Use of cannabis during pregnancy is on the rise, yet little is known about how women administer cannabis during the perinatal period. This study examined self-reported modes of cannabis administration among women in the year before and during pregnancy, and their association with self-reported cannabis use frequency using data from 585 women screened in 2018-2019 for cannabis use during standard prenatal care in two medical centers in Northern California. The prevalence of cannabis use was 12% before pregnancy and 3% during pregnancy. Among the 71 women who reported cannabis use before pregnancy and the 19 women who reported cannabis use during pregnancy, smoking was the most common mode of administration (58% and 42%), followed by edibles (27% and 16%), vaping (23% and 16%), lotions (11% and 5%), and other (10% and 0%). In the year before pregnancy and during pregnancy, monthly or less use was most common (56% and 58%), followed by weekly use (24% and 26%) and daily use (20% and 16%). Among cannabis users, 43% used more than one mode before pregnancy compared to 15% during pregnancy. Daily cannabis use was most common among women who reported smoking only or smoking in combination with other modes. These novel results indicate that while smoking is the most common mode of cannabis administration during the perinatal period, there is variation in use and co-use of alternative modes. Future studies are needed to understand the relative health effects associated with individual and combined modes of cannabis administration during pregnancy.

BACKGROUND:Cross-sectional studies indicate an elevated prevalence of prenatal marijuana use in women with nausea and vomiting in pregnancy (NVP). However, it is unknown whether differences in marijuana use by NVP status have persisted over time as marijuana becomes more acceptable and accessible and prenatal use increases overall. We compared trends in prenatal marijuana use by NVP status in the first trimester of pregnancy using data from Kaiser Permanente Northern California's (KPNC) large healthcare system. METHODS:The sample comprised KPNC pregnant women aged ≥12 who completed a self-administered questionnaire on marijuana use and a urine toxicology test for cannabis during standard prenatal care from 2009 to 2016. The annual prevalence of marijuana use via self-report or toxicology by NVP status was estimated using Poisson regression with a log link function, adjusting for sociodemographics and parity. We tested for linear trends and differences in trends by NVP. RESULTS:Of 220,510 pregnancies, 38,831 (17.6%) had an NVP diagnosis. Prenatal marijuana use was elevated each year among women with NVP. The adjusted prevalence of use increased significantly from 2009 to 2016 at an annual rate of 1.086 (95%CI = 1.069-1.104) among women with NVP, from 6.5% (95%CI = 5.7%-7.2%) to 11.1% (95%CI = 0.2%-12.0%), and 1.069 (95%CI = 1.059-1.080) among women without NVP, from 3.4% (95%CI = 3.2%-3.7%) to 5.8% (95%CI = 5.5%-6.1%). Trends did not vary by NVP status. DISCUSSION:The prevalence of prenatal marijuana use has remained elevated over time among women with NVP. Clinicians should ask pregnant patients about their reasons for marijuana use and treat NVP with evidence-based interventions.

Cannabis use among individuals before and during pregnancy is increasing alongside the proliferation of new products with various modes of administration. Preconception cannabis use is a strong predictor of prenatal cannabis use. Yet little is known about how individuals administer cannabis during the preconception period, particularly in socioeconomically vulnerable populations. This study examined the prevalence and correlates of modes of cannabis administration (smoke, vape, blunts, edible/oral, dabs/wax, lotion/topical) during the year before conception, among patients who self-reported preconception cannabis use during universal screening in prenatal care. Descriptive statistics included sociodemographic characteristics, preconception cannabis use frequency, and modes of administration. Chi-square tests examined whether mode was associated with sociodemographic characteristics and use frequency. The sample (N = 11,936, screened from February 2020-May 2021) was 59.8% non-White and 26.1% were < 26 years old; 50.7% reported monthly or less, 21.8% weekly, and 27.4% daily preconception cannabis use; 69.7% smoked (any method), 34.5% smoked blunts, 53.4% used edibles/oral, 28.2% vaped, 9.9% used lotion/topical; 54.2% reported 1 mode, 30.4% reported 2 modes, 15.4% reported 3+ modes. Smoking was more common among daily users, younger patients, those with greater neighborhood deprivation, and Black and Hispanic patients, while edibles/oral were more common among ≤ monthly users, older patients, those with less neighborhood deprivation, and Asian patients. Use of other modes also varied by sociodemographic characteristics and use frequency. Research is needed to understand preconception cannabis use in vulnerable subpopulations, continuation of use during pregnancy, and whether health risks associated with preconception and prenatal cannabis use differ by administration mode.

Background and aims

Cannabis use is increasingly common among pregnant individuals and might be a risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to test whether prenatal cannabis use is associated with increased risk of SARS-CoV-2 infection during pregnancy.

Design

This is a retrospective cohort study.

Setting

The study was conducted in California, USA.

Participants

A total of 58 114 pregnancies (with outcomes from 5 March 2020 to 30 September 2021) among 57 287 unique pregnant women aged 14-54 years who were screened for prenatal substance use, enrolled in Kaiser Permanente Northern California (KPNC) (a health-care system) and had not tested positive for COVID-19 prior to pregnancy onset.

Measurements

We utilized data from the KPNC electronic health record. Cannabis use status (current, recently quit and non-user) was based on universal screenings during prenatal care (including urine toxicology testing and self-reported use on a self-administered questionnaire). SARS-CoV-2 infection [based on polymerase chain reaction (PCR) tests] was estimated in time-to-event analyses using Cox proportional hazard regression models adjusting for covariates. Secondary analyses examined differences in (a) SARS-CoV-2 testing rates and (b) SARS-CoV-2 infection rates among those tested.

Findings

We observed 348 810 person-months of follow-up time in our cohort with 41 064 SARS-CoV-2 PCR tests and 6% (n = 2414) of tests being positive. At the start of follow-up, 7% of pregnant individuals had current use, 12% had recently quit and 81% did not use cannabis. Adjusting for covariates, current use was associated with lower rates of SARS-CoV-2 infection [adjusted hazard ratio (aHR) = 0.60, 95% confidence interval (CI) = 0.49-0.74 than non-use. Those who had recently quit did not differ from non-cannabis users in infection rates (aHR = 0.96, 95% CI = 0.86-1.08). Sensitivity analyses among patients who received a SARS-CoV-2 test also found lower odds of infection associated with current versus no cannabis use (aOR = 0.76, CI = 0.61-0.93).

Conclusions

Current cannabis use appears to be associated with a reduced risk of SARS-CoV-2 infection among pregnant individuals.

Objective

To examine trends and correlates of frequency of self-reported alcohol and nicotine use among pregnant women.

Methods

Cross-sectional study of 363,240 pregnancies from 2009 to 2017 screened for self-reported substance use at their first prenatal visit in Kaiser Permanente Northern California. Poisson regression with a log link function was used to estimate the annual prevalences of self-reported daily, weekly, and ≤ monthly alcohol and nicotine use, adjusting for socio-demographics. Generalized estimating equation models were used to estimate the adjusted odds ratios (aOR) of any self-reported prenatal alcohol or nicotine use among those who self-reported use in the year prior to pregnancy, by frequency of pre-pregnancy substance use and socio-demographics.

Results

The sample was 64 % non-White [mean (SD) age = 30.1 (5.6)]. From 2009-2017, alcohol use before pregnancy increased from 63.4%-65.9% (trend p-value = .008), and prenatal alcohol use decreased from 11.6%-8.8% (trend p-value<.0001). Nicotine use before pregnancy decreased from 12.7 % to 7.7 % (trend p-value<.0001), and prenatal use decreased from 4.3 % to 2.0 % (trend p-value<.0001). Trends by use frequency were similar to overall trends. The odds of continued use of alcohol and nicotine during pregnancy were higher among those who used daily or weekly (versus monthly or less) in the year before pregnancy and varied with socio-demographics.

Discussion

Prenatal alcohol and nicotine use decreased from 2009 to 2017. More frequent pre-pregnancy use predicted higher odds of prenatal use. Results suggest that interventions and education about the harms of prenatal substance use for frequent users prior to conception may reduce substance use during pregnancy.

Objectives

The goal of this study was to evaluate the association between pregnancy intentions and substance use in early pregnancy among pregnant women receiving prenatal care in a large, integrated healthcare system.

Methods

The sample comprised 29,787 Kaiser Permanente Northern California pregnant women (12.1% aged <25, 36.4% non-Hispanic White) screened for prenatal substance use in 2018 via a self-reported questionnaire and urine toxicology test given as part of standard prenatal care (at ∼8 weeks gestation). Multivariable logistic regression models tested for associations of pregnancy intentions with prenatal substance use (any use and specific substances) by self-report and/or a positive urine toxicology test.

Results

Adjusting for covariates, women with an unintended pregnancy (23.9% of the sample) had higher odds of any prenatal substance use than women with an intended pregnancy (28.8% vs 16.1%; adjusted odds ratio [aOR] = 1.80, 95% confidence interval [CI]:1.67-1.93). Having an unintended pregnancy was also associated with higher odds of using alcohol (14.4% vs 10.4%; aOR = 1.73, 95%CI:1.59-1.89), cannabis (15.6% vs 5.6%; aOR = 1.91, 95%CI:1.73-2.11), nicotine (3.8% vs 1.3%; aOR = 2.33, 95%CI:1.92-2.82), pain medication (2.3% vs 1.2%; aOR = 1.64, 95%CI:1.32-2.03), and stimulants (0.8% vs 0.3%; aOR = 1.85, 95%CI:1.23-2.79) early in pregnancy.

Discussion

Having an unintended pregnancy was associated with higher odds of substance use during early pregnancy. Connecting women of reproductive age with health education about pregnancy prevention and recognition of early signs of pregnancy, effective contraception, and early screening and interventions for prenatal substance use may help to reduce prenatal substance use and its associated consequences.

Drug resistance represents a major challenge to achieving durable responses to cancer therapeutics. Resistance mechanisms to epigenetically targeted drugs remain largely unexplored. We used bromodomain and extra-terminal domain (BET) inhibition in neuroblastoma as a prototype to model resistance to chromatin modulatory therapeutics. Genome-scale, pooled lentiviral open reading frame (ORF) and CRISPR knockout rescue screens nominated the phosphatidylinositol 3-kinase (PI3K) pathway as promoting resistance to BET inhibition. Transcriptomic and chromatin profiling of resistant cells revealed that global enhancer remodeling is associated with upregulation of receptor tyrosine kinases (RTKs), activation of PI3K signaling, and vulnerability to RTK/PI3K inhibition. Large-scale combinatorial screening with BET inhibitors identified PI3K inhibitors among the most synergistic upfront combinations. These studies provide a roadmap to elucidate resistance to epigenetic-targeted therapeutics and inform efficacious combination therapies.

Pharmacologically difficult targets, such as MYC transcription factors, represent a major challenge in cancer therapy. For the childhood cancer neuroblastoma, amplification of the oncogene MYCN is associated with high-risk disease and poor prognosis. Here, we deployed genome-scale CRISPR-Cas9 screening of MYCN-amplified neuroblastoma and found a preferential dependency on genes encoding the polycomb repressive complex 2 (PRC2) components EZH2, EED, and SUZ12. Genetic and pharmacological suppression of EZH2 inhibited neuroblastoma growth in vitro and in vivo. Moreover, compared with neuroblastomas without MYCN amplification, MYCN-amplified neuroblastomas expressed higher levels of EZH2. ChIP analysis showed that MYCN binds at the EZH2 promoter, thereby directly driving expression. Transcriptomic and epigenetic analysis, as well as genetic rescue experiments, revealed that EZH2 represses neuronal differentiation in neuroblastoma in a PRC2-dependent manner. Moreover, MYCN-amplified and high-risk primary tumors from patients with neuroblastoma exhibited strong repression of EZH2-regulated genes. Additionally, overexpression of IGFBP3, a direct EZH2 target, suppressed neuroblastoma growth in vitro and in vivo. We further observed strong synergy between histone deacetylase inhibitors and EZH2 inhibitors. Together, these observations demonstrate that MYCN upregulates EZH2, leading to inactivation of a tumor suppressor program in neuroblastoma, and support testing EZH2 inhibitors in patients with MYCN-amplified neuroblastoma.

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.