Hyperemesis gravidarum theories dispelled by recent research: a paradigm change for better care and outcomes.

Nausea and vomiting (NVP) affect most pregnant women. At the severe end of the clinical spectrum, hyperemesis gravidarum (HG) can be life-threatening. The condition is fraught with misconceptions that have slowed progress and left women undertreated. Herein, recent scientific advances are presented that dispel common myths associated with HG related to maternal/offspring outcomes, etiology, and evolution. There is now strong evidence that (i) HG is associated with poor outcomes, (ii) a common cause of NVP and HG has been identified, and (iii) NVP is likely a protective evolutionary mechanism that occurs throughout the animal kingdom but is no longer necessary for human survival. Therefore, it is encouraging that we are finally on the cusp of testing treatments that may put an end to unnecessary suffering.

[Nausea and vomiting in pregnancy]. / Nausées et vomissements gravidiques.

NAUSEA AND VOMITING IN PREGNANCY. Nausea and vomiting during pregnancy are common symptoms experienced by pregnant women. In more severe cases, known as hyperemesis gravidarum, these symptoms can become a pathological condition that can lead to significant complications in both the short and long term. Short-term complications include hydro-electrolyte imbalances, pregnancy termination, and growth retardation. Long-term complications may include anxiety disorders, depression, and post-traumatic stress disorder. Mild cases can often be alleviated through lifestyle and dietary adjustments or non-pharmacological treatments like ginger, acupuncture, or acupressure. However, moderate to severe cases require specific psychological support, anti-emetic treatments, and sometimes hospitalization with intravenous treatment and parenteral rehydration. Managing these cases is complex and challenging because it does not guarantee the complete disappearance of symptoms, which can pose difficulties for caregivers.

NAUSÉES ET VOMISSEMENTS GRAVIDIQUES. Les nausées et vomissements de la grossesse sont un symptôme classique chez la femme enceinte. Le plus souvent sans gravité, les formes modérées à sévères, appelées hyperémèse gravidique, constituent une pathologie qui peut être invalidante, source de complications de la grossesse à court terme (troubles hydroélectrolytiques, arrêt de grossesse, retard de croissance) mais aussi à long terme (troubles anxiodépressifs, état de stress post-traumatique). Les formes minimes peuvent être atténuées par des règles hygiénodiététiques ou des traitements non médicamenteux (gingembre, acupuncture, acupression). Les formes modérées à sévères nécessitent un accompagnement psychologique spécifique, des traitements antiémétiques et, parfois, une hospitalisation avec traitement par voie intraveineuse et réhydratation parentérale. Leur prise en charge est complexe et difficile car elle ne permet pas toujours une disparition des symptômes, ce qui peut mettre en difficulté les soignants.

The Effect of Hyperemesis Gravidarum on Macular Thickness, Corneal Thickness, and Intraocular Pressure in Pregnancy.

AIM: Physiological changes in intraocular pressure as well as in the cornea and macula may occur during pregnancy. Therefore, we decided to investigate the effect of hyperemesis gravidarum on macular thickness, corneal thickness and intraocular pressure (IOP). MATERIAL AND METHODS: A total of 110 people, 55 of whom were diagnosed with hyperemesis gravidarum and 55 of whom were in the control group, were included in the study. The inclusion criteria for the study were as follows: first trimester (8-14 weeks of gestation) pregnancy with positive fetal heartbeat and no history of systemic disease, no continuous use of medication, diagnosis of hyperemesis gravidarum (ketonuria and weight loss of more than 3 kilograms or 5% of body weight), body mass index (BMI) within normal limits, age between 18 and 40, no alcohol use or smoking. RESULTS: In the HG group compared to the control group, there was a difference between the CCT values of both the right and left eyes (p<0.01). There was a difference in both right and left IOP values in patients in the HG group compared to the control group (p<0.05), and there was no correlation between ketonuria scores and right and left eye CCT values, right and left eye macular thickness, and right and left eye pressure in patients diagnosed with HG (p>0.05). CONCLUSION: In hyperemesis gravidarum, changes occur in IOP, corneal thickness, and macular thickness. In ophthalmic examinations in the pregestational period, especially for women with systemic disease, it may be important for clinicians to take the necessary precautions in this regard.

The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69).

An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].

Oral rehydration therapy versus intravenous rehydration therapy in the first 12 h following hospitalization for hyperemesis gravidarum: A randomized controlled trial.

OBJECTIVE: To evaluate oral rehydration therapy (ORT) compared with intravenous rehydration therapy (IVT) in the early inpatient management of hyperemesis gravidarum (HG). METHODS: A total of 124 women hospitalized for HG from February 10, 2021 till January 6, 2023 were randomized to ORT (n = 61) or IVT (n = 63) for an initial 12 h. Inclusion criteria includes women older than 18 years, with a viable intrauterine pregnancy less than 14 weeks at their first hospitalization for HG with ketonuria of at least 2+. Primary outcomes were (1) satisfaction score with allocated intervention, (2) weight change, and (3) ketonuria change at 12 h. Secondary outcomes included vomiting frequency, nausea score, serial vital signs, hematocrit and electrolyte levels at 12 h, deviation from treatment protocol (cross-over therapy), participant recommendation of allocated treatment to a friend, and length of hospital stay. RESULTS: Primary outcomes of (1) participant satisfaction score (on a 0-10 visual numerical rating scale) was 7 (interquartile range [IQR] 5-8) versus 9 (IQR 8-10), P < 0.001; (2) weight gain was 293 ± 780 g versus 948 ± 758 g, P < 0.001; and (3) ketonuria improvement was 50/61 (82.0%) versus 49/63 (77.8%) (relative risk [RR] 1.05, 95% confidence interval [CI] 0.88-1.26, P = 0.561) for ORT versus IVT, respectively. For secondary outcomes, vomiting frequency was 2.6 ± 2.7 versus 1.1 ± 1.4 episodes (P < 0.001), participant cross-over rate to opposing treatment 20/61 (32.8%) versus 0/63 (0%) (P < 0.001) (in the 12-h study period) and participant recommendation of allocated treatment to a friend rate 24/61 (39.3%) versus 61/63 (96.8%) (RR 0.41, 95% CI 0.30-0.56, P < 0.001) for ORT versus IVT, respectively. By hospital discharge, 31/61 (50.8%) of women allocated to ORT had required IVT. Other secondary outcomes of serial assessments of nausea score and vital signs, hematocrit and electrolyte levels, and length of hospital stay were not different. CONCLUSIONS: ORT was inferior to IVT in two primary outcomes and three secondary outcomes. Cross-over rate to intravenous therapy from oral therapy was 50.8% by hospital discharge. Intravenous rehydration therapy should remain as first-line rehydration therapy in the early inpatient treatment of HG. CLINICAL TRIAL REGISTRATION: The present study was registered in ISRCTN registry on December 6, 2020 with trial identification number: ISRCTN 40152556 (https://doi.org/10.1186/ISRCTN40152556). The first participant was recruited on February 10, 2021.

Inpatient Management of Hyperemesis Gravidarum.

Hyperemesis gravidarum has a reported incidence of approximately 0.3-3% of pregnancies. Without treatment, refractory hyperemesis gravidarum can result in dehydration, electrolyte deficiencies, and severe nutritional deficiencies, resulting in significant maternal morbidity. The overall goals of inpatient management of refractory hyperemesis gravidarum are the resumption of oral intake to an adequate level to maintain hydration and nutrition, including the ability to tolerate oral pharmacotherapy. Patients initially are stabilized with rehydration and electrolyte repletion. There are numerous pharmacotherapeutics available that can be administered intravenously to control symptoms when oral intake is not an option. However, despite maximizing typical antiemetics, there will be cases refractory to these medications, and alternative pharmacotherapeutics and nutrition-support modalities must be considered. Mirtazapine, olanzapine, corticosteroids, and gabapentin are examples of alternative pharmacotherapeutics, and enteral and parenteral nutrition are alternative therapies that can be used when oral intake is not tolerated for prolonged time periods with ongoing weight loss. In refractory cases of hyperemesis gravidarum, the risks and benefits of these alternative forms of management must be considered, along with the risks of undertreated hyperemesis gravidarum and the overall effect of hyperemesis gravidarum on patients' quality of life.

GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Treatments for hyperemesis gravidarum: A systematic review.

INTRODUCTION: Hyperemesis gravidarum affects 0.3%-3% of pregnant women each year and is the leading cause of hospitalization in early pregnancy. Previous systematic reviews of available treatments have found a lack of consistent evidence, and few studies of high quality. Since 2016, no systematic review has been conducted and an up-to date review is requested. In a recent James Lind Alliance collaboration, it was clear that research on effective treatments is a high priority for both patients and clinicians. MATERIAL AND METHODS: Searches without time limits were performed in the AMED, CINAHL, Cochrane Library, EMBASE, Medline, PsycINFO, and Scopus databases until June 26, 2023. Studies published before October 1, 2014 were identified from the review by O'Donnell et al., 2016. Selection criteria were randomized clinical trials and non-randomized studies of interventions comparing treatment of hyperemesis gravidarum with another treatment or placebo. Outcome variables included were: degree of nausea; vomiting; inability to tolerate oral fluids or food; hospital treatment; health-related quality of life, small-for-gestational-age infant; and preterm birth. Abstracts and full texts were screened, and risk of bias of the studies was assessed independently by two authors. Synthesis without meta-analysis was performed, and certainty of evidence was assessed using the GRADE approach. PROSPERO (CRD42022303150). RESULTS: Twenty treatments were included in 25 studies with low or moderate risk of bias. The certainty of evidence was very low for all treatments except for acupressure in addition to standard care, which showed a possible moderate decrease in nausea and vomiting, with low certainty of evidence. CONCLUSIONS: Several scientific knowledge gaps were identified. Studies on treatments for hyperemesis gravidarum are few, and the certainty of evidence for different treatments is either low or very low. To establish more robust evidence, it is essential to use validated scoring systems, the recently established diagnostic criteria, clear descriptions and measurements of core outcomes and to perform larger studies.

Survivors' Experiences of Hyperemesis Gravidarum.

Hyperemesis gravidarum can result in life-threatening physical and psychological maternal morbidity, including severe dehydration, weight loss, electrolyte imbalance, depression, and suicidal ideation. The reported prevalence of hyperemesis gravidarum ranges from 0.3% to 3.6%. The purpose of this qualitative study was to investigate what blogs can tell us about women's experiences of hyperemesis gravidarum. Thirty-three blogs written by hyperemesis gravidarum survivors posted on Hyperemesis Australia's website were analyzed using Krippendorff's qualitative content analysis method. Clustering was used and yielded 6 themes: (1) debilitating physical and mental health problems: digging deep to persevere, (2) heartbreaking choices, (3) lack of understanding and dismissed, (4) so much guilt surrounding their unborn infant, (5) it takes a village to support women with hyperemesis gravidarum, and (6) warriors and survivors: giving back. Infusion nurses are in a perfect position to provide support and compassionate care for women who are repeatedly coming to the hospital for rehydration treatment. Infusion nurses can validate women's physical and emotional struggles with hyperemesis gravidarum and help to no longer make women feel stigmatized.

When time is brain: a systematic review about Wernicke encephalopathy as a dramatic consequence of thiamin deficiency in hyperemesis gravidarum.

Nausea and vomiting affect up to 80% of all pregnancies, sometimes so severely that the condition of hyperemesis gravidarum (HG) is established. HG may in addition be a predisposing factor for Wernicke encephalopathy (WE), a severe and life-threatening condition due to vitamin B1 (thiamin) deficiency. If untreated, WE may progress to Korsakoff's syndrome, an irreversible cognitive disorder. We reported a case that recently occurred at our clinic and performed a systematic review of the literature to investigate the clinical presentation, maternal and perinatal outcomes and treatment of WE in women with HG. METHODS: We performed a systematic review of case series and case reports searching the Medline database on Pubmed from inception until December 2021. We used as search terms (Wernicke encephalopathy) OR (Wernicke-Korsakoff syndrome) AND (hyperemesis gravidarum) AND (pregnancy) AND (thiamin deficiency). Articles were considered eligible for inclusion in our review if they described at least one case of WE due to thiamin deficiency in relation to HG. An overall of 82 cases of WE due to HG in pregnancy from 66 manuscripts, including our own, were selected. RESULTS: The maternal mean age was 26.38 ± 5.23 years, while mean gestational week at hospitalization was 14.57 ± 4.12 after a mean of 6.6 ± 3.14 weeks of vomiting duration. WE manifestation occurred at a mean gestational age of 16.54 ± 3.06 weeks. Regarding clinical presentation, ocular signs and symptoms were reported by 77/82 (93.9%) women, 61/82 (74.4%) presented with ataxia and 63/82 (76.8%) with confusion. Dysarthria affected 15/82 women (18,3%), while muscular weakness was present in 36/82 (43.9%) and impaired reflexes in 42/82 (51.2%). Memory impairment involved 25/82 (30.5%) of the study population. Almost all cases reported a thiamin administration treatment, however data regarding the clinical course of the neurological condition and the perinatal outcomes were often missing and showed a great heterogeneity when reported. CONCLUSION: WE is a challenging diagnosis, as its clinical presentation is nonspecific. A high clinical suspicion and the awareness of its possible predisposing conditions such as HG may help clinicians to get a prompt diagnosis and starting treatment, which are vital to prevent possible life-impairing neurological sequelae.

The role of the systemic inflammatory index in determining the length of hospital stay in patients with hyperemesis gravidarum.

OBJECTIVE: In this study, we aimed to investigate the role of peripheral blood parameters and the systemic inflammatory index (SII) in the diagnosis of hyperemesis gravidarum (HG) and whether they have a predictive value in determining the length of hospital stay and the risk of rehospitalization in HG cases. MATERIALS AND METHODS: In the retrospective study, pregnant women who were hospitalized due to HG (n = 112) and pregnant women who were completely healthy (n = 112) were matched for gestational age. Peripheral blood inflammation parameters of the entire study group were evaluated. The length of hospital stay and rehospitalization rate for HG cases were recorded. A total of 224 patients, 112 (50%) in the control group and 112 (50%) in the HG group were included in the study. There was a positive correlation between increased ketonuria and length of hospitalization, peripheric blood parameters, and SII. The degree of ketonuria was found to be statistically insignificant in determining the risk of rehospitalization (p = 0.927). About 28.57% (n = 32) of all HG cases were readmitted to the hospital. When the length of hospital stay was considered, SII was found to be statistically significant in hospitalizations lasting more than 2 days (p = 0.001), but not in rehospitalizations (p = 0.3). CONCLUSION: SII is significant in diagnosing and determining hospitalization of HG. It is sufficient to determine the length of hospital stay but not rehospitalization risk, which is an indicator of disease severity.

Watermelon and dietary advice compared to dietary advice alone following hospitalization for hyperemesis gravidarum: a randomized controlled trial.

BACKGROUND: Hyperemesis gravidarum (HG) affects about 2% of pregnancies and is at the severe end of the spectrum of nausea and vomiting of pregnancy. HG causes severe maternal distress and results in adverse pregnancy outcomes long after the condition may have dissipated. Although dietary advice is a common tool in management, trial evidence to base the advice on is lacking. METHODS: A randomized trial was conducted in a university hospital from May 2019 to December 2020. 128 women at their discharge following hospitalization for HG were randomized: 64 to watermelon and 64 to control arm. Women were randomized to consume watermelon and to heed the advice leaflet or to heed the dietary advice leaflet alone. A personal weighing scale and a weighing protocol were provided to all participants to take home. Primary outcomes were bodyweight change at the end of week 1 and week 2 compared to hospital discharge. RESULTS: Weight change (kg) at end of week 1, median[interquartile range] -0.05[-0.775 to + 0.50] vs. -0.5[-1.4 to + 0.1] P = 0.014 and to the end of week 2, + 0.25[-0.65 to + 0.975] vs. -0.5[-1.3 to + 0.2] P = 0.001 for watermelon and control arms respectively. After two weeks, HG symptoms assessed by PUQE-24 (Pregnancy-Unique Quantification of Emesis and Nausea over 24 h), appetite assessed by SNAQ (Simplified Nutritional Appetite Questionnaire), wellbeing and satisfaction with allocated intervention NRS (0-10 numerical rating scale) scores, and recommendation of allocated intervention to a friend rate were all significantly better in the watermelon arm. However, rehospitalization for HG and antiemetic usage were not significantly different. CONCLUSION: Adding watermelon to the diet after hospital discharge for HG improves bodyweight, HG symptoms, appetite, wellbeing and satisfaction. TRIAL REGISTRATION: This study was registered with the center's Medical Ethics Committee (on 21/05/2019; reference number 2019327-7262) and the ISRCTN on 24/05/2019 with trial identification number: ISRCTN96125404 . First participant was recruited on 31/05/ 2019.

Fetal demise and Wernicke-Korsakoff syndrome in a patient with hyperemesis gravidarum: a case report.

BACKGROUND: Wernicke-Korsakoff syndrome is a neuropsychiatric disorder caused by thiamine deficiency composed of two related disorders accounting for an acute presentation and chronic progression. Hyperemesis gravidarum presents a significant risk factor for Wernicke-Korsakoff syndrome as symptoms may rapidly progress in the setting of pregnancy. We present the first-reported case of hyperemesis-gravidarum-associated Wernicke encephalopathy in a patient in the first half of pregnancy in which a missed diagnosis led to septic shock, fetal demise, and eventual profound Korsakoff syndrome. CASE PRESENTATION: We present the case of a 33-year-old primigravid African American woman at 15 weeks gestational age who initially presented at a community emergency department with nausea and vomiting that ultimately progressed to severe hyperemesis-gravidarum-associated Wernicke-Korsakoff syndrome, fetal demise, and septic shock. The patient received a total of 6 weeks of high-dose parenteral thiamine. Magnetic resonance imaging of the head and formal neuropsychological assessment following treatment plateau confirmed the diagnosis of Wernicke-Korsakoff syndrome. CONCLUSIONS: The multisystem complications seen in severe thiamine deficiency can delay timely administration of high-dose thiamine, particularly in pregnancy, in which the classic triad of Wernicke-Korsakoff syndrome may not raise clinical suspicion due to rapid progression of neurological sequelae in this population. We advise a low threshold for parenteral thiamine repletion in pregnant women with persistent vomiting as hyperemesis gravidarum-induced severe thiamine deficiency can result in Wernicke-Korsakoff syndrome, sepsis, and fetal demise.

Pneumomediastinum in late pregnancy: a case report and review of the literature.

BACKGROUND: Pneumomediastium is a rare complication of pregnancy or labor. METHODS: Here, we report our findings in a case report (gravid 5, para 2, gestational age 33 + 4 weeks) and narratively review the current literature on pneumomediastinum in pregnancy or labor. RESULTS: Our case is the first case that experienced pneumomediastinum after relatively limited exposure to barotrauma in the current pregnancy. Other reports describe pneumomediastinum after hyperemesis gravidarum or during labor. Treatment is usually conservatively due to the trauma mechanism of barotrauma to the alveoli. CONCLUSION: Physicians should be aware of the possibility of pneumomediastinum in pregnant women with acute thoracic pain in cases of (previous) hyperemesis gravidarum or during labor.

Hyperemesis Gravidarum: Risk of Recurrence in Subsequent Pregnancies.

This study aimed to examine whether the recurrence risk of hyperemesis gravidarum (HG) is modified by the timing of diagnosis, the severity of illness, and interpregnancy interval. The Kaiser Permanente Southern California 1998-2020 longitudinally linked medical records were used to examine the recurrence risk of HG in the first two (n = 93,444) and first three (n = 17,492) successive pregnancies. The timing of diagnosis- and the severity of illness-specific recurrence risks were examined by estimating the adjusted relative risks (aRR). The risks of HG in the second pregnancy among patients with and without previous HG were 23.8% and 3.4%, respectively (aRR: 8.20; 95% confidence interval [CI]: 7.52, 8.94). The recurrence risk persisted regardless of the trimester at diagnosis and the gestational age of delivery in the first pregnancy. The recurrence risk was greater for patients with metabolic disturbances requiring in-hospital treatment (30.0%) than those managed on an outpatient basis (18.6%) in the first pregnancy (aRR: 10.84 95% CI: 9.66, 12.16). Although Asian/Pacific Islander (RR = 12.9) and White (RR = 8.9) patients had higher HG recurrence risk regardless of the gestational age at delivery in the first pregnancy, all patients had significant recurrence risk only if their first pregnancy was delivered after 32 weeks of gestation. African American patients had the highest recurrence rate (34.4%). HG recurrence risk was unaffected by interpregnancy interval and correlated with the number of previous pregnancies complicated by HG. There is an increased recurrence risk of HG in subsequent pregnancies that is influenced by race/ethnicity and gestational age at delivery. The number of pregnancies complicated by HG synergistically adds to the recurrence risk.