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.

Liver pathology in pregnancy.

Liver dysfunction occurs in up to 3% of pregnancies and can be due to pregnancy-associated liver injury, exacerbation of pre-existing liver disease, or co-incident with pregnancy. The most common form of pregnancy-associated liver injury is intrahepatic cholestasis of pregnancy (ICP). This condition is typically benign and self-limited, but is associated with fetal morbidity and mortality with high levels of serum bile acids. Acute fatty liver of pregnancy (AFLP) and the hypertensive disorders of pregnancy (including pre-eclampsia, eclampsia, and hemolysis, elevated liver enzymes, and low platelets [HELLP] syndrome) are more commonly associated with maternal and fetal complications and may necessitate expedient delivery. Histologically, ICP shows nonspecific features of cholestasis, while AFLP and the hypertensive disorders have more characteristic histologic findings. While not a true liver disease, hyperemesis gravidarum can cause elevated liver enzymes. Pregnant patients are at increased risk of developing severe hepatitis E and herpesvirus infections, Budd-Chiari syndrome, and gallstones, and they may also experience worsening of known chronic liver disease. Mass lesions in pregnancy including hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas and carcinomas can present unique challenges for diagnosis and management. This review will explore the pathophysiology, presentation, histologic features, and management of these conditions.

Olfactory dysfunction and oxidative stress in pregnant women with hyperemesis gravidarum.

PURPOSE: This study aimed to compare the first-trimester pregnancy serum total oxidative status (TOS), total antioxidant status (TAS), and serum estradiol levels as well as the olfactory functions assessed using the brief smell identification test (BSIT) of women with healthy pregnancies and those with hyperemesis gravidarum (HG). METHODS: In this prospective study, 60 pregnant women in the first trimester of their pregnancies were divided into two groups: 30 pregnant women with HG (study group) and 30 healthy pregnant women (control group). The following parameters were compared in the HG group and the healthy controls: TOS, TAS, serum levels of estradiol (E2), and olfactory function, which was measured using BSIT. RESULTS: Both groups were similar in terms of age, gravida, and parity. The mean total smell score was lower in the HG group than the healthy control group (p < 0.05). TOS was significantly higher in the HG group than the control group. TAS was significantly higher in the control group than the HG group (p < 0.05). CONCLUSION: The removal of sharp odors that will trigger the perception of odor in pregnant women with HG can contribute to the effective control of this disease; moreover, adding fetal-safe antioxidants to the treatment can contribute to the effective control of this disease.

Polyunsaturated Fatty Acids and Their Metabolites in Hyperemesis Gravidarum.

Polyunsaturated fatty acids (PUFAs) have been studied in relation to pregnancy. However, there is limited knowledge on PUFAs and their metabolites in relation to hyperemesis gravidarum (HG), a pregnancy complication associated with nutritional deficiencies and excessive vomiting. In order to survey the field, a systematic review of the literature was performed, which also included nausea and vomiting of pregnancy (NVP) due to its close relationship with HG. In the very few published studies found, the main subjects of the research concerned free fatty acids (four records), lipid profiles (three records), and bioactive lipids (one article about prostaglandin E2 and one about endocannabinoids). The authors of these studies concluded that, although no cause-and-effect relationship can be established, HG is linked to increased sympathetic responsiveness, thermogenic activity and metabolic rate. In addition, NVP is linked to a metabolic perturbance (which lasts throughout pregnancy). The low number of retrieved records underlines the need for more research in the area of PUFAs and HG, especially with regard to the underlying mechanism for the detected effects, potentially involving growth differentiation factor 15 (GDF15) since evidence for GDF15 regulation of lipid metabolism and the role for GDF15 and its receptor in nausea and vomiting is emerging.

GDF15: A Hormone Conveying Somatic Distress to the Brain.

GDF15 has recently gained scientific and translational prominence with the discovery that its receptor is a GFRAL-RET heterodimer of which GFRAL is expressed solely in the hindbrain. Activation of this receptor results in reduced food intake and loss of body weight and is perceived and recalled by animals as aversive. This information encourages a revised interpretation of the large body of previous research on the protein. GDF15 can be secreted by a wide variety of cell types in response to a broad range of stressors. We propose that central sensing of GDF15 via GFRAL-RET activation results in behaviors that facilitate the reduction of exposure to a noxious stimulus. The human trophoblast appears to have hijacked this signal, producing large amounts of GDF15 from early pregnancy. We speculate that this encourages avoidance of potential teratogens in pregnancy. Circulating GDF15 levels are elevated in a range of human disease states, including various forms of cachexia, and GDF15-GFRAL antagonism is emerging as a therapeutic strategy for anorexia/cachexia syndromes. Metformin elevates circulating GDF15 chronically in humans and the weight loss caused by this drug appears to be dependent on the rise in GDF15. This supports the concept that chronic activation of the GDF15-GFRAL axis has efficacy as an antiobesity agent. In this review, we examine the science of GDF15 since its identification in 1997 with our interpretation of this body of work now being assisted by a clear understanding of its highly selective central site of action.

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.

The relationship between the helicobacter pylori seropositivity with systemic and local oxidative status and hyperemesis gravidarum: a pilot study.

OBJECTIVES: The aim of study was to determine the helicobacter pylori (HP) seropositivity and oxidative parameters in serum and saliva of pregnant women with poor oral hygiene and hyperemesis gravidarum (HG). METHODS: A case-control study was conducted involving 50 pregnant women in their first trimester of pregnancy. Twenty-five subjects had a diagnosis of HG, and remaining 25 were healthy pregnant women who served as control subjects were included. The groups were adjusted for age, parity and gestational week. All patients were subjected to the measurement of total oxidant status (TOS) and total antioxidant status in serum and saliva. Also HP seropositivity was investigated. RESULTS: Serum TAS and TOS values were similar, although oxidative burden in saliva of women with HG were significantly higher than controls. HP seropositivity was found to be 24% in women with HG and 4% of controls. CONCLUSIONS: Our results suggest that significantly increased oxidative burden and slightly decreased antioxidative capacity of saliva may be involved in the pathogenesis of HG and this condition may be the result of HP infection which was found to be significantly more common in women with poor oral hygiene and HG.

Investigation of the relationship between salivary cortisol, dehydroepiandrosterone sulfate, anxiety, and depression in patients with hyperemesis gravidarum.

BACKGROUND: The aim of this study was to determine the relationship of the salivary levels of dehydroepiandrosterone sulfate (DHEA-S) and cortisol with factors related to depression and anxiety in patients with hyperemesis gravidarum (HG). METHODS: Forty patients with a diagnosis of HG were selected for the study and matched with 40 control patients according to body mass index, parity, and age. Symptoms of depression and anxiety were investigated using the Beck Depression Inventory and Beck Anxiety Inventory for Adults, respectively. Saliva samples were collected in the morning and at night and subjected to enzyme-linked immunosorbent assay for the determination of DHEA-S and cortisol levels. RESULTS: We observed a positive correlation between increased levels of depression and anxiety and increased salivary levels of cortisol and DHEA-S in patients with HG. CONCLUSIONS: Salivary cortisol and DHEA-S levels, as well as mood disorders, should be monitored in patients with HG, although further large, prospective studies are needed to confirm our results.

The oxidative stress index increases among patients with hyperemesis gravidarum but not in normal pregnancies.

OBJECTIVE: The etiology and pathogenesis of hyperemesis gravidarum (HG) is still undetermined and has been suggested to involve oxidative stress. We aimed to evaluate the status of oxidative stress in HG by measuring the levels of total oxidant status (TOS), total antioxidant status (TAS), and by calculating the oxidative stress index (OSI). METHODS: In a case-control trial, fasting morning blood samples of patients with HG (n = 41) and healthy pregnant women (n = 39) were collected for analysis of serum TOS and TAS values as well as for calculation of OSI according to the formula: OSI = TOS / TAS × 100. RESULTS: Serum TOS and TAS levels were similar in both groups. However, serum TAS levels were lower among HG patients compared to controls, which resulted in an increase in OSI (P = 0.025). DISCUSSION: The present study supports the role of systemic oxidative stress, reflected by an imbalance between the TOS and TAS, in patients with HG. Our findings distinguish the mechanism underlying oxidative stress to result from reduction of antioxidants rather than an increase in oxidants.

Direct analysis of hCGßcf glycosylation in normal and aberrant pregnancy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

The analysis of human chorionic gonadotropin (hCG) in clinical chemistry laboratories by specific immunoassay is well established. However, changes in glycosylation are not as easily assayed and yet alterations in hCG glycosylation is associated with abnormal pregnancy. hCGß-core fragment (hCGßcf) was isolated from the urine of women, pregnant with normal, molar and hyperemesis gravidarum pregnancies. Each sample was subjected to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) analysis following dithiothreitol (DTT) reduction and fingerprint spectra of peptide hCGß 6-40 were analyzed. Samples were variably glycosylated, where most structures were small, core and largely mono-antennary. Larger single bi-antennary and mixtures of larger mono-antennary and bi-antennary moieties were also observed in some samples. Larger glycoforms were more abundant in the abnormal pregnancies and tri-antennary carbohydrate moieties were only observed in the samples from molar and hyperemesis gravidarum pregnancies. Given that such spectral profiling differences may be characteristic, development of small sample preparation for mass spectral analysis of hCG may lead to a simpler and faster approach to glycostructural analysis and potentially a novel clinical diagnostic test.

Severe hyperemesis gravidarum is associated with reduced insulin sensitivity in the offspring in childhood.

BACKGROUND: Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood. METHODS: Healthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergman's minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry. RESULTS: Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 × 10(-4)·min(-1)·(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar. CONCLUSION: Children born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long-term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease.

Dietary antioxidant levels in hyperemesis gravidarum: a case control study.

OBJECTIVES: Dietary antioxidant intake decreases the risk of many diseases. Hyperemesis gravidarum (HG) is the most common eating disorder during pregnancy Therefore, the authors conducted this prospective and case control study to evaluate dietary antioxidant levels of women with HG and compare with healthy pregnant women. MATERIAL AND METHODS: This prospective case control study was conducted at a government hospital in the southeastern region of Turkey from February 2010 to May 2010. A total of 100 pregnant women were included into the study Dietary antioxidant levels (DAL) were measured according to the new 92-item antioxidant nutrient questionnaire developed by Satia et al. 50 women with HG and 50 healthy pregnant women were evaluated. Statistical analyses were carried out with statistical packages for SPSS 15.0 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: There were no statistically significant differences between the groups regarding the age of the patients, gestational age, educational status, body height and weight (p > .05). Vitamin E, E equivalent, vitamin C, carotene and vitamin A levels were significantly lower in women with HG (p < .05). The results of logistic regression method for these variables including odds ratio (95 % CI) were as follows: 10.07 (1.52-66.51), 7.37 (2.66-20.41), 4.26 (2.66-20.41), 3.66 (2.38-5.63) and 2.75 (1.56-4.85), respectively CONCLUSION: According to this study, vitamin E, E equivalent, vitamin C, carotene and vitamin A levels of women may play a role in the pathogenesis of HG. Therefore, diet recommendations should be given by clinicians before pregnancy

Posttraumatic oxytocin dysregulation: is it a link among posttraumatic self disorders, posttraumatic stress disorder, and pelvic visceral dysregulation conditions in women?

This article explicates a theory that oxytocin, a sexually dimorphic neurotransmitter and paracrine hormone, is a plausible mechanism linking early relational trauma with posttraumatic self disorders (e.g., dissociation, somatization, and interpersonal sensitivity), posttraumatic stress disorder, and pelvic visceral dysregulation disorders (e.g., irritable bowel syndrome, chronic pelvic pain, interstitial cystitis, and hyperemesis gravidarum). This posttraumatic oxytocin dysregulation disorders theory is consistent with the historical and contemporary literature. It integrates attention to psychological and physical comorbidities and could account for the increased incidence of these disorders among females. Specific propositions are explored in data from studies of traumatic stress and women's health.

Is hyperthyroidism underestimated in pregnancy and misdiagnosed as hyperemesis gravidarum?

Thyroid changes are considered to be normal events that happen as a large maternal multiorganic adjustment to pregnancy. However, hyperthyroidism occurs in pregnancy with clinical presentation similar to hyperemesis gravidarum (HG) and pregnancy itself. Moreover, 10% of women with HG will continue to have symptoms throughout the pregnancy suggesting that the underlying cause might not be elevation of human chorionic gonadotropin in the first trimester. Variable frequency of both hyperthyroidism and HG worldwide might suggest the puzzlement of inclusion criteria for both diagnoses enhanced by the alternation of thyroid hormone levels assessed in normal pregnancy. Increased number of hyperthyroidism among women population without the expected rise in gestational hyperthyroidism encouraged us for creating the hypotheses that hyperthyroidism could be underestimated in normal pregnancy and even misdiagnosed as HG. This hypothesis, if confirmed, might have beneficial clinical implications, such as better detection of hyperthyroidism in pregnancies, application of therapy when needed with the reduction of maternal or fetal consequences.

Serum lipid profile, oxidative status, and paraoxonase 1 activity in hyperemesis gravidarum.

The aim of this study was to investigate lipid profile, paraoxonase 1 (PON1) activity, and oxidative stress status in the serum of hyperemesis gravidarum (HG) patients. Thirty-six HG cases and 36 normal pregnants were included in the study. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoproteins A1 (apo A1) and B (apo B), malondialdehyde (MDA), and total antioxidant activity (TAO) values and PON1 and arylesterase activities were determined. Although serum TC, TG, LDL-C, and apo B levels were not different among; the groups (P>0.05), HDL-C (P=0.01) and apo A1 (P=0.007) levels were lower in HG patients than in normal pregnants. HG group had significantly lower serum PON1 (P=0.03) and arylesterase activities (P=0.03) compared with the control group. Additionally, mean TAO values were lower (P=0.01) and MDA levels were higher (P=0.02) in HG group than in the healthy pregnants. A significant negative correlation between PON1 and MDA was found in HG group (r=-0.33, P<0.05). The findings of this study have revealed that HG may be one of the conditions in which oxidant and antioxidant balance is impaired.

Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum.

OBJECTIVE: To investigate the association between the leptin, leptin receptor and hormone levels and hyperemesis gravidarum, and to determine whether these two parameters may be early markers for hyperemesis gravidarum. METHODS: The study group consisted of 18 pregnant women with hyperemesis gravidarum and the control group consisted of 18 healthy pregnant women. Demographic characteristics were recorded and body mass index (BMI) values were calculated for all the pregnant women. Serum leptin, leptin receptor, insulin, cortisol, thyroid hormone and human chorionic gonadotrophin (hCG) levels were measured. RESULTS: When the two groups were compared with respect to leptin levels, the group with hyperemesis gravidarum was found to have significantly higher leptin levels (P = 0.037). No intergroup differences were observed in serum cortisol, insulin, hCG, thyroid hormone levels or BMI values. In the group with hyperemesis gravidarum, an inverse correlation was detected between cortisol and leptin (r = -0.762, P < 0.01), and hCG and thyroid-stimulating hormone (r = -0.503, P < 0.05), whereas a significant correlation was detected between insulin and leptin (r = 0.538, P < 0.05), leptin and BMI (r = 0.711, P < 0.01), and between TT3 and hCG (r = 0.605, P < 0.01). CONCLUSION: It was concluded that leptin could play a role in, and be defined as, a marker of hyperemesis gravidarum.

Hyperemesis gravidarum: is an ultrasound scan necessary?

BACKGROUND: Traditionally, in cases of hyperemesis gravidarum (HG), an ultrasound evaluation is recommended to confirm viability and to exclude multiple pregnancies and gestational trophoblastic disease (GTD). Our aim was to perform a case-control study to evaluate the incidence of these findings. METHODS: Each case of HG was matched for gestational age with the next ultrasound examination performed in an asymptomatic pregnancy. The findings were compared between the two groups. RESULTS: Two hundred and eighty-six cases of HG were matched with 286 asymptomatic women. The total number of viable pregnancies was higher in the HG group (280/286, 97.9%) than that in the control group (265/286, 92.6%; P = 0.006). The incidence of twins was 3.1% in each group (P > 0.999). The incidence of early pregnancy failure was 0.7% in women with HG compared to 7.0% in asymptomatic women (odds ratio 0.09, 95% CI 0.01-0.04, P < 0.0001). The one case of GTD was in the HG group; however, this case also presented with vaginal bleeding. CONCLUSIONS: Pregnancies complicated by HG had a similar risk of twin pregnancy, and a lower risk of early pregnancy failure compared to controls. In the absence of vaginal bleeding, there was no increase in GTD in women with HG. We conclude that an ultrasound scan is not clinically necessary in women presenting with HG, other than for maternal reassurance.

Relationship between adenosine and T-helper 1/T-helper 2 balance in hyperemesis gravidarum.

BACKGROUND: Adenosine modulates the T-helper (Th) 1/T-helper (Th) 2 balance. We evaluated the relationship between changes in plasma adenosine and the T-helper (Th) 1/T-helper (Th) 2 balance in hyperemesis gravidarum. METHODS: Plasma adenosine concentrations and the Th1/Th2 ratio were examined in the peripheral blood of 24 women with hyperemesis gravidarum and normal pregnancies. The proportion of CD4-positive cells that expressed intracellular cytokines (interferon gamma and interleukin 4) was analyzed by flow cytometry. The ratio of interferon-gamma-secreting cells to interleukin-4-secreting cells was taken as the Th1/Th2 ratio in vivo. The change induced by adenosine-receptor blocker 8-sulfophenyltheophylline was also measured in vitro to evaluate the possible role of adenosine in modifying the Th1/Th2 balance. RESULTS: In hyperemesis gravidarum, plasma adenosine and the proportion of interleukin-4-secreting cells were increased significantly, and the Th1/Th2 ratio was significantly lower than in normal pregnancy (p<0.05). The decrease in the proportion of IL-4-secreting cells after adenosine receptor blockade in hyperemesis gravidarum significantly exceeded that of normal pregnancy (p<0.05). CONCLUSIONS: Increased plasma adenosine may be involved in regulating the Th1/Th2 balance in hyperemesis gravidarum.