Birth Outcomes in Women Who Have Taken Hydroxycholoroquine During Pregnancy: A Prospective Cohort Study.

OBJECTIVE: Findings from previous small studies have been reassuring regarding the safety of treatment with hydroxychloroquine (HCQ) during pregnancy. In one recent study, it was demonstrated that the frequency of major birth defects was increased in women who had received HCQ at a dose of ≥400 mg/day during pregnancy. This study was undertaken to examine pregnancy outcomes among women following the use of HCQ. METHODS: The study cohort comprised pregnant women who were prospectively enrolled in the MotherToBaby/Organization of Teratology Information Specialists Autoimmune Diseases in Pregnancy Study and were receiving treatment with HCQ. For the control groups, disease-matched women without HCQ exposure and healthy women were randomly selected from the same source, with subject matching using a 1:1 ratio. Data were collected through interviews, medical records, and dysmorphology examinations. Pregnancy outcome measures included the presence or absence of major and minor birth defects, rates of spontaneous abortion, rates of preterm delivery, and infant growth measures. RESULTS: Between 2004 and 2018, 837 pregnant women met the criteria for study inclusion, including 279 women exposed to HCQ during pregnancy and 279 women in each unexposed control group. Sixty pregnant women (7.2%) were lost to follow-up. Among the women with live births, major birth defects occurred as a pregnancy outcome in 20 (8.6%) of 232 women with HCQ exposure in the first trimester, compared to 19 (7.4%) of 256 disease-matched unexposed controls (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 0.61-2.26) and 13 (5.4%) of 239 healthy controls (adjusted OR 0.76, 95% CI 0.28-2.05). Risks did not differ in women who were receiving an HCQ dose of ≥400 mg/day. No pattern of birth defects was identified. There were no differences in the rates of spontaneous abortion or preterm delivery between groups. Occurrence of infant growth deficiencies did not differ in the HCQ-exposed group compared to the disease-matched unexposed control group, except in the infant's head circumference at birth (adjusted OR 1.85, 95% CI 1.07-3.20). CONCLUSION: In this study, there was no evidence of an increased risk of structural birth defects or other adverse outcomes among women receiving HCQ during pregnancy, with the exception of infant head circumference at birth. For pregnant women being treated with HCQ, these findings are reassuring.

Oral corticosteroid use during pregnancy and risk of preterm birth.

OBJECTIVE: To evaluate the associations between oral corticosteroid (OCS) dose early and late in pregnancy and preterm birth (PTB) among women with RA. METHODS: Pregnant women in the MotherToBaby Pregnancy Studies (2003-2014) with RA (n = 528) were included in the primary analysis. Information was collected by phone interview and from medical records. We estimated risk ratios (RR) for OCS dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after gestational day 139. RESULTS: PTB risk was 15.5% overall. Compared with no OCS, PTB risk was increased in high (adjusted (a)RR: 4.77 (95% CI: 2.76, 8.26)) and medium (aRR: 1.81 (95% CI: 1.10, 2.97)) cumulative OCS dose trajectories during the first 139 gestational days. The low cumulative trajectory group was associated with an increased risk of PTB that was not statistically significant (aRR: 1.38 (95% CI: 0.79, 2.38)), and DMARDs were not associated with PTB (biologic DMARDs aHR: 1.08 (95% CI: 0.70, 1.66); non-biologic DMARDs aHR: 0.87 (95% CI: 0.55, 1.38)). OCS exposure to ⩾10 mg of prednisone equivalent daily dose after gestational day 139 vs none was associated with increased PTB rate (aHR: 2.45 (95% CI: 1.32, 4.56)), whereas <10 mg was associated with a modestly increased rate of PTB that was not statistically significant (aHR: 1.18 (95% CI: 0.60, 2.30)). CONCLUSION: Higher OCS doses vs no OCS use, both earlier and later in pregnancy, were associated with an increase in PTB among women with RA.

Birth outcomes in women who have taken adalimumab in pregnancy: A prospective cohort study.

BACKGROUND: Information is needed on the safety of adalimumab when used in pregnancy for the treatment of certain autoimmune diseases. METHODS AND FINDINGS: Between 2004 and 2016, the Organization of Teratology Information Specialists Research Center at the University of California San Diego conducted a prospective controlled observational cohort study in 602 pregnant women who had or had not taken adalimumab. Women in the adalimumab-exposed cohort had received at least one dose of the drug in the first trimester for the treatment of rheumatoid arthritis or Crohn's Disease (N = 257). Women in the disease comparison cohort had not used adalimumab in pregnancy (N = 120). Women in the healthy comparison cohort had no rheumatic or inflammatory bowel diseases (N = 225). Women and their infants were followed to one year postpartum with maternal interviews, medical records abstraction, and physical examinations. Study outcomes were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, pre and post-natal growth deficiency, serious or opportunistic infections and malignancies. 42/602 (7.0%) of pregnancies were lost-to-follow-up. 22/221 (10.0%) in the adalimumab-exposed cohort had a live born infant with a major birth defect compared to 8/106 (7.5%) in the diseased unexposed cohort (adjusted odds ratio 1.10, 95% confidence interval [CI] 0.45 to 2.73). Women in the adalimumab-exposed cohort were more likely to deliver preterm compared to the healthy cohort (adjusted hazard ratio [aHR] 2.59, 95% CI 1.22 to 5.50), but not compared to the diseased unexposed cohort (aHR 0.82, 95% CI 0.66 to 7.20). No significant increased risks were noted with adalimumab exposure for any other study outcomes. CONCLUSIONS: Adalimumab exposure in pregnancy compared to diseased unexposed pregnancies was not associated with an increased risk for any of the adverse outcomes examined. Women with rheumatoid arthritis or Crohn's Disease were at increased risk of preterm delivery, irrespective of adalimumab exposure.

No Association of Discontinuing Tumor Necrosis Factor Inhibitors Before Gestational Week Twenty in Well-Controlled Rheumatoid Arthritis and Juvenile Idiopathic Arthritis With a Disease Worsening in Late Pregnancy.

OBJECTIVE: To investigate whether the discontinuation of tumor necrosis factor inhibitors (TNFi) during pregnancy is associated with any changes of the disease course in women with rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). METHODS: Pregnant women with RA and JIA from the US and Canada were enrolled in the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Project, a prospective cohort study. Information about medication and disease activity (patient-reported outcome measures) was collected prior to gestational week 20 and at gestational week 32. Associations between patterns of TNFi continuation or discontinuation and disease activity changes were tested in unadjusted and multivariate analyses. RESULTS: Among 490 women (397 with RA, 93 with JIA) enrolled between 2005 and 2017, 122 (24.9%) discontinued a TNFi before gestational week 20, 201 (41.0%) received a TNFi beyond week 20, and 167 (34.1%) did not receive a TNFi during pregnancy. At the time of enrollment, disease activity was low to minimal in 72.9% of women. TNFi discontinuation was not associated with a clinically important worsening of patient reported outcome measures at the third trimester. Univariate but not multivariate analysis showed that women receiving TNFi beyond week 20 were more likely to experience improved disease activity scores at the third trimester. CONCLUSION: Discontinuing TNFi before gestational week 20 seems feasible in women with RA and JIA who enter pregnancy with well-controlled disease.

Approach to evaluating pregnancy safety of anti-rheumatic medications in the OTIS MotherToBaby pregnancy studies: what have we learned?

For the last 30 years, pregnancy exposure studies, with varying methodologies, have been the mainstay of post-marketing surveillance for new drugs likely to be used by women of reproductive age. While they provide valuable data to inform use during pregnancy, they have limitations that render them necessary but not sufficient in supplying timely information to patients and prescribers. The Organization of Teratology Information Specialists MotherToBaby Pregnancy Studies' collaborative research group operates to help fill this gap. This paper provides an overview of the research that has been and is currently being conducted, as well as best practices determined over the past two decades. The Organization of Teratology Information Specialists MotherToBaby studies can provide earlier signaling with regard to concerns following possible teratogenic exposures, which when examined in conjunction with larger database studies and case-control designs, can move us closer to developing a fuller picture of drug safety for women of reproductive age.

Risk of infantile hemangiomas in the offspring of women with autoimmune disease and the pathogenic implications of these lesions.

The purpose of this study was to analyze the risk of maternal autoimmune disease or associated treatments on infantile hemangiomas (IHs), a common benign vascular tumor in infants, and to better understand how maternal chronic inflammation may play a factor in the pathogenesis of these lesions. Eligible women from the United States and Canada who enrolled before 19 weeks' gestation and delivered at least one live born infant were recruited as part of the Organization of Teratology Information Specialists (OTIS) Autoimmune Disease in Pregnancy Project from 2004-2013. A total of 51/969 (5.3%) and 8/240 (3.3%) infants with IH were born to mothers with and without autoimmune disease, respectively (OR 1.61; 95%CI, 0.75-.44). The presence of ulcerative colitis (UC) in the mother was significantly associated with IH in the child (OR 3.46; 95%CI, 1.29-9.26). The five largest IH occurred within the autoimmune disease cohort and to women taking a biologic medication. These results imply that UC may be a risk factor for IH development, and that chronic inflammation may influence the development of these lesions. This potential link between IH and autoimmune disease warrants further investigation.

Consistency of maternal telephone administration of the asthma control test using postpartum recall compared to repeated measures during pregnancy.

BACKGROUND: Suboptimal asthma control during pregnancy may impact perinatal outcomes. U.S. guidelines recommend questionnaires to assess asthma control including the Asthma Control Test (ACT). It is unknown in a research setting to what extent recall differs by the time between symptom occurrence and the administration of the questionnaire. METHODS: Between 2009-2014, 196 pregnant asthmatic women were recruited by the Organization of Teratology Information Specialists (OTIS) MotherToBaby Pregnancy Studies. Participants were administered the ACT at enrollment, gestational weeks 20 and 32, and shortly after delivery. The same women were also administered the ACT retrospectively at approximately 6 months postpartum. RESULTS: The Pearson correlation coefficients between the in-pregnancy and retrospective continuous ACT scores for the 1st, 2nd and 3rd trimesters were: 0.67 (95% CI: 0.58, 0.74), 0.61 (0.52, 0.70) and 0.65 (0.56, 0.72), respectively. When dichotomized into well-controlled asthma (ACT score ≥ 20) versus otherwise, the chi-square test for all three trimesters resulted in p values <0.0001. Cohen's Kappa statistics for the same dichotomized scores were 0.51, 0.45 and 0.40 for each trimester respectively. There was no evidence that adverse outcome of pregnancy (recall bias) influenced postpartum responses. CONCLUSIONS: The retrospectively recalled ACT score obtained postpartum was substantially different compared to in-pregnancy administration of the same questionnaire which could reflect test-retest variability as well as attenuation of recall. Documentation of the magnitude and direction of these differences could be useful in interpretation of the impact of asthma control when the ACT is used in retrospective case-control studies for pregnancy outcomes.

Safety of the 2010-11, 2011-12, 2012-13, and 2013-14 seasonal influenza vaccines in pregnancy: Birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants, a study from the cohort arm of VAMPSS.

INTRODUCTION: There is a need for pregnancy safety information overall and for each seasonal formulation of the influenza vaccine. METHODS: As part of the cohort arm of the Vaccines and Medications in Pregnancy Surveillance System, vaccine-exposed and unexposed women in the U.S. or Canada were recruited during pregnancy in the 2010-2014 vaccine seasons and followed to pregnancy outcome. For the four seasons combined, crude and adjusted relative risks (RRs) were estimated with 95% confidence intervals (CIs) for major birth defects overall and infants small for gestational age. Crude and adjusted hazard ratios (HRs) were estimated with 95% CIs for spontaneous abortion and preterm delivery. Specific influenza season subanalyses were also conducted. RESULTS: Of 1730 women, 1263 were exposed to an influenza vaccine and 467 were unexposed to any influenza vaccine. Among pregnancies with first-trimester exposure excluding lost-to-follow-up, 26/457 (5.7%) resulted in an infant with a major birth defect compared to 13/427 (3.0%) in the unexposed (RR 1.87, 95% CI 0.97, 3.59). No specific pattern of defects was evident in the vaccine-exposed cohort. The overall risk of spontaneous abortion was not elevated (HR 1.09, 95% CI 0.49, 2.40). Adjusted HRs for preterm delivery approximated 1.0 (adjusted HR 1.23, 95% CI 0.75, 2.02). RRs for small for gestational age infants on weight, length and head circumference ranged from 1.19 to 1.49 with all CIs including 1. Season-by-season analyses resulted in variation by season; however, estimates were based on small numbers. CONCLUSIONS: Combining the 2010-2014 influenza seasons, we found a moderately elevated RR for major birth defects overall, but no evidence of a specific pattern; 95% CIs included 1, and this finding could be due to chance. In the combined seasons, we found no meaningful evidence of an increased risk for spontaneous abortion or preterm delivery following exposure to the seasonal influenza vaccine.

Validation of the Pregnancy Asthma Control Test.

BACKGROUND: Suboptimal asthma control during pregnancy may affect perinatal outcomes. US guidelines recommend questionnaires to assess asthma control including the Asthma Control Test (ACT). OBJECTIVE: To validate telephone administration of a modified version of ACT during pregnancy. METHODS: MotherToBaby Pregnancy Studies (2011-2013) enrolled 159 pregnant women with asthma. Participants were interviewed by telephone at intake, at approximately gestational weeks 20 and 32, and postpartum. The ACT was modified to address dyspnea specifically due to asthma; the modified version is the Pregnancy Asthma Control Test (p-ACT). Women answered the p-ACT and guideline-based asthma impairment questions and reported asthma course changes and exacerbations. Possible p-ACT scores ranged from 5 to 25; higher score indicated better control. Reliability, criterion validity, construct validity, prospective validity, and responsiveness were assessed. RESULTS: Cronbach's alpha for internal consistency was similar across time points (0.84-0.90). The p-ACT score varied by impairment; for example, at intake, the mean score was 23.2 for well-controlled versus 13.7 for very poorly controlled asthma. The p-ACT score change between interviews differed by asthma course; for example, women reporting that their asthma was much better at week 20 than at intake had a mean score increase of 4.7; women reporting that their asthma was a little worse had a mean score decrease of 1.3. Lower p-ACT score was associated with previous exacerbations, whereas intake p-ACT score was not associated with future exacerbations during pregnancy. CONCLUSIONS: The p-ACT demonstrated good internal consistency, varied in the expected direction by impairment level, and was responsive to changes in asthma course. Telephone administration of the p-ACT is reliable and valid for assessing asthma control during pregnancy.

The dynamic proliferation of CanSINEs mirrors the complex evolution of Feliforms.

BACKGROUND: Repetitive short interspersed elements (SINEs) are retrotransposons ubiquitous in mammalian genomes and are highly informative markers to identify species and phylogenetic associations. Of these, SINEs unique to the order Carnivora (CanSINEs) yield novel insights on genome evolution in domestic dogs and cats, but less is known about their role in related carnivores. In particular, genome-wide assessment of CanSINE evolution has yet to be completed across the Feliformia (cat-like) suborder of Carnivora. Within Feliformia, the cat family Felidae is composed of 37 species and numerous subspecies organized into eight monophyletic lineages that likely arose 10 million years ago. Using the Felidae family as a reference phylogeny, along with representative taxa from other families of Feliformia, the origin, proliferation and evolution of CanSINEs within the suborder were assessed. RESULTS: We identified 93 novel intergenic CanSINE loci in Feliformia. Sequence analyses separated Feliform CanSINEs into two subfamilies, each characterized by distinct RNA polymerase binding motifs and phylogenetic associations. Subfamily I CanSINEs arose early within Feliformia but are no longer under active proliferation. Subfamily II loci are more recent, exclusive to Felidae and show evidence for adaptation to extant RNA polymerase activity. Further, presence/absence distributions of CanSINE loci are largely congruent with taxonomic expectations within Feliformia and the less resolved nodes in the Felidae reference phylogeny present equally ambiguous CanSINE data. SINEs are thought to be nearly impervious to excision from the genome. However, we observed a nearly complete excision of a CanSINEs locus in puma (Puma concolor). In addition, we found that CanSINE proliferation in Felidae frequently targeted existing CanSINE loci for insertion sites, resulting in tandem arrays. CONCLUSIONS: We demonstrate the existence of at least two SINE families within the Feliformia suborder, one of which is actively involved in insertional mutagenesis. We find SINEs are powerful markers of speciation and conclude that the few inconsistencies with expected patterns of speciation likely represent incomplete lineage sorting, species hybridization and SINE-mediated genome rearrangement.

Novel animal pole-enriched maternal mRNAs are preferentially expressed in neural ectoderm.

BACKGROUND: Many animals utilize maternal mRNAs to pre-pattern the embryo before the onset of zygotic transcription. In Xenopus laevis, vegetal factors specify the germ line, endoderm, and dorsal axis, but there are few studies demonstrating roles for animal-enriched maternal mRNAs. Therefore, we carried out a microarray analysis to identify novel maternal transcripts enriched in 8-cell-stage animal blastomeres. RESULTS: We identified 39 mRNAs isolated from 8-cell animal blastomeres that are >4-fold enriched compared to vegetal pole mRNAs. We characterized 14 of these that are of unknown function. We validated the microarray results for 8/14 genes by qRT-PCR and for 14/14 genes by in situ hybridization assays. Because no developmental functions are reported yet, we provide the expression patterns for each of the 14 genes. Each is expressed in the animal hemisphere of unfertilized eggs, 8-cell animal blastomeres, and diffusely in blastula animal cap ectoderm, gastrula ectoderm and neural ectoderm, neural crest (and derivatives) and cranial placodes (and derivatives). They have varying later expression in some mesodermal and endodermal tissues in tail bud through larval stages. CONCLUSIONS: Novel animal-enriched maternal mRNAs are preferentially expressed in ectodermal derivatives, particularly neural ectoderm. However, they are later expressed in derivatives of other germ layers.

Emerging data on the use of anti-tumor necrosis factor-alpha medications in pregnancy.

Anti-tumor necrosis factor (TNF) α medications are used for the treatment of a number of autoimmune diseases. Evaluation of pregnancy safety for these medications is complicated by the contribution of the underlying maternal disease to adverse pregnancy outcomes, such as preterm delivery and reduced birth weight. Placental transport of these medications is thought to be minimal in the first trimester, thereby providing some reassurance regarding theoretical risks for congenital malformations. Available human exposure data are sparse; however, to date there has been no convincing evidence to support an increased risk for a specific pattern of major congenital malformations with any of the drugs in this group for which some data is currently available. As a result of the improvement of symptoms during pregnancy in some women with autoimmune diseases, it may be possible to discontinue treatment before or shortly after conception. However, in some cases the benefits of treatment and concerns for disease flares in pregnancy have warranted continued treatment during pregnancy. Because of the relatively long half-life of these medications, and theoretical concerns for immune compromise of the infant following exposure in the latter two trimesters, some clinicians recommend discontinuation of treatment in the third trimester to avoid potentially prolonged infant exposure in the postpartum period. Currently ongoing controlled cohort studies for some of the TNF blocker medications will help to provide more definitive answers for clinicians and patients.

Carnivore-specific SINEs (Can-SINEs): distribution, evolution, and genomic impact.

Short interspersed nuclear elements (SINEs) are a type of class 1 transposable element (retrotransposon) with features that allow investigators to resolve evolutionary relationships between populations and species while providing insight into genome composition and function. Characterization of a Carnivora-specific SINE family, Can-SINEs, has, has aided comparative genomic studies by providing rare genomic changes, and neutral sequence variants often needed to resolve difficult evolutionary questions. In addition, Can-SINEs constitute a significant source of functional diversity with Carnivora. Publication of the whole-genome sequence of domestic dog, domestic cat, and giant panda serves as a valuable resource in comparative genomic inferences gleaned from Can-SINEs. In anticipation of forthcoming studies bolstered by new genomic data, this review describes the discovery and characterization of Can-SINE motifs as well as describes composition, distribution, and effect on genome function. As the contribution of noncoding sequences to genomic diversity becomes more apparent, SINEs and other transposable elements will play an increasingly large role in mammalian comparative genomics.

Birth outcomes in women who have taken leflunomide during pregnancy.

OBJECTIVE: In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. METHODS: Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. RESULTS: There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P = 0.13). The rate was similar to the 3-4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomide-exposed and non-leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non-leflunomide-exposed RA groups. CONCLUSION: Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.

Evolution of the GST omega gene family in 12 Drosophila species.

Gene families provide a unique system to study the evolutionary relationships between related genes both within and between organisms. We can ascertain whether members of a gene family in different species are orthologs or paralogs. We may also search for evidence that may explain why duplicate genes are present. The availability of genome sequences for 12 Drosophila species allows us to address these questions with respect to the evolution of one gene family, the glutathione S transferase (GST) omega class. This gene family is of particular interest because of its relationship with human disease and its presence in a wide range of species.

Characterization of human control region sequences for Spanish individuals in a forensic mtDNA data set.

Population data on the hypervariable regions of the mitochondrial DNA (mtDNA) genome are used to convey the relative rarity of mtDNA profiles obtained from evidence samples and of profiles used to identify missing persons. In this study, mtDNA profiles of Spanish individuals (n=312) were analyzed to describe haplogroup distributions and to determine relevant single nucleotide polymorphisms (SNPs) of those haplogroups. All nine common European haplogroups were observed in the sample, and these were divided into subgroups when possible. Haplogroup H was the most common haplogroup. The haplogroups U, J, T, and V were the next most frequent groups, each occurring at a frequency of 6.4% or greater. In addition, African and Asian sequences were present though rare in the samples. The data were compared with and found to be similar to other published data sets. There were 109 SNPs observed in the data set, including 10 positions not previously reported. The most variable sites are consistent with other studies.