The mean number of procedures per hospital per year was 1.5, and the overall mortality was 14%. The volume of procedures per year increased from the rural to the urban nonteaching hospitals to the urban teaching hospitals (.6, 1.1, and 2.7, respectively), with a steady decrease in mortality among the three hospital types (18%, 15%, and 11%). A multiple logistic regression model with mortality odds ratios (ORs) showed that male sex (OR, 1.3), increasing age (OR, 1.6 to 6.7 in decades from 50 to > or=80 vs. <50 years), emergency admission (OR, 1.5), and hospital volume (less than one vs. one or more cases per year; OR, 1.5) were significantly predictive for increased in-hospital mortality. CONCLUSIONS: In-hospital mortality in the low-volume hospital setting is prohibitive, and review of each institution's mortality rates must occur before these procedures are performed in those institutions. In addition, patients over the age of 60 years, male patients, and those with an urgent admission are at a significant risk of in-hospital death, and consideration should be given toward transfer to an experienced institution.

Conocimientos y practicas de las distribuidoras comunitarias de anticonceptivos en Honduras / Knowledges and practices of the community contraceptive distributors in Honduras

En Honduras, entre febrero y abril de 1983 se evaluó la capacitación de las distribuidoras comunitarias de anticonceptivos integrantes de un programa de planificación de la familia. El objetivo fue determinar la aplicación de los procedimientos especificados de selección que seguían y el asesoramiento ulterior que proporcionaban a las usuarias sobre los anticonceptivos que distribuían: dos marcas de anticonceptivos orales de dosis común, una de dosis baja, espermicidas y preservativos. Si bien las distribuidoras reconocían muchas de las contraindicaciones del uso de anticonceptivos orales, no prestaban la atención suficiente a ciertos trastornos de probable gravedad (por ejemplo, dolores torácidos). No obstante, en presencia de una amplia gama de síntomas clínicos vinculados con el uso de anticonceptivos orales enviaban a las usuarias e otros niveles de atención de salud e, incluso, a las mujeres que manifestaban posibles efectos secundarios pasajeros como náuseas y cefalalgias les aconsejaban que abandonaran la píldora o acudieran a un médico. Convendría que las distribuidoras se preocuparan menos por los efectos secundarios leves y se mostraran más atentas a los síntomas de posibles efectos secundarios graves. Si el programa ha de continuar vendiendo marcas múltiples de anticonceptivos orales, sería conveniente acrecentar los conocimientos de las distribuidoras a este respecto y también acerca de las diferencias que existen entre las marcas de dosis común y baja