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.

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.

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.

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.

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.

A low-fidelity total abdominal hysterectomy teaching model for obstetrics and gynecology residents.

INTRODUCTION: The objective is to develop a low-fidelity total abdominal hysterectomy (TAH) model for resident training with the purpose to improve residents' knowledge of anatomy, instruments, instrument handling, suture selection, and steps of a TAH. METHODS: A TAH model was created using products purchased from a crafts store. Obstetrics and gynecology residents (second-year residents and fourth-year residents) were subjected to a lecture followed by a simulated TAH. Before and after the course, subjects were given a survey to assess their confidence regarding the different surgical aspects of the TAH. Confidence was assessed regarding knowledge of anatomy, instruments, instrument handling, suture selection, incision site, steps of the TAH, and global confidence. Statistical analysis was performed using nonparametric tests. A P < 0.05 was considered significant. RESULTS: A low-fidelity TAH model was created. Eight second-year residents and seven fourth-year residents were studied. As expected, second-year residents had a lower median number of hysterectomies performed as primary surgeon when compared with fourth-year residents [0.5 (0.0-1.75) vs. 51.0 (50.0-53.0); P < 0.05]. Despite this difference, after having undergone the course, both resident classes demonstrated either statistical trends or significantly increased surgical confidence in all areas studied. CONCLUSION: Our novel, low-fidelity TAH simulation model and course improves obstetrics and gynecology residents' confidence in surgical skills and knowledge, particularly for those with less surgical experience. The total cost to make approximately 18 models was US $60.00.

Risk factors, treatments, and outcomes associated with prolonged hyperemesis gravidarum.

OBJECTIVE: To identify factors associated with prolonged Hyperemesis Gravidarum (HG). STUDY DESIGN: About 395 women completed a survey regarding pre-existing conditions, treatments and outcomes. Responses were compared using two-sided t-tests or the F-test. RESULTS: Participants with prolonged HG are slightly younger and weigh more. Pre-existing factors associated with prolonged HG include allergies and a restrictive diet. Prolonged HG is associated with hematemesis, dizziness, fainting and antiemetic treatment. Following pregnancy, those with prolonged HG reported more posttraumatic stress, motion sickness, muscle weakness and infants with irritability, severe colic and growth restriction. CONCLUSION: Multiple pre-existing conditions and poor maternal and infant outcomes were associated with prolonged HG. The most significant condition prior to pregnancy was allergies suggesting a possible autoimmune component affecting duration of HG. In addition, the most significant lifestyle choice linked to prolonged HG was a restrictive diet. Future research is needed to determine whether a change in diet prior to pregnancy may lead to a shorter duration of HG and its associated outcomes.

Change in paternity and recurrence of hyperemesis gravidarum.

OBJECTIVE: To determine whether change in paternity changes recurrence risk of hyperemesis gravidarum (HG). STUDY DESIGN: Survey data on recurrence of HG was compared between cases who had a paternity change between pregnancies and cases who did not. RESULTS: The percentage of HG pregnancies in women with the same partner for all pregnancies was not significantly different from the percentage of HG pregnancies in women who changed partners for at least one pregnancy (78% vs 71%, p > 0.05). Participants who did and did not change partners between their first and second pregnancies, were asked to rate their first and second pregnancy in regards to symptoms of HG. Neither the ratings nor the change in rating between pregnancies was significantly different between the two groups. CONCLUSION: Women reported HG in over 70% of their pregnancies regardless of a paternity change. Paternal genes expressed through the fetus do not have a significant effect on incidence or recurrence of HG. This study supports a strong maternal genetic factor involved in HG. However, because the recurrence risk is not 100%, other factors play a role. Identification of the predisposing gene(s) and other factors will determine the cause of this poorly understood complication of pregnancy.

Posttraumatic stress symptoms following pregnancy complicated by hyperemesis gravidarum.

OBJECTIVE: Hyperemesis gravidarum (HG) can be accompanied by severe physical and emotional distress. Most studies have focused on the physical and psychological stress associated with this condition during the affected pregnancy. This study explores posttraumatic stress symptoms (PTSS) and negative life outcomes following HG pregnancies. METHODS: A total of 610 women (HG = 377 and control = 233) were recruited and completed an online survey. χ-square analyses were used to compare the HG and control groups on various life outcome variables. RESULTS: Eighteen percent of women with HG reported full criteria PTSS (n = 68). Negative life outcomes regarding financial and marital status, career, as well as psychological and physical well-being differed significantly for the HG groups compared to the control group (0.001 < p < 0.05). CONCLUSIONS: PTSS is common following HG pregnancies and is associated with negative life outcomes including inability to breastfeed, marital problems, financial problems, and inability of self care.

Prevention of pre-eclampsia with low-dose aspirin or vitamins C and E in women at high or low risk: a systematic review with meta-analysis.

UNLABELLED: The aim of this study is to review literature about the efficacy of low dose aspirin (LDA) and vitamins C/E (VCE) to prevent pre-eclampsia in women at high and low risk. Randomized clinical trials were included and stratified for high and low risk women. Inclusion criteria were: assignment of patients in treated or placebo groups, definition of pre-eclampsia according to the guidelines of the International Society for the Study of Hypertension in Pregnancy. Exclusion criteria were: omitting at least one of the inclusion criteria, trials involving women with pre-eclampsia at trial entry, studies investigating hypertensive disorders other than pre-eclampsia, prophylaxis of intrauterine growth restriction with low-dose aspirin or vitamins C/E, non-randomized studies and data reported in graphs or percentages. The incidence of pre-eclampsia, perinatal outcomes and adverse effects attributable to LDA and VCE were compared between treated women and placebo. Inter-studies heterogeneity was tested. P<0.05 was considered significant. pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated. PRISMA guidelines were followed. Fifteen studies were pooled. LDA did not decrease the incidence of pre-eclampsia in high-risk (396/5025 - 8% vs placebo: 464/5027 - 9%; P=0.05; OR: 0.72; 95% CI: 0.51-1.00) and low-risk (137/4939 - 3% vs placebo: 166/4962 - 3%; P=0.10; OR: 0.82; 95% CI: 0.65-1.04) women. Similarly, VCE did not reduce the incidence of pre-eclampsia in high-risk (VCE: 250/1744 - 14% vs placebo: 275/1741 - 16%; P=0.24; OR: 0.84; 95% CI: 0.63-1.12) and low-risk (VCE: 56/935 - 6% vs placebo 47/942 - 5%; P=0.57; OR: 1.20; 95% CI: 0.82-1.75) women. In high-risk women, other hypertensive disorders were more frequent in VCE (121/1692 - 7%) than placebo (79/1693 - 5%; P=0.002). Perinatal outcomes were not improved by LDA or VCE. CONCLUSION: there is no evidence to support the administration of LDA or VCE to prevent pre-eclampsia.

Recurrence risk of hyperemesis gravidarum.

INTRODUCTION: The purpose of this study is to describe the recurrence risk for hyperemesis gravidarum (HG). METHODS: Women who registered on a Web site sponsored by the Hyperemesis Education and Research Foundation as having had one HG-complicated pregnancy were contacted to follow-up on a subsequent pregnancy. Participants completed an online survey. RESULTS: One hundred women responded. Fifty-seven had become pregnant again, 2 were trying to conceive, 37 were not willing to get pregnant again because of HG, and 4 did not have a second pregnancy for other reasons. Among the 57 women who responded that they had become pregnant again, 81% reported having severe nausea and vomiting in their second pregnancy. Among the women reporting recurrent HG, 98% reported losing weight and taking prescribed medication for HG, 83% reported treatment with intravenous fluids, 20% reported treatment with total parenteral nutrition or nasogastric tube feeding, and 48% reported hospitalization for HG. DISCUSSION: This study demonstrates both a high recurrence rate of HG and a large percentage of women who change reproductive plans because of their experiences with HG.

Familial aggregation of hyperemesis gravidarum.

OBJECTIVE: This study was undertaken to determine whether there is familial aggregation of hyperemesis gravidarum (HG), making it a disease amenable to genetic study. STUDY DESIGN: Cases with severe nausea and vomiting in a singleton pregnancy treated with intravenous hydration and unaffected friend controls completed a survey regarding family history. RESULTS: Sisters of women with HG have a significantly increased risk of having HG themselves (odds ratio, 17.3; P = .005). Cases have a significantly increased risk of having a mother with severe nausea and vomiting; 33% of cases reported an affected mother compared to 7.7% of controls (P < .0001). Cases reported a similar frequency of affected second-degree maternal and paternal relatives (18% maternal lineage, 23% paternal lineage). CONCLUSION: There is familial aggregation of HG. This study provides strong evidence for a genetic component to HG. Identification of the predisposing gene(s) may determine the cause of this poorly understood disease of pregnancy.