Pregnant, miserable, and starving in 21st century America.

Severe nausea and vomiting of pregnancy is too common and devastating to be trivialized any longer. Authors of recent studies observed that children exposed in utero to severe nausea and vomiting of pregnancy had an increased risk for autism spectrum disorder, a decreased brain cortical volume, and developmental deficits. Research on severe nausea and vomiting of pregnancy and hyperemesis gravidarum has been disturbingly slow. It was not until 2021 that an international consensus definition was published. Hyperemesis gravidarum starts before 16 weeks' gestation, is characterized by severe nausea with or without vomiting and an inability to eat and drink normally, and greatly limits daily activities. Maternal misery is caused by unrelenting nausea, intractable retching or vomiting, ptyalism, dehydration, reflux, malnutrition, and social isolation. Hyperemesis gravidarum is the second most common reason for hospitalization in pregnancy. Symptoms can persist until delivery in one-third of individuals who experience extreme weight loss. Significant associations have been identified between hyperemesis gravidarum and multiple adverse outcomes. Maternal deaths owing to hyperemesis gravidarum continue to be reported, and hyperemesis gravidarum is associated with high fetal loss and termination rates. These grim findings highlight the critical public health importance of treating severe nausea and vomiting of pregnancy early to mitigate serious complications that compromise maternal and offspring health during pregnancy and beyond. Despite suffering extreme debility, individuals with hyperemesis gravidarum report feeling that their experiences were dismissed by healthcare professionals, contributing to therapeutic termination, suicidal ideation, perinatal depression, and posttraumatic stress disorder. Hyperemesis gravidarum must be recognized early and treated aggressively with frequent monitoring. Although medications can be effective in reducing symptoms, many patients do not gain adequate relief, and new treatments are needed. A promising new avenue for treatment comes from genetic discoveries. The gene, growth differentiation factor-15, which codes for a nausea and vomiting hormone produced by the placenta, is the greatest genetic risk factor for hyperemesis gravidarum, and therapies are currently in clinical trials in cancer. However, until treatment is universally effective, abortion access must be available for refractory hyperemesis gravidarum. Herein, we emphasize data published since the most recent American College of Obstetrics and Gynecology report (2018), such as long-term neuropsychiatric consequences in offspring exposed to hyperemesis gravidarum and suggest interventions anticipated to prevent progression of early symptoms to hyperemesis gravidarum.

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.

A patient-clinician James Lind Alliance partnership to identify research priorities for hyperemesis gravidarum.

OBJECTIVE: There are many uncertainties surrounding the aetiology, treatment and sequelae of hyperemesis gravidarum (HG). Prioritising research questions could reduce research waste, helping researchers and funders direct attention to those questions which most urgently need addressing. The HG priority setting partnership (PSP) was established to identify and rank the top 25 priority research questions important to both patients and clinicians. METHODS: Following the James Lind Alliance (JLA) methodology, an HG PSP steering group was established. Stakeholders representing patients, carers and multidisciplinary professionals completed an online survey to gather uncertainties. Eligible uncertainties related to HG. Uncertainties on nausea and vomiting of pregnancy and those on complementary treatments were not eligible. Questions were verified against the evidence. Two rounds of prioritisation included an online ranking survey and a 1-hour consensus workshop. RESULTS: 1009 participants (938 patients/carers, 118 professionals with overlap between categories) submitted 2899 questions. Questions originated from participants in 26 different countries, and people from 32 countries took part in the first prioritisation stage. 66 unique questions emerged, which were evidence checked according to the agreed protocol. 65 true uncertainties were narrowed via an online ranking survey to 26 unranked uncertainties. The consensus workshop was attended by 19 international patients and clinicians who reached consensus on the top 10 questions for international researchers to address. More patients than professionals took part in the surveys but were equally distributed during the consensus workshop. Participants from low-income and middle-income countries noted that the priorities may be different in their settings. CONCLUSIONS: By following the JLA method, a prioritised list of uncertainties relevant to both HG patients and their clinicians has been identified which can inform the international HG research agenda, funders and policy-makers. While it is possible to conduct an international PSP, results from developed countries may not be as relevant in low-income and middle-income countries.

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.

Hyperemesis Gravidarum: Strategies to Improve Outcomes.

Hyperemesis gravidarum (HG) is a debilitating and potentially life-threatening pregnancy disease marked by weight loss, malnutrition, and dehydration attributed to unrelenting nausea and/or vomiting; HG increases the risk of adverse outcomes for the mother and child(ren). The complexity of HG affects every aspect of a woman's life during and after pregnancy. Without methodical intervention by knowledgeable and proactive clinicians, life-threatening complications may develop. Effectively managing HG requires an understanding of both physical and psychosocial stressors, recognition of potential risks and complications, and proactive assessment and treatment strategies using innovative clinical tools.

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.

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.

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.

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.

Psychiatric factors do not affect recurrence risk of hyperemesis gravidarum.

AIM: The aim of this study is to determine whether psychiatric symptoms affect recurrence risk of hyperemesis gravidarum (HG). METHODS: The study sample included 108 women with HG treated with i.v. fluids in their first pregnancy. Women were divided into two groups based on recurrence of HG in their second pregnancy. Participants submitted medical records and completed a survey regarding pregnancy characteristics and psychiatric symptoms. The χ(2) -test and Student's t-test were performed to compare the two groups. RESULTS: Eighty-four women (71%) had a recurrence of HG requiring i.v. fluid for dehydration, and were compared with 34 women (29%) who did not have a recurrence. There were no significant differences in obstetric history, although there was a trend toward greater time between first and second pregnancy in the recurrence group (P = 0.08). There were no differences in pre-existing psychiatric diagnoses including anxiety, depression, bipolar disorder, panic or eating disorders. Following the first HG pregnancy, participants in both groups were well matched for all post-traumatic stress symptoms. CONCLUSION: This study is the first to analyze the relationship of psychiatric factors to risk of recurrence of HG. No factors were identified that increase the risk of recurrence including stress symptoms following a HG pregnancy. Psychological sequelae associated with HG are probably a result of the physical symptoms of prolonged severe nausea and vomiting, medication and/or hospitalization, and likely play no role in disease etiology.

Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum.

OBJECTIVE: The purpose of this study is to determine the frequency of adverse perinatal outcome in women with hyperemesis gravidarum and identify prognostic factors. STUDY DESIGN: This is a case-control study in which outcomes of first pregnancies were compared between 254 women with hyperemesis gravidarum treated with intravenous fluids and 308 controls. Prognostic factors were identified by comparing the clinical profile of patients with hyperemesis gravidarum with a normal and an adverse pregnancy outcome. Binary responses were analyzed using either a Chi-square or Fisher exact test and continuous responses were analyzed using a t-test. RESULTS: Women with hyperemesis gravidarum have over a 4-fold increased risk of poor outcome including preterm birth and lower birth weight (p<0.0001). Among maternal characteristics, only gestational hypertension had an influence on outcome (p<0.0001). Treatment as an outpatient and/or by alternative medicine (acupuncture/acupressure/Bowen massage) was associated with a positive outcome (p<0.0089). Poor outcomes were associated with early start of symptoms (p<0.019), and treatment with methylprednisolone (p<0.0217), promethazine (p<0.0386), and other antihistamines [diphenhydramine (Benadryl), dimenhydrinate (Gravol), doxylamine (Unisom), hydroxyzine (Vistaril/Atarax), doxylamine and pyridoxine (Diclectin/Bendectin)] (p<0.0151) independent of effectiveness. Among these medications, only the other antihistamines were prescribed independent of severity: they were effective in less than 20% of cases and were taken by almost 50% of patients with an adverse outcome. CONCLUSION: Poor outcomes are significantly greater in women with HG and are associated with gestational hypertension, early symptoms, and antihistamine use. Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy.