Patterns of Use and Self-reported Effectiveness of Cannabis for Hyperemesis Gravidarum.

Introduction There is limited research on effective treatment of Hyperemesis Gravidarum (HG), the most extreme version of nausea and vomiting during pregnancy (NVP). This paper examines current patterns of use and self-reported effectiveness of cannabis/cannabis-based products (CBP) to treat HG. Materials/Methods The study employed a 21-question survey to gather information on demographics, antiemetic prescription use, and experience with cannabis/CBPs among individuals who experienced extreme nausea and vomiting or HG during their pregnancy. Age-adjusted unconditional logistic regression was used to compare odds of symptom relief and weight gain between respondents who used prescription antiemetics and those who used cannabis. Results Of the 550 survey respondents, 84% experienced weight loss during pregnancy; 96% reported using prescription antiemetics and 14% reported cannabis use for HG. Most respondents reported using cannabis/CBPs (71%) because their prescribed antiemetics were self-reported to be ineffective. More than half of cannabis/CBP users reported using products daily or multiple times per day (53%), primarily via smoke inhalation (59%), and mainly either delta-9-tetrahydrocannabinol (THC) only or THC dominant preparations (57%). Eighty-two percent of cannabis/CBP users reported symptom relief, compared to 60% of prescription antiemetic users. Among patients who reported weight loss during pregnancy, 56% of cannabis users reported gaining weight within two weeks of treatment, compared to 25% of prescription antiemetic users. Conclusions Respondents reported using cannabis primarily because prescribed medications were self-reported to be ineffective. Although the survey approach has inherent limitations so results should be interpreted with caution, in this sample, cannabis was self-reported to be more effective than prescription medications in alleviating HG symptoms and enabling pregnancy weight gain. Therefore, depending on the safety profiles, randomized, double-blinded, placebo-controlled trials of cannabis compared to other antiemetics are warranted to determine whether cannabinoids may provide an effective alternative treatment for HG.

Marijuana use and perinatal outcomes in obstetric patients at a safety net hospital.

OBJECTIVE: To characterize the association between antepartum marijuana exposure and maternal and neonatal outcomes at our institution. STUDY DESIGN: Retrospective chart review identified an obstetric cohort of singleton gestations. Women with self-reported marijuana use were compared with non-users. Demographic characteristics, risk factors, and maternal-fetal outcomes were evaluated. Associations between outcomes and marijuana use were assessed with regression analysis. RESULTS: Of 2792 deliveries, 5.4% reported marijuana use. Compared to non-users, marijuana users entered prenatal care later, were younger, non-Hispanic, and used other illicit substances. Marijuana users had a higher rate of cesarean delivery (p = 0.01). After adjusting for confounders, marijuana use remained associated with 4.1-fold risk of delivering a small for gestational age (SGA) infant and 2.89-fold risk of neonatal oxygen use. CONCLUSION: At a safety net hospital, antepartum marijuana use is significantly associated with cesarean delivery, SGA and supplemental oxygen use at birth. Healthcare disparities associated with marijuana use make this a population of critical interest.

HyperEmesis Level Prediction (HELP Score) Identifies Patients with Indicators of Severe Disease: a Validation Study.

Objective Hyperemesis gravidarum (HG) severity can be underestimated resulting in undertreatment and adverse outcomes. This study was conducted to validate a tool (HELP Score) designed to score HG severity. Materials and Methods A survey link which included PUQE and HELP Score (HELP) tool questions was posted on websites related to HG. HELP scores were compared to PUQE scores for indicators of severe disease. Results HELP classified 92% of women reporting "nothing goes or stays down" as severe, compared to 58% using PUQE. Women self-categorizing symptoms as severe were more likely categorized as severe using HELP. Women hospitalized for HG were more likely classified as severe using HELP. HELP performs better than PUQE in identifying patients with severe symptoms requiring intervention. Conclusion This study provides a novel tool that should be implemented to determine the need for intervention for NVP that may be overlooked using PUQE or empirical assessment.

Effect of gabapentin on hyperemesis gravidarum: a double-blind, randomized controlled trial.

BACKGROUND: Hyperemesis gravidarum is a disabling disease of nausea, vomiting, and undernutrition in early pregnancy for which there are no effective outpatient therapies. Poor weight gain in hyperemesis gravidarum is associated with several adverse fetal outcomes including preterm delivery, low birthweight, small for gestational age, low 5-minute Apgar scores, and neurodevelopmental delay. Gabapentin is most commonly used clinically for treating neuropathic pain but also substantially reduces chemotherapy-induced and postoperative nausea and vomiting. Pregnancy registry data have shown maternal first-trimester gabapentin monotherapy to be associated with a 1.2% rate of major congenital malformations among 659 infants, which compares favorably with the 1.6% to 2.2% major congenital malformation rate in the general population. Open-label gabapentin treatment in hyperemesis gravidarum was associated with reduced nausea and vomiting and improved oral nutrition. OBJECTIVE: This study aimed to determine whether gabapentin is more effective than standard-of-care therapy for treating hyperemesis gravidarum. STUDY DESIGN: A double-blind, randomized, multicenter trial was conducted among patients with medically refractory hyperemesis gravidarum requiring intravenous hydration. Patients were randomized (1:1) to either oral gabapentin (1800-2400 mg/d) or an active comparator of either oral ondansetron (24-32 mg/d) or oral metoclopramide (45-60 mg/d) for 7 days. Differences in Motherisk-pregnancy-unique quantification of nausea and emesis total scores between treatment groups averaged over days 5 to 7, using intention-to-treat principle employing a linear mixed-effects model adjusted for baseline Motherisk-pregnancy-unique quantification of nausea and emesis scores, which served as the primary endpoint. Secondary outcomes included Motherisk-pregnancy-unique quantification of nausea and emesis nausea and vomit and retch subscores, oral nutrition, global satisfaction of treatment, relief, desire to continue therapy, Nausea and Vomiting of Pregnancy Quality of Life, and Hyperemesis Gravidarum Pregnancy Termination Consideration. Adjustments for multiple comparisons were made employing the false discovery rate. RESULTS: A total of 31 patients with hyperemesis gravidarum were enrolled from October 2014 to May 2019. Among the 21 patients providing primary outcome data (12 assigned to gabapentin and 9 to the active comparator arm), 18 were enrolled as outpatients and all 21 were outpatients from days 5 to 7. The study groups' baseline characteristics were well matched. Gabapentin treatment provided a 52% greater reduction in days 5 to 7 baseline adjusted Motherisk-pregnancy-unique quantification of nausea and emesis total scores than treatment with active comparator (95% confidence interval, 16-88; P=.01). Most secondary outcomes also favored gabapentin over active comparator treatment including 46% and 49% decreases in baseline adjusted Motherisk-pregnancy-unique quantification of nausea and emesis nausea (95% confidence interval, 19-72; P=.005) and vomit and retch subscores (95% confidence interval, 21-77; P=.005), respectively; a 96% increase in baseline adjusted oral nutrition scores (95% confidence interval, 27-165; P=.01); and a 254% difference in global satisfaction of treatment (95% confidence interval, 48-459; P=.03). Relief (P=.06) and desire to continue therapy (P=.06) both showed trends favoring gabapentin treatment but Nausea and Vomiting of Pregnancy Quality of Life (P=.68) and Hyperemesis Gravidarum Pregnancy Termination Consideration (P=.58) did not. Adverse events were roughly equivalent between the groups. There were no serious adverse events. CONCLUSION: In this small trial, gabapentin was more effective than standard-of-care therapy for reducing nausea and vomiting and increasing oral nutrition and global satisfaction in outpatients with hyperemesis gravidarum. These data build on previous findings in other patient populations supporting gabapentin as a novel antinausea and antiemetic therapy and support further research on gabapentin for this challenging complication of pregnancy.

Nausea and vomiting of pregnancy and hyperemesis gravidarum.

Nausea and vomiting of pregnancy (NVP) is a common condition that affects as many as 70% of pregnant women. Although no consensus definition is available for hyperemesis gravidarum (HG), it is typically viewed as the severe form of NVP and has been reported to occur in 0.3-10.8% of pregnant women. HG can be associated with poor maternal, fetal and child outcomes. The majority of women with NVP can be managed with dietary and lifestyle changes, but more than one-third of patients experience clinically relevant symptoms that may require fluid and vitamin supplementation and/or antiemetic therapy such as, for example, combined doxylamine/pyridoxine, which is not teratogenic and may be effective in treating NVP. Ondansetron is commonly used to treat HG, but studies are urgently needed to determine whether it is safer and more effective than using first-line antiemetics. Thiamine (vitamin B1) should be introduced following protocols to prevent refeeding syndrome and Wernicke encephalopathy. Recent advances in the genetic study of NVP and HG suggest a placental component to the aetiology by implicating common variants in genes encoding placental proteins (namely GDF15 and IGFBP7) and hormone receptors (namely GFRAL and PGR). New studies on aetiology, diagnosis, management and treatment are under way. In the next decade, progress in these areas may improve maternal quality of life and limit the adverse outcomes associated with HG.

Analysis of GDF15 and IGFBP7 in Hyperemesis Gravidarum Support Causality.

Objective Hyperemesis gravidarum, severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies and leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. It is associated with both maternal and fetal morbidity. Familial aggregation studies and twin studies suggest a genetic component. In a recent GWAS, we showed that placentation, appetite, and cachexia genes GDF15 and IGFBP7 are linked to hyperemesis gravidarum (HG). The purpose of this study is to determine whether GDF15 and IGFBP7 are upregulated in HG patients. Methods We compared serum levels of GDF15 and IGFBP7 at 12 and 24 weeks' gestation in women hospitalized for HG, and two control groups, women with nausea and vomiting of pregnancy (NVP), and women with no NVP. Results We show GDF15 and IGFBP7 serum levels are significantly increased in women with HG at 12 weeks' gestation. Serum levels of hCG are not significantly different between cases and controls. At 24 weeks gestation, when symptoms have largely resolved, there is no difference in GDF15 and IGFBP7 serum levels between cases and controls. Conclusion This study supports GDF15 and IGFBP7 in the pathogenesis of HG and may be useful for prediction and diagnosis. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under intense investigation. Based on our findings, HG should be included.

Analysis of neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum reveals increased reporting of autism spectrum disorder.

The purpose of this study was to follow up on the reporting of neurodevelopmental disorders in children exposed in utero to Hyperemesis Gravidarum (HG). This was an exploratory descriptive study whereby neurodevelopmental outcomes of 267 children delivered by 177 mothers with HG were compared to neurodevelopmental outcomes from 93 children delivered by 60 unaffected mothers. Similar to at age 8, the children (now 12) exposed in utero to HG had over 3-fold increase in odds of neurodevelopmental disorders including attention, anxiety, sensory, sleep difficulty, and social development delay/social anxiety. However, with the longer follow-up, there was also a significant increase in Autism Spectrum Disorder (ASD), reported in 22/267 (8%) of children exposed to HG in utero and no unexposed children. As early intervention for ASD can be critical to prognosis, larger studies are urgently needed to determine whether ASD is associated with exposure to HG.

Evidence GDF15 Plays a Role in Familial and Recurrent Hyperemesis Gravidarum.

Introduction Hyperemesis gravidarum (HG), a pregnancy complication characterized by severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies. It is associated with both maternal and fetal morbidity. HG is highly heritable and recurs in approximately 80% of women. In a recent genome-wide association study, it was shown that placentation, appetite, and the cachexia gene GDF15 are linked to HG. The purpose of this study was to explore whether GDF15 alleles linked to overexpression of GDF15 protein segregate with the condition in families, and whether the GDF15 risk allele is associated with recurrence of HG. Methods We analyzed GDF15 overexpression alleles for segregation with disease using exome-sequencing data from 5 HG families. We compared the allele frequency of the GDF15 risk allele, rs16982345, in patients who had recurrence of HG with its frequency in those who did not have recurrence. Results Single nucleotide polymorphisms (SNPs) linked to higher levels of GDF15 segregated with disease in HG families. The GDF15 risk allele, rs16982345, was associated with an 8-fold higher risk of recurrence of HG. Conclusion The findings of this study support the hypothesis that GDF15 is involved in the pathogenesis of both familial and recurrent cases of HG. The findings may be applicable when counseling women with a familial history of HG or recurrent HG. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under development. Based on our findings, patients carrying GDF15 variants associated with GDF15 overexpression should be included in future studies of GDF15-GFRAL-based therapeutics. If safe, this approach could reduce maternal and fetal morbidity.

Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3-2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10-8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.

Analysis of pre- and post-pregnancy issues in women with hyperemesis gravidarum.

The purpose of this study is to determine the frequency of reporting of both pre-pregnancy and post-pregnancy psychosocial and physical issues in women with hyperemesis gravidarum (HG). Conditions in 449 women with HG were compared to 459 unaffected women (controls). Binary responses were analyzed using either Chi-squared or Fishers Exact test. Continuous responses were analyzed using a t-test. Among 60 pre-pregnancy conditions surveyed, 10 common (>5%) maternal pre-pregnancy conditions were significantly more frequently reported by women with HG. Twenty rare (<5% controls) pre-pregnancy conditions with significantly increased reporting in the HG group were identified. Thirty (50%) pre-pregnancy conditions were similarly reported between cases and controls. Among 80 post-pregnancy factors surveyed, women with HG also showed significantly higher reporting for 7 common and 50 rare post-pregnancy outcomes. Women with HG are significantly more likely to self-report physical and psychosocial issues both before and after pregnancy.

Genetic analysis of hyperemesis gravidarum reveals association with intracellular calcium release channel (RYR2).

Hyperemesis Gravidarum (HG), severe nausea/vomiting in pregnancy (NVP), can cause poor maternal/fetal outcomes. Genetic predisposition suggests the genetic component is essential in discovering an etiology. We performed whole-exome sequencing of 5 families followed by analysis of variants in 584 cases/431 controls. Variants in RYR2 segregated with disease in 2 families. The novel variant L3277R was not found in any case/control. The rare variant, G1886S was more common in cases (p = 0.046) and extreme cases (p = 0.023). Replication of G1886S using Norwegian/Australian data was supportive. Common variants rs790899 and rs1891246 were significantly associated with HG and weight loss. Copy-number analysis revealed a deletion in a patient. RYR2 encodes an intracellular calcium release channel involved in vomiting, cyclic-vomiting syndrome, and is a thyroid hormone target gene. Additionally, RYR2 is a downstream drug target of Inderal, used to treat HG and CVS. Thus, herein we provide genetic evidence for a pathway and therapy for HG.

Ondansetron in pregnancy and risk of adverse fetal outcomes in the United States.

This is an analysis of fetal outcome in pregnancies exposed to ondansetron to treat Hyperemesis Gravidarum (HG). In this retrospective cohort study, U.S. data on outcome were collected on 1070 pregnancies exposed to ondansetron and compared to outcomes in two control groups: 771 pregnancies in women with a history of HG with no ondansetron exposure and 1555 pregnancies with neither a history of HG nor ondansetron exposure. Ventricular septal defects were reported in 2/952 of infants in the HG/Ondansetron-exposure group and 4/1286 in the No HG/No Ondansetron-exposure group. Cleft palate was reported in 1/952 live births in the HG/Ondansetron and 2/1286 in the No HG/No Ondansetron-exposure groups. Women with a history of HG who took ondansetron reported less miscarriages and terminations, and higher live birth rates. The overall results do not support evidence of teratogenicity of ondansetron.

Neurodevelopmental delay in children exposed in utero to hyperemesis gravidarum.

OBJECTIVE: The purpose of this study is to determine the frequency of emotional, behavioral, and learning disorders in children exposed in utero to hyperemesis gravidarum (HG) and to identify prognostic factors for these disorders. STUDY DESIGN: Neurodevelopmental outcomes of 312 children from 203 mothers with HG were compared to neurodevelopmental outcomes from 169 children from 89 unaffected mothers. Then the clinical profiles of patients with HG and a normal child outcome were compared to the clinical profiles of patients with HG and a child with neurodevelopmental delay to identify prognostic factors. Binary responses were analyzed using either a Chi-square or Fisher Exact test and continuous responses were analyzed using a t-test. RESULTS: Children exposed in utero to HG have a 3.28-fold increase in odds of a neurodevelopmental diagnosis including attention disorders, learning delay, sensory disorders, and speech and language delay (P<0.0005). Among characteristics of HG pregnancies, only early onset of symptoms (prior to 5 weeks gestation) was significantly linked to neurodevelopmental delay. We found no evidence for increased risk of 13 emotional, behavioral, and learning disorders, including autism, intellectual impairment, and obsessive-compulsive disorder. However, the study was not sufficiently powered to detect rare conditions. Medications, treatments, and preterm birth were not associated with an increased risk for neurodevelopmental delay. CONCLUSION: Women with HG are at a significantly increased risk of having a child with neurodevelopmental delay. Common antiemetic treatments were not linked to neurodevelopmental delay, but early symptoms may play a role. There is an urgent need to address whether aggressive treatment that includes vitamin and nutrient supplementation in women with early symptoms of severe nausea of pregnancy decreases the risk of neurodevelopmental delay.

A comparison of obstetrical outcomes with labor induction agents used at term.

OBJECTIVE: To compare the obstetrical outcomes of term pregnancies induced with one of four commonly used labor induction agents. METHODS: This is a retrospective cohort study of induced deliveries between 1 August 1995 and 31 December 2007 occurring at the Los Angeles County + University of Southern California Medical Center. Viable, singleton, term pregnancies undergoing induction were identified. Exclusion criteria included gestational age less than 37 weeks, previous cesarean delivery, breech presentation, stillbirth, premature rupture of membranes, and fetal anomaly. Induction methods studied were oxytocin, misoprostol, dinoprostone and Foley catheter. Our primary outcome was cesarean delivery rate among the four induction agents. Secondary outcomes included rate of failed induction, obstetrical complications, and immediate neonatal complications. RESULTS: A total of 3707 women were included in the study (1486 nulliparous; 2221 multiparous). Outcomes were compared across induction methods using Chi-square Tests (Pearson or Fisher's, as appropriate). Among the nulliparous patients, there was no statistical difference among the four induction agents with regards to cesarean delivery rate (p = 0.51), frequency of failed inductions (p = 0.49), the cesarean delivery frequency for "fetal distress" (p = 0.82) and five minute Apgar score <7 (p = 0.24). Among parous patients, the cesarean delivery rate varied significantly by induction method (p < 0.001), being lowest among those receiving misoprostol (10%). Those receiving oxytocin and transcervical Foley catheter had cesarean rates of 22%, followed by dinoprostone at 18%. The rate of failed inductions was 2% among those receiving misoprostol, compared to 7-8% among those in the other groups (p < 0.01). Although cases of "fetal distress" between the four induction agents was not significantly different amongst multipara women, the cesarean delivery indication for "fetal distress" was higher among multipara receiving misoprostol (p = 0.004). There was no difference among the different induction agents with regards to five minute Apgar <7 (p = 0.34). CONCLUSION: Among nulliparous women, all induction methods have similar rate of cesarean delivery. The use of misoprostol appears to be associated with a lower risk of cesarean birth among parous women induced at our institution.

Perioperative characteristics associated with preterm birth in twin-twin transfusion syndrome treated by laser surgery.

OBJECTIVE: To identify perioperative risk factors for preterm delivery (PTD) in laser-treated patients with twin-twin transfusion syndrome (TTTS). STUDY DESIGN: Twin-twin transfusion syndrome patients who underwent laser surgery were followed prospectively. Univariate and multivariate analyses were performed to identify gestational and surgical characteristics associated with preterm delivery. RESULTS: Of 318 eligible patients, the mean (SD) gestational age of delivery was 32.8 (4.2) weeks. The number of days from laser surgery to delivery had a bimodal distribution; group I delivered within 21 days and group II delivered after 21 days of surgery. Eighteen patients (5.7%) were in group I and demonstrated the following risk factors for delivery within 21 days: incomplete laser surgery suspected (odds ratio [OR], 11.14; P = .0106), preoperative subchorionic hematoma (OR, 7.92, P = .0361), preoperative cervical length <2.0 cm (OR, 4.71; P = .0117), and recipient's maximum vertical pocket ≥14 cm (OR, 3.23; P = .0335). In group II, 92 of 300 patients (30.7%) delivered <32 weeks, and 25 (8.3%) delivered <28 weeks; multivariate logistic regression analyses identified 5 risk factors for delivery <32 weeks: incomplete laser surgery suspected (OR, 10.0; P = .0506); incidental septostomy (OR, 4.4; P = .0009); triplet gestation (OR, 2.6; P = .0689); postoperative membrane detachment (OR, 2.4; P = .0393); and nonposterior placental location (OR, 1.8; P = .0282). CONCLUSION: Timing of delivery after laser for twin-twin transfusion syndrome has a bimodal distribution with distinct gestational and surgical risk factors. This information may be useful in counseling patients and in directing future avenues of research.