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.

Approaches to screening for hyperglycaemia in pregnant women during and after the COVID-19 pandemic.

AIM: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA1c , during the COVID-19 pandemic. METHODS: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004-2008; 826 consecutive gestational diabetes pregnancies, 2014-2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver-operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA1c performance. RESULTS: Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks [area under the receiver-operating characteristic curve for both criteria 0.81 (95% CI 0.79-0.83)], fasting plasma glucose [National Institute of Health and Clinical Excellence: area under the receiver-operating characteristic curve 0.75 (95% CI 0.65-0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver-operating characteristic curve 0.92 (95% CI 0.85-0.98)] and HbA1c at 28 weeks' gestation [National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75-0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77-0.91)]. Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2-5.4 mmol/l (sensitivity 18-41%; specificity 97-98%). CONCLUSIONS: Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.

Barriers to completing oral glucose tolerance testing in women at risk of gestational diabetes.

AIM: Complications of gestational diabetes (GDM) can be mitigated if the diagnosis is recognized. However, some at-risk women do not complete antenatal diagnostic oral glucose tolerance testing (OGTT). We aimed to understand reasons contributing to non-completion, particularly to identify modifiable factors. METHODS: Some 1906 women attending a tertiary UK obstetrics centre (2018-2019) were invited for OGTT based on risk-factor assessment. Demographic information, test results and reasons for non-completion were collected from the medical record. Logistic regression was used to analyse factors associated with non-completion. RESULTS: Some 242 women (12.3%) did not complete at least one OGTT, of whom 32.2% (n = 78) never completed testing. In adjusted analysis, any non-completion was associated with younger maternal age [≤ 30 years; odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.4; P < 0.001], Black African ethnicity (OR 2.7, 95% CI 1.2-5.5; P = 0.011), lower socio-economic status (OR 0.9, 95% CI 0.8-1.0; P = 0.021) and higher parity (≥ 2; OR 1.8, 95% CI 1.1-2.8; P = 0.013). Non-completion was more likely if testing indications included BMI ≥ 30 kg/m2 (OR 1.7, 95% CI 1.1-2.4; P = 0.009) or family history of diabetes (OR 2.2, 95% CI 1.5-3.3; P < 0.001) and less likely if the indication was an ultrasound finding (OR 0.4, 95% CI 0.2-0.9; P = 0.035). We identified a common overlapping cluster of reasons for non-completion, including inability to tolerate test protocol (21%), social/mental health issues (22%), and difficulty keeping track of multiple antenatal appointments (15%). CONCLUSIONS: There is a need to investigate methods of testing that are easier for high-risk groups to schedule and tolerate, with fuller explanation of test indications and additional support for vulnerable groups.

Seasonal variations in incidence and maternal-fetal outcomes of gestational diabetes.

AIMS: To determine whether the neonatal and delivery outcomes of gestational diabetes vary seasonally in the context of a relatively cool temperate climate. METHODS: A retrospect cohort of 23 735 women consecutively delivering singleton, live-born term infants in a single tertiary obstetrics centre in the UK (2004-2008) was identified. A total of 985 (4.1%) met the diagnostic criteria for gestational diabetes. Additive dynamic regression models, adjusted for maternal age, BMI, parity and ethnicity, were used to compare gestational diabetes incidence and outcomes over annual cycles. Outcomes included: random plasma glucose at booking; gestational diabetes diagnosis; birth weight centile; and delivery mode. RESULTS: The incidence of gestational diabetes varied by 30% from peak incidence (October births) to lowest incidence (March births; P=0.031). Ambient temperature at time of testing (28 weeks) was strongly positively associated with diagnosis (P<0.001). Significant seasonal variation was evident in birth weight in gestational diabetes-affected pregnancies (average 54th centile June to September; average 60th centile December to March; P=0.027). Emergency Caesarean rates also showed significant seasonal variation of up to 50% (P=0.038), which was closely temporally correlated with increased birth weights. CONCLUSIONS: There is substantial seasonal variation in gestational diabetes incidence and maternal-fetal outcomes, even in a relatively cool temperate climate. The highest average birth weight and greatest risk of emergency Caesarean delivery occurs in women delivering during the spring months. Recognizing seasonal variation in neonatal and delivery outcomes provides new opportunity for individualizing approaches to managing gestational diabetes.

Improving outcomes in gestational diabetes: does gestational weight gain matter?

AIM: Excessive gestational weight gain increases risk of gestational diabetes mellitus (GDM) but it remains unclear whether weight control after GDM diagnosis improves outcomes. We assessed whether: (1) total gestational weight gain during pregnancy (0-36 weeks); (2) early gestational weight gain (0-28 weeks, before GDM diagnosis); or (3) late gestational weight gain (28-36 weeks, after diagnosis) are associated with maternal-fetal outcomes. METHODS: Some 546 women with GDM who delivered viable singleton infants at a single UK obstetric centre (October 2014 to March 2017) were included in this retrospective observational study. RESULTS: Higher total gestational weight gain was associated with Caesarean section [n = 376; odds ratio (OR) 1.05; confidence intervals (CI) 1.02-1.08, P < 0.001] and large for gestational age (OR 1.08; CI 1.03-1.12, P < 0.001). Higher late gestational weight gain (28-36 weeks; n = 144) was associated with large for gestational age (OR 1.17; CI 1.01-1.37, P < 0.05), instrumental deliveries (OR 1.26; CI 1.03-1.55, P < 0.01), higher total daily insulin doses (36 weeks; beta coefficient 4.37; CI 1.92-6.82, P < 0.001), and higher post-partum 2-h oral glucose tolerance test concentrations (beta coefficient 0.12; CI 0.01-0.22, P < 0.05). Women who avoided substantial weight gain after GDM diagnosis had 0.7 mmol/l lower postnatal 2-h glucose and needed half the amount of insulin/day at 36 weeks compared with women with substantial weight gain after diagnosis. There were no significant associations between early gestational weight gain (0-28 weeks) and pregnancy outcomes. CONCLUSIONS: These findings suggest that controlling gestational weight gain should be a priority following GDM diagnosis to optimize pregnancy outcomes and improve maternal postnatal glucose homeostasis. The period after diagnosis of GDM (often 28 weeks gestation) is not too late to offer lifestyle advice or intervention to improve weight management and pregnancy outcomes.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Evidence of biochemical hyperandrogenism in women: the limitations of serum testosterone quantitation.

Hyperandrogenism in women is a common clinical scenario and is characterised by menstrual disturbance, hirsutism and infertility. Accurate measurement of serum testosterone is often used in these patients to diagnose polycystic ovary syndrome (PCOS) and to prompt further investigation in patients with suspected androgen-secreting tumours. Immunoassay methods are commonly used for serum testosterone quantitation, although the 'gold standard' reference method is mass spectrometry (MS), which is only available at certain tertiary centres. In this retrospective observational study, 57 female patients were investigated for possible hyperandrogenism. Biochemical testing for testosterone using an immunoassay was compared to an MS method. Correlation between the immunoassay and MS method was worse at lower testosterone concentrations, however overall, gave a reasonably strong correlation coefficient of 0.73. This study highlights the ongoing controversy over the most reliable test for hyperandrogenism in clinical practice. It is vital that clinicians are aware of the limitations of these methods and the clinical repercussions.

Use of high-intensity statin therapy with simvastatin 80 mg and atorvastatin 80 mg in primary care.

AIMS: Cardiovascular disease (CVD) is the most common cause of death worldwide. Pharmaceutical risk reduction with high-intensity statin therapy is advisable for high-risk patients. Clinicians face a conflict between prescribing for cost (simvastatin 80 mg) or for efficacy (atorvastatin 80 mg). The aim of this audit was to examine the use, efficacy and tolerability of high intensity statin treatment (simvastatin 80 mg; atorvastatin 80 mg) in primary care. METHODOLOGY: Electronic medical records were examined from two general practitioners' surgeries. Analyses involved Mann-Whitney U and χ(2) tests. RESULTS: A total of 116 patients had taken simvastatin 80 mg or atorvastatin 80 mg. Patients were similar between treatment groups: mostly men (62.9%), over 60 years old (68.1%), non-smokers (81.0%) taking statins for secondary prevention (56.9%). More patients on simvastatin withdrew from treatment as a result of inefficacy (49.3% vs. 23.2%, p=0.025) compared with the atorvastatin group. Furthermore, patients on simvastatin were more likely to be failing conventional targets of lipid control, compared with patients on atorvastatin 80 mg (43.5% vs. 21.3%, p=0.006). Tolerability was similar between the two groups. DISCUSSION: UK guidelines recommend simvastatin 80 mg as an economic choice, despite scant evidence at this dose and recent safety concerns. Conversely, robust evidence exists for atorvastatin 80 mg. Head-to-head clinical trials or clinical studies comparing these agents are lacking. The present study suggests that atorvastatin 80 mg compares favourably to simvastatin in terms of efficacy and has a similar tolerability profile. CONCLUSION: This retrospective observational study suggests that despite national guidelines, atorvastatin 80 mg is used in clinical practice and is more effective and at least as well tolerated as simvastatin 80 mg.

Dispersal and distribution of Calliphoridae (Diptera) immatures from animal carcasses in southern Louisiana.

Spatial distributions of calliphorid pupae (based on adult emergence) from swine carcasses located in woods and pasture were determined during 4 seasons in southern Louisiana. Adult emergence was substantially greater in pastures than woods for all seasons except winter. Secondary screwworm, Cochliomyia macellaria (F.), was the predominant calliphorid species collected ( > 95%) during summer and fall; whereas, black blow fly, Phormia regina (Meigen), was the primary species (86%) during spring. The highest densities of calliphorid pupae per square meter were located within 0.9 m of the animal carcasses in the woods and the pasture (summer); however, the number of calliphorid pupae per square meter during the summer was substantially greater in the pastures than in the woods (2,370/m2 compared with 77/m2). Postfeeding calliphorid larvae preferred to disperse toward the southeastern quadrant during summer and spring and toward the southeastern to southwestern quadrants in fall. The winter evaluation period was the most prolonged (85 d), had the least number of emergent adults (only 6-11% of the populations that emerged in the other seasons), and consisted of predominantly, Phaenicia sericata (Meigen).

Mosquito (Diptera: Culicidae) host compatibility and vector competency for the human myositic parasite Trachipleistophora hominis (Phylum Microspora).

Microsporidian spores of Trachipleistophora hominis Hollister, isolated from a human, readily infected larval stages of both Anopheles quadrimaculatus Say sensu lato and Culex quinque-fasciatus Say. Mosquito infections with T. hominis were located, primarily, in abdominal muscles in segment numbers 4 through 6; other spores were found in the hemocoel and proboscis. Nearly 50% of the infected mosquito larvae survived to the adult stage. Spores recovered from adult mosquitoes were inoculated into mice and resulted in significant muscle infection at the site of injection. Preliminary observations also showed that T. hominis spores can be passively transferred from infected mosquitoes to a sugar water substrate.

Validation of a ribosomal DNA-polymerase chain reaction species diagnostic assay for the common malaria mosquito (Diptera:Culicidae) sibling species complex.

A polymerase chain reaction method for identifying individuals in the Anopheles quadrimaculatus Say sibling species complex was validated for wild mosquitoes from Louisiana and Mississippi. This method distinguished An. quadrimaculatus species A, B, C, and D by detecting species-specific differences in the 2nd internal transcribed spacer of ribosomal DNA and was 100% specific and 95% sensitive.

Les maringouins du meche and the legacy of two men.

E. S. Hathaway and his colleague, A. B. Ritter, were directly responsible for establishing organized mosquito control in Louisiana in the late 1950s and early 1960s. They jointly sought to educate governmental officials and Louisiana citizens that mosquitoes could be controlled if the efforts were based on scientific knowledge, trained personnel and appropriate funding. These men were instrumental also in establishing the Louisiana Mosquito Control Association and subsequently involved with the formation of the first 5 parish-wide mosquito control districts in Louisiana.

Record of Anopheles quadrimaculatus species C in Louisiana.

Sibling species C of the Anopheles quadrimaculatus species complex was found south of Abbeville (Vermilion Parish), Louisiana, during a state-wide survey in 1993. This constitutes a new state record and currently represents its westernmost distribution.

Dose-mortality responses of crawfish and mosquitoes to selected pesticides.

A study was conducted to determine the toxicities (LC50S) of several pesticides on the commercially important red swamp crawfish, Procambarus clarkii, and 3 mosquito species common in Louisiana ricelands--Anopheles quadrimaculatus, Culex salinarius and Psorophora columbiae. Pesticides tested in laboratory bioassays included Bacillus sphaericus, B. thuringiensis var. israelensis, bendiocarb, glyphosate, isostearyl alcohol, malathion, propoxur, resmethrin synergized with piperonyl butoxide (PBO) and thiobencarb. Isostearyl alcohol was the least toxic compound to crawfish, with a LC50 of greater than 10,000 ppm, while resmethrin + PBO (1:3 ratio) was the most toxic with a LC50 of 0.00082 ppm. The herbicides glyphosate and thiobencarb were the least toxic compounds for the mosquito species tested, while B. t. var. israelensis and resmethrin + PBO were the most toxic.

A self-marking device for emergent adult mosquitoes.

A portable, tent-like device with powdered fluorescent pigment for marking emergent adult mosquitoes was evaluated in the field using Culex quinquefasciatus adults. The top of the device was equipped with cheesecloth partitions impregnated with the pigment. Eighty-six percent of the emergent adults passed through the partitions, and all were marked.

Blood-feeding of Culex mosquitoes in an urban environment.

The modified capillary tube precipitin test was used to identify blood meal sources of Culex quinquefasciatus emerging from sewage ditches in East Baton Rouge Parish, Louisiana. Canines were the primary hosts, but Passeriformes and humans were also suitable blood meal sources. The percentage of Cx. quinquefasciatus feeding on these 3 hosts fluctuated with the habitat and the season.

Mortality and survival patterns for the immature stages of Psorophora columbiae.

To determine the patterns of Psorophora columbiae survival and mortality, methods were employed that involved the simultaneous use of laboratory-reared cohorts, predator-exclusion cages, and field estimates of larval dynamics. Laboratory studies indicated that the maximum daily survival averaged from 0.92 for day-old larvae to 1.0 for the older age classes with no significant differences (P greater than 0.05) in survival among days. Data from predator-exclusion cages indicated that mortality inflicted by factors other than predation was significantly (P less than 0.05) more intense in the younger age classes and the relatively few individuals that survived to the older age classes had a high expectation of successful emergence. A quantitative estimate of the mortality inflicted on Ps. columbiae larvae by all indigenous natural enemies indicated that mortality rates were higher in the older age classes. This supports the view that the predator complex is a major source of irreplaceable mortality for immature mosquitoes inhabiting Louisiana rice fields.

Nocturnal distribution of Louisiana riceland mosquito adults.

Nocturnal riceland mosquito populations in southern Louisiana were monitored using nonbaited CDC miniature light traps. A mixed population of Anopheles quadrimaculatus, An. crucians, Psorophora columbiae and Culex salinarius adults was collected in a livestock occupied barn. Highly variable numbers of all 4 species were trapped in areas away from the barns. Species density at any given trap location was not related to trap location, type of habitat surrounding the trap or brush density near the trap. Captures of anophelines were not affected by moonlight, whereas trap collections of culicines were lower on moonlit nights. Mean numbers of anophelines captured at night in traps exhibited a linear function of trap distance from the barn, with higher catches at locations farther from the barn. No such function was observed for culicines.

An improved model of a battery-powered aspirator.

Detailed instructions are provided to modify a commercially available, battery-powered, leaf/grass blower into a portable, hand-held aspirator for collecting adult mosquitoes and other small dipterans. Directions are given also to convert paper cups into interchangeable collection containers for use with the aspirator.

Effects of ivermectin in canine blood on Anopheles quadrimaculatus, Aedes albopictus and Culex salinarius.

Blood from ivermectin-treated dogs was tested against adult mosquitoes. Mosquitoes were allowed to bloodfeed on mixed breed dogs 4 h after dogs were given oral dosages of ivermectin. In test 1, Anopheles quadrimaculatus and Aedes albopictus fed on dogs that had been given ivermectin dosages of 0, 6, 12, and 24 micrograms/kg. In test 2, Culex salinarius and Ae. albopictus fed on dogs that had been given dosages of 0, 15, 30, 60, and 120 micrograms/kg. In both tests, mosquitoes were observed for mortality at 1, 12, and 24 h postfeeding. Surviving mosquitoes were observed for oviposition and egg hatching. In the first test, there was a significant increase in mortality and a significant decrease in number of eggs/female and egg hatchability in An. quadrimaculatus but not in Ae. albopictus (P < 0.05). An LD50 of 9.9 micrograms/kg (95% FL 6.0-13.8) was determined for An. quadrimaculatus. In the 2nd test, there were no significant differences in any variable for Cx. salinarius or Ae. albopictus, except that eggs from Ae. albopictus had reduced hatching at all dosages.