Improving Clinical Practice Through Patient Registries in Allergy and Immunology.

Patient registries are a mechanism for collecting data on allergic and immunologic diseases that provide important information on epidemiology and outcomes that can ultimately improve patient care. Key criteria for establishing effective registries include the use of a clearly defined purpose, identifying the target population and ensuring consistent data collection. Registries in allergic diseases include those for diseases such as inborn errors of immunity (IEI), food allergy, asthma and anaphylaxis, pharmacological interventions in vulnerable populations, and adverse effects of pharmacologic interventions including hypersensitivity reactions to drugs and vaccines. Important insights gained from patient registries in our field include contributions in phenotype and outcomes in IEI, the risk for adverse reactions in food-allergic patients in multiple settings, the benefits and risk of biologic medications for asthma during pregnancy, vaccine safety, and the categorization and genetic determination of risk for severe cutaneous adverse reactions to medications. Impediments to the development of clinically meaningful patient registries include the lack of funding resources for registry establishment and the quality, quantity, and consistency of available data. Despite these drawbacks, high-quality and successful registries are invaluable in informing clinical practice and improving outcomes in patients with allergic and immunological diseases.

Ascertainment of malformations in pregnancy registries: Lessons learned in the North American AED Pregnancy Registry.

BACKGROUND: Pregnancy registries, designed to assess the safety of medications and vaccines for the exposed mother and fetus, have been developed since the 1990s. Malformations present in the exposed liveborn or stillborn infant or fetuses in elective terminations are the outcome of greatest concern. The experiences of the North American AED (antiepileptic drug) Pregnancy Registry (NAAPR) can be used to identify the challenges and limitations of a pregnancy registry in identifying congenital malformations. METHODS: The NAAPR enrolls pregnant women who are taking one or more AEDs for any medical condition, but primarily to prevent seizures, and an unexposed comparison group. Participants are interviewed by clinical research coordinators (CRCs) at enrollment, later in pregnancy and postpartum. Malformations are identified in the mother's reports and her infant's medical records through age 12 weeks. A teratologist, blinded to exposure status, evaluates each potential malformation identified. RESULTS: Among 10,982 pregnancies enrolled between 1997 and 2022, 282 malformations were identified in the 9677 AED-exposed and 15 among the 1305 unexposed infants. Isolated malformations, such as cleft palate, accounted for 84% of the malformations identified. Increased frequencies of oral clefts and myelomeningocele were associated with exposure to several different AEDs. Copies of reports from many diagnostic studies were not obtained and very few pregnancy losses had autopsies. CONCLUSIONS: The evaluation of the AED-exposed infants in a pregnancy registry is indirect. Improvements rely on the rapport established with the mothers by the CRCs and the mothers' willingness to assist in obtaining information from her infants' physicians.

Nurses experience increased clinical and organisational competence by working with a medical quality register, RevNatus - a qualitative study.

BACKGROUND: RevNatus is a consent-based, nationwide medical quality register that collects data on patients with inflammatory rheumatic diseases during pregnancy and one year postpartum. The entering of data takes place in outpatient clinics in rheumatology wards in hospitals. The aim of this study is to explore how rheumatology nurses experience organizing and working with the medical quality register RevNatus in addition to their normal clinical patient-care tasks. METHODS: Qualitative focus group interviews and individual in-depth interviews were conducted in 2018 to gain insights into how nurses organize performing quality register work and clinical work simultaneously. Data were analysed using systematic text condensation. RESULTS: The informants represented seven different rheumatology outpatient clinics in Norway. The analyses showed that working with RevNatus increased the nurses' knowledge about pregnancy and rheumatic diseases, improved the content of their nurse consultations and found the 'register form' as a useful template to structure the nurse consultations. The nurses took the main responsibility for RevNatus, but lack of routines and uncoordinated collaboration with the rheumatologists and secretaries made the nurses spend too much time verifying the accuracy of data or post-registering missing data. CONCLUSION: The nurses experienced work with RevNatus as time-consuming, but the register work increased both their clinical and organisational competences. Routines and collaboration within the registry team are important to ensure the data quality and reduce the workload.

Effects of Motherwort Injection Versus Intramuscular Oxytocin for Preventing Postpartum Hemorrhage Among Women Who Underwent Cesarean Section.

Objectives: Subject to ethical constraints, real-world data are an important resource for evaluating treatment effects of medication use during pregnancy and the postpartum period. This study investigated whether motherwort injection, a traditional Chinese medicine preparation, was more effective than intramuscular (IM) oxytocin for preventing postpartum hemorrhage (PPH) in a real-world setting when intravenous (IV) oxytocin is administered. Methods: We conducted an active-controlled, propensity-score matched cohort study using an established pregnancy registry database. Women who underwent cesarean section and received IV oxytocin at the third stage of labor were included. We used an active-comparator design to minimize indication bias, in which we compared IM motherwort injection in the uterus versus IM oxytocin, both on top of IV oxytocin use. We applied 1:1 propensity-score matching (PSM) to balance patient baseline characteristics and used a logistic regression model to estimate treatment effect (i.e., risk difference (RD) and odds ratio (OR)) by using the counterfactual framework. The outcomes of interest were blood loss over 500 ml within 2 h after delivery (PPH, primary) and blood loss over 1,000 ml (severe PPH, secondary). We conducted four sensitivity analyses to examine the robustness of the results. Results: A total of 22,519 pregnant women underwent cesarean sections, among which 4,081 (18.12%) PPH and 480 (2.13%) severe PPH occurred. Among included women, 586 (2.60%) were administrated with IM motherwort injection, and 21,933 (97.40%) used IM oxytocin. After PSM, patient baseline characteristics were well balanced. Compared with IM oxytocin, the use of IM motherwort injection was associated with significantly lower risk of PPH (RD -25.26%, 95% CI -30.04% to -20.47%, p < 0.001; OR 0.25, 95% CI 0.18 to 0.32, p < 0.001) and severe PPH (RD -3.58%, 95% CI -5.87% to -1.30%, p < 0.001; OR 0.39, 95% CI 0.20 to 0.71, p < 0.002). Sensitivity analyses showed that the results were similar. Conclusion: With the use of data from a real-world setting, the findings consistently showed that among women undergoing cesarean section who had received IV oxytocin, the additional use of IM motherwort injection could achieve a lower risk of PPH as compared to the additional use of IM oxytocin. Our study suggested a paradigm for investigating the treatment effect of Chinese herbal medicine in the real-world practice setting.

Fourteen years of the Pregnancy Registry on maternal immunisation with a reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap) vaccine.

BACKGROUND: GSK initiated a Pregnancy Registry in the United States (US) for the reduced-antigen-content tetanus-diphtheria-acellular pertussis (Tdap; Boostrix, GSK) vaccine with the aim to detect and describe pregnancy outcomes in women vaccinated with Boostrix 28 days before estimated conception or during pregnancy. METHODS: Voluntary reports of pregnancy exposure to Boostrix received from spontaneous and post-marketing surveillance sources in the US were assessed. Reports were classified as prospective or retrospective based on the knowledge of pregnancy outcomes at the time of reporting. For completeness, reports of exposure to Boostrix or to the Tdap-inactivated poliovirus vaccine (Boostrix-IPV, GSK) reported to the global safety database from countries outside the US were also evaluated. RESULTS: From May 2005 to August 2019, 1517 (1455 prospective and 62 retrospective) pregnancy reports were received in the Boostrix US Pregnancy Registry. Of the prospective reports, 250 had known outcomes: 244 live infants with no apparent birth defects (BDs), three live infants with BDs, and three spontaneous abortions with no apparent BDs. Of the retrospective reports, 55 had known outcomes: 33 live infants with no apparent BDs, 16 live infants with BDs, one spontaneous abortion with no apparent BDs, four stillbirths with no apparent BDs, and one stillbirth with BDs. Cumulatively, 1321 pregnancy reports (1006 for Boostrix; 315 for Boostrix-IPV) were received from countries outside the US. Of these, 163 prospective reports and 551 retrospective reports had known outcomes. Results were in line with those from the Boostrix US Pregnancy Registry. CONCLUSIONS: Data currently available from the Boostrix US Pregnancy Registry and from countries outside the US suggested that exposure to Boostrix or Boostrix-IPV during pregnancy does not raise safety concerns related to adverse pregnancy outcomes or BDs.

Exposure to quadrivalent influenza vaccine during pregnancy: Results from a global pregnancy registry.

BACKGROUND: The Fluzone® Quadrivalent (IIV4, Sanofi Pasteur) Pregnancy Registry was created to monitor vaccine safety during pregnancy (clinicaltrials.gov, NCT01945424). Here, we describe maternal, pregnancy, obstetrical and neonatal outcomes after vaccine exposure in pregnant women between August 2013 and September 2019. METHODS: All women exposed to IIV4 during their pregnancy were eligible for inclusion. Outcomes were prospective (reported following vaccine exposure but before knowledge of pregnancy outcome ascertained through prenatal tests) or retrospective (prenatal tests were undertaken before the exposure was reported). RESULTS: Among 239 IIV4 vaccine exposure reports received, there were 105 prospective and 10 retrospective reports of maternal adverse events (AEs). The most frequent prospectively reported maternal AEs were medication errors (expired product [n = 8, 3.8%]; extra dose [n = 7, 3.3%]) and injection site pain (n = 7, 3.3%). Among 62 prospectively reported pregnancy and obstetrical events with available follow-up information, seven AEs were reported, four (6.4%) of which were spontaneous abortions. A further seven AEs were reported among the 29 retrospective pregnancy and obstetrical events with available follow-up information. Among neonatal outcomes (15 prospective; 28 retrospective), >85% were reported as full-term births. One premature birth was reported prospectively. Four other neonatal AEs were reported, all retrospectively: two cases of talipes (club foot), one central nervous system anomaly and one atrial septal defect. All infants with available information had normal APGAR scores at 5 minutes. CONCLUSIONS: The frequency of AEs following exposure to IIV4 during pregnancy did not indicate new safety concerns.

Seasonal influenza vaccine exposure in pregnancy: 5-year results from a pregnancy registry.

The World Health Organization recommends that all pregnant women receive seasonal influenza vaccine. Under a post-authorization safety study protocol (NCT02148211), a pregnancy exposure registry was established in the United States to monitor spontaneously reported pregnancy outcomes in women vaccinated with GSK's seasonal inactivated influenza vaccines (IIVs). From 1 June 2014 to 31 May 2019, 507 pregnancies were prospectively reported: 352 (69.4%) were lost to follow-up and 40 (7.9%) were ongoing. Reported outcomes for the remaining 115 were: 101 (87.8%) live births without congenital anomalies; 3 (2.6%) live births with congenital anomalies; 2 (1.7%) spontaneous abortions with no congenital anomalies; 1 (0.9%) spontaneous abortion with a congenital anomaly; 1 stillbirth with no apparent congenital anomaly; 7 (6.1%) 'Unknown'. Results from 493 prospective reports received via worldwide spontaneous, passive surveillance showed similar outcomes. All cases with congenital anomaly were assessed as not likely/unlikely/unrelated to vaccination. Despite the limited number of cases and outcomes, no safety signal was identified. The study findings are aligned with previously published data and should be confirmed with other robust data sources.

PLAIN LANGUAGE SUMMARYWhat is the context?The pneumococcus bacterium can cause infections of the meninges, blood, lung, middle ear and sinuses.Two vaccins, Synflorix (GSK) and Prevnar 13 (Pfizer Inc.), are widely used to protect young children against these infections.The vaccines' compositions differ: Synflorix includes antigens from 10 pneumococcus strains (or "serotypes") and Prevnar 13 from 13 serotypes.However, both have a similar effect on the total pneumococcal disease burden in children.What does this commentary highlight?This commentary summarizes the evidence beihnd the two vaccines' comparable impact on pneumococcal disase.It also looks at why the vaccines have a similar effect on the total pneumococcal disease burden despite their different compositions.What is the impact on current thinking?Given that Synflorix and Prevnar 13 have a comparable impact on pneumococcal disease, a country's choice between the two vaccines will depend on vaccine supply, cost, logistical factors (e.g., transport, storage, training requirements of health workers) and the local pneumococcal epidemiology.

Safety and use of tetanus-diphtheria-acellular pertussis-5 (Tdap5) vaccine during pregnancy: findings from 11 years of reporting to a pregnancy registry.

The "Adacel (Tdap5) Pregnancy Registry" was used to identify 1182 women who received the tetanus, diphtheria, acellular pertussis [5 components] (Tdap5) vaccine during pregnancy from 2005 to 2016. To evaluate the safety and use of prenatal Tdap5, we calculated the rate of maternal, obstetrical, pregnancy and neonatal outcomes following Tdap5 pregnancy exposure and assessed vaccine uptake by year and trimester of exposure. The most commonly reported maternal adverse events included injection site reactions (2.6%; 95% Confidence Interval 1.8%, 3.7%), nervous system events (1.3%; 0.8%, 2.1%) and musculoskeletal events (1.1%; 0.6%, 1.9%). The most commonly reported complications of pregnancy were hypertension/preeclampsia (5.5%; 3.3%, 8.9%) and gestational diabetes (2.5%; 1.1%, 5.3%), while those for labor and delivery were premature labor (2.9%; 1.4%, 5.7%) and premature membrane rupture (1.5%; 0.4%, 3.8%). These rates were similar to, or lower than those reported for the general population of pregnant women. Among pregnancies with known birth outcomes (N = 275), 90.4% (86.2%, 93.4%) resulted in a live birth, 5.9% (3.6%, 9.5%) in spontaneous abortion, 3.0% (1.4%, 5.8%) in stillbirth, and 0.7% (0.0%, 2.8%) in ectopic pregnancies. Most newborns had normal APGAR scores and birth weights (98.1% and 93.0%, respectively), and only two reported a congenital anomaly (0.7%; 0.0%, 2.8%). An influx of reports in 2012 with third trimester Tdap5 exposure coincided with the 2012 updated Advisory Committee on Immunization Practices recommendations. This analysis did not identify any safety concerns across the continuum of maternal, obstetrical, pregnancy, and neonatal outcomes in women who received Tdap5 vaccination during pregnancy.

Construction and exploration of pregnancy registries for medicine based on pharmaceutical service / 中华医院管理杂志

The pregnancy registry for medicine is a common method for risk evaluation for drug safety evaluation during pregnancy. The authors introduced the exploration and practice of the pregnancy drug registry mode based on pharmacy service in Women′s Hospital School of Medicine Zhejiang University. The registry of pregnancy medication with the drug consultation clinic as the fulcrum was managed by the pharmacist team in a homogenization way, and implemented according to the information process of consultation, pharmacy guidance and regular follow-up. In the consultation and follow-up work, the pharmacists established the consultation drug history through three data sources: independent report of the consultant, inquiry of pharmaceutical personnel and case sampling. The pharmacists designed and constructed information screening system, classified the consultation medicine history according to the pregnancy exposure of specific drugs. The prospective research method was designed to meet the characteristics of pregnancy medication. The study was carried out on the relationship between pregnancy exposure and birth defects of offspring. Relying on the improvement of standardization, refinement and information management level of pharmaceutical services, multi center cooperation will be strengthened in the future to carry out continuous research on pregnancy drug exposure registry and follow-up system.

Factors associated with study protocol adherence and bio banking participation in reproductive medicine clinical trials and their relationship to live birth.

STUDY QUESTION: What demographic and baseline characteristics are predictive of adherence to reproductive medicine clinical trial protocols, live birth or participation in genetic studies? SUMMARY ANSWER: Race, BMI and lower income are associated with likelihood of non-adherent to reproductive medicine clinical trial protocols, while race influences collection of biological samples and non-adherent to study protocols is associated with lower probability of live birth. WHAT IS KNOWN ALREADY: Although aspects of adherence to study protocol have previously been evaluated as individual factors in infertile women, the factors that affect overall non-adherent to study protocol have not been previously evaluated. STUDY DESIGN, SIZE, DURATION: A secondary data analysis of 1650 participants from two prospective multicenter, double-blind controlled studies was carried out: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were women aged 18-40 years old with either polycystic ovary syndrome (PCOS) with ovulatory dysfunction in combination with either hyperandrogenemia and/or polycystic ovarian morphology (PPCOS II), or regular ovulatory cycles with unexplained infertility (AMIGOS). The study was carried out in 14 clinical sites in the USA. Non-adherence to clinical trial protocol was chosen as the primary outcome for this analysis. To evaluate whether demographic and baseline characteristics were predictive of adherence to study protocols, live birth or participation in blood sampling for DNA and repository, and pregnancy registry, these putative factors were compared between the outcome measures. Logistic regression was used to establish a prediction model using the putative predictors introduced above. MAIN RESULTS AND THE ROLE OF CHANCE: Women who self-identified as African American or Asian and those with higher BMI and lower household income were less likely to adhere to protocol. Non-adherence to the study protocol was associated with a lower probability of live birth (odds ratio: 0.180, 95% CI: 0.120, 0.272, P < 0.001). African Americans or Asians were less likely to participate in optional study DNA collection compared to Whites. Participants who were African American or with high annual income or from the Southwest sites or had PCOS were less likely to participate in the blood repository studies. LIMITATIONS, REASONS FOR CAUTION: Race and ethnicity were self-reported and such self-classification to strict race and ethnicity may not always be representative of a whole racial or ethnic group. This study included two US multicenter trials and therefore the findings may not be extrapolated to international trials. WIDER IMPLICATIONS OF THE FINDINGS: Identification of populations with low participation is an important initial step, as further investigation can develop specific measures to improve adherence to study protocols and participation in biospecimen banking and thereby extend the representativeness of reproductive medicine clinical trial findings. STUDY FUNDING/COMPETING INTEREST(S): Supported by NIH Eunice Kennedy Shriver NICHD Grants: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, U10HD055925, PPCOSII: U10 HD27049, U10 HD38992, U10 HD055925, U10 HD39005, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944; Clinical Reproductive Endocrine Scientist Training Program (CREST): R25HD075737. Outside this study, M.P.D. received NIH/NIHCD research grant and R.S.L. received research grant from Ferring and was consultant for Bayer, Kindex, Odega, Millendo and AbbVie. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT00719186; NCT01044862.

COVID-19 coagulopathy in pregnancy: Critical review, preliminary recommendations, and ISTH registry-Communication from the ISTH SSC for Women's Health.

BACKGROUND: Novel coronavirus (SARS-CoV-2), which causes COVID-19, has thus far affected more than 15 million individuals, resulting in more than 600 000 deaths worldwide, and the number continues to rise. In a large systematic review and meta-analysis of the literature including 2567 pregnant women, 7% required intensive care admission, with a maternal mortality ~1% and perinatal mortality below 1%. There has been a rapid increase in publications on COVID-19-associated coagulopathy, including disseminated intravascular coagulopathy and venous thromboembolism, in the non-pregnant population, but very few reports of COVID-19 coagulopathy during pregnancy; leaving us with no guidance for care of this specific population. METHODS: This is a collaborative effort conducted by a group of experts that was reviewed, critiqued, and approved by the International Society on Thrombosis and Haemostasis Subcommittee for Women's Health Issues in Thrombosis and Hemostasis. A structured literature search was conducted, and the quality of current and emerging evidence was evaluated. Based on the published studies in the non-pregnant and pregnant population with a moderate to high risk of bias as assessed by Newcastle-Ottawa scale and acknowledging the absence of data from randomized clinical trials for management of pregnant women infected with SARS-CoV-2, a consensus in support of a guidance document for COVID-19 coagulopathy in pregnancy was identified. RESULTS AND CONCLUSIONS: Specific hemostatic issues during pregnancy were highlighted, and preliminary recommendations to assist in the care of COVID-19-affected pregnant women with coagulopathy or thrombotic complications were developed. An international registry to gather data to support the management of COVID-19 and associated coagulopathy in pregnancy was established.

Memories of the Teratology Society: 1972-2020.

BACKGROUND: My career goal in 1971 was to learn about the causes of malformations. Attending the annual meetings of the Teratology Society and reading the articles in Teratology exposed me to the scientists and clinicians involved in this research and the methods being used. METHODS: Over a period of 49 years (1972-2020), I heard many presentations about several exposures in pregnancy that can cause birth defects. Symposia and platform presentations provided unique and stimulating information on the fetal effects of the teratogen thalidomide. RESULTS: I developed research studies and presented the results from our studies on teratogenic exposures, such as anticonvulsant drugs, the prenatal diagnosis procedure chorionic villus sampling, and the abortifacient misoprostol. The annual Pregnancy Registry Workshop was developed as a forum for discussing issues related to this new method of evaluating potential teratogenic exposures in pregnancy. CONCLUSION: Attending the annual meetings and reading the articles in the journal Teratology (now Birth Defects Research) have been an instructive and enjoyable way to learn about the causes of malformations.

Pregnancy outcomes in heart transplant recipients.

BACKGROUND: The population of female heart transplant recipients of reproductive age is growing, and counseling regarding reproductive decisions is important. We describe maternal and fetal outcomes of pregnancy in the Transplant Pregnancy Registry International. METHODS: Data regarding pregnancies between 1987 and 2016 were collected via questionnaires, phone interviews, and medical records review. Demographics, comorbidities, changes in immunosuppressive regimens, rejection episodes during pregnancy, data on maternal retransplants, and deaths were recorded. RESULTS: A total of 91 patients reported 157 pregnancies. Mean maternal age at conception was 27 ± 5.6 years. The most common indications for transplant were congenital heart disease (22%) and viral myocarditis (18%). Average transplant to conception interval was 7 ± 6.1 years. Immunosuppression was calcineurin inhibitor-based in almost all patients, with 20% of recipients taking mycophenolic acid (MPA) while pregnant. Complications during pregnancy included pre-eclampsia (23%) and infections (14%). Rejection was reported during 9% of pregnancies and within 3 months postpartum in 7%. Livebirths occurred in 69%, with no neonatal deaths. Miscarriages occurred in 26% of pregnancies, 49% of which had MPA exposure. Mean follow-up post pregnancy was 8.9 ± 6.5 years. At last follow-up, 30 recipients had died, an average of 9.4 ± 6.2 years after pregnancy. The most common causes included allograft vasculopathy and rejection. CONCLUSIONS: This is the largest reported series of pregnancies in heart transplant recipients and demonstrates that two thirds of pregnancies reported are successful. MPA exposure is associated with increased risk of teratogenicity and miscarriage. Pre-pregnancy counseling should include discussions of risk of MPA exposure, rejection, graft dysfunction, and maternal survival.

Safety of MenACWY-CRM vaccine exposure during pregnancy.

BACKGROUND: Although the meningococcal conjugate MenACWY-CRM vaccine is not approved for use in pregnant women, unintentional exposure during pregnancy can occur, especially during early pregnancy among women of child-bearing age. This study provides safety information about inadvertent MenACWY-CRM vaccination during pregnancy. METHODS: The evaluated population consisted of pregnant female members of Kaiser Permanente Southern California who inadvertently received MenACWY-CRM at 11-21 years of age during 09/30/2011-06/30/2013 within 28 days prior to conception or during pregnancy. Chart abstraction was conducted to identify pregnancy and birth outcomes, including spontaneous and induced abortions, preterm births, low weight births, and major congenital malformations (MCMs). RESULTS: There were 92 women who received MenACWY-CRM during the pregnancy exposure period, mainly during the first trimester (76.1%). Hispanics represented the largest race/ethnicity category (68.5%). Among the known pregnancy outcomes (n = 66; excluding induced abortions and unknown pregnancy outcomes), the prevalence of spontaneous abortions was 18.2% (n = 12). Among live born infants (n = 55; from 54 pregnancies), 14.5% (n = 8) were born preterm (<37 weeks gestation) and 9.1% (n = 5) had a low birthweight (<2500 g). The prevalence rate of MCMs among live born infants (n = 55) was 1.8% (n = 1). CONCLUSIONS: This study provides baseline prevalence estimates of spontaneous abortions, preterm births, low weight births, and MCMs among women inadvertently exposed to MenACWY-CRM during the pregnancy period. These estimates appear to be comparable with U.S. background prevalence estimates.

Defect evaluation by infant photographs in a multicenter pharmaceutical clinical trial.

OBJECT: The NT-04 clinical trial of investigational medication NT100 had a limited, though geographically diverse, study population. To enhance potential birth defect identification, photographic dysmorphology exam of infants was performed along with review of prenatal and postnatal medical records. METHODS: Standardized photographic views were developed: full body (prone and supine), face, both profiles, dorsal and ventral hands and feet, genitalia, and birthmarks/skin lesions. Professional photographers were identified and trained. Photos were taken in the first month of life at the subject's home and uploaded to a secure electronic online photo viewer. The evaluating geneticist accessed the photos electronically and submitted an evaluation. RESULTS: Forty subjects had 39 evaluable outcomes (55 babies). Twelve photographers were recruited, 10 of whom worked with multiple subjects. Photographic dysmorphology evaluation was done on 38 pregnancy outcomes. Only one baby had missing photos due to an apparent protocol error. Four babies were photographed with diaper on. CONCLUSIONS: The standardized photographs worked well. Advantages include: a single clinician evaluating all infants, the photographs could be reviewed repeatedly as needed, and minor malformations were more uniformly identified. Difficulties were: identifying local photographers and supplying training and training materials. There was no protocol for retaking or obtaining new photos and the study consent form did not include permission to publish the photographs. This was a successful pilot study of infant photographic assessment to detect congenital anomalies in a clinical trial.

Registries supporting new drug applications.

PURPOSE: Knowledge of the benefits and risks of new drugs is incomplete at the time of marketing approval. Registries offer the possibility for additional, post-approval, data collection. For all new drugs, which were approved in the European Union between 2007 and 2010, we reviewed the frequency, the type, and the reason for requiring a registry. METHODS: The European Public Assessment Reports, published on the website of the European Medicine Agency, were reviewed for drugs approved by the Committee for Medicinal Products for Human Use. We searched for key characteristics of these drugs, including therapeutic area (ATC1 level), level of innovation (the score is an algorithm based on availability of treatment and therapeutic effect), and procedural characteristics. In addition, we identified if these registries were defined by disease (disease registry) or exposure to a single drug (drug registry). RESULTS: Out of 116 new drugs approved in the predefined period, for 43 (37%), 1 to 6 registry studies were identified, with a total of 73 registries. Of these 46 were disease registries and 27 (single) drug registries. For 9 drugs, the registry was a specific obligation imposed by the regulators. The level of innovation and the orphan status of the drugs were determinants positively predicting post-approval registries (OR 10.3 [95% CI 1.0-103.9] and OR 2.8 [95% CI 1.0-7.5], respectively). CONCLUSIONS: The majority of registries required by regulators are existing disease registries. Registries are an important and frequently used tool for post-approval data collection for orphan and innovative drugs.

A systematic review of pregnancy exposure registries: examination of protocol-specified pregnancy outcomes, target sample size, and comparator selection.

PURPOSE: Our study sought to systematically evaluate protocol-specified study methodology in prospective pregnancy exposure registries including pre-specified pregnancy outcomes, power calculations for sample size, and comparator group selection. METHODS: U.S. pregnancy exposure registries designed to evaluate safety of drugs or biologics were identified from www.clinicaltrials.gov, the FDA's Office of Women's Health website, and the FDA's list of postmarketing studies. Protocols or similar documentation were obtained. RESULTS: We identified 35 U.S. registries for drugs or biologic use during pregnancy. All registries assessed risk for overall major congenital malformations. Pre-specified target enrollment was stated for 18 (51%) registries, and ranged from 150 to 500 exposed pregnancies (median 300). Thirty-two (91%) registries identified at least one comparison group, but only nine (26%) planned to use an internal comparator. The most common external comparator group (n = 24, 69%) was the Metropolitan Atlanta Congenital Defects Program (MACDP). CONCLUSIONS: No registries were designed to have sufficient power to assess specific malformations, despite the plausibility that most teratogens cause specific defects. Only half of the registries included a power analysis. Despite their common use, external comparators, including MACDP, have important limitations. In the absence of randomized controlled trial data in pregnant women, pregnancy registries remain an important tool as part of a comprehensive pregnancy surveillance program; however, pregnancy registries alone may not be sufficient to obtain adequate data regarding risks of specific malformations. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Birth defects and neonatal morbidity caused by teratogen exposure after the embryonic period.

BACKGROUND: Pharmaceutical pregnancy exposure registries seek to evaluate temporal associations between drug exposures and adverse outcomes, particularly congenital anomalies. These registries record observed associations that may or may not be causally-related to the exposure. Most major congenital malformations (i.e., structural birth defects) result from abnormal development during embryogenesis. A standardized catalog of defects of concern (colloquially the "BPA Codes") is used both in public health surveillance programs and pregnancy exposure registries. There are, however, some anomalies that cause significant morbidity and mortality for which isolated second or third trimester exposures may be pathogenically significant. There currently exists no standardized list of defects for which exposure limited to the fetal period may be problematic. METHODS: The six-digit-code list was used to determine anomalies that might result from medication exposures limited to the fetal period. RESULTS: Defects with documented first trimester pathogenesis (e.g., anencephaly, heterotaxy) were eliminated from consideration, as were chromosomal and single gene disorders (e.g., trisomy 21, achondroplasia). The remaining defects include the following: (1) those that are known to or could reasonably originate or manifest after the embryonic period (e.g., porencephaly, cataracts); (2) those for which pathogenesis is unclear or variable enough that exposure at any gestational age might be considered relevant (e.g., club foot, microcephaly); and (3) those that include some component of abnormal growth (e.g., hemihyperplasia). "Unspecified" defects (e.g., "abnormality of the leg") were included by default because there is insufficient information to assume first trimester embryogenesis. CONCLUSION: The final result is a list of major and minor anomalies in 11 organ system categories that may be caused by teratogen exposure during the fetal period. Birth Defects Research (Part A) 106:935-939, 2016. © 2016 Wiley Periodicals, Inc.

The need for a disease-specific prospective pregnancy registry for multiple sclerosis (MS).

Multiple sclerosis (MS) is the most commonly acquired neurological disorder affecting young adults of reproductive age with an approximately 3:1 female to male ratio. Although pregnancy is not contraindicated in MS, data are limited regarding pregnancy outcome among MS patients, and the safety or risk to the fetus associated with most maternal MS treatments, such as disease modifying therapies (DMTs), during pregnancy is unknown. We review available epidemiological and registry data on MS and pregnancy and discuss the need to initiate a North American Multiple Sclerosis Pregnancy Registry that will prospectively identify pregnancies in women with MS, obtain information on the disease, and its treatment during gestation and lactation and follow the children to determine their health status.