Rhombencephalitis in Pregnancy-A Challenging Case of Probable Listeria Infection.

Rhombencephalitis refers to inflammation of the brainstem and cerebellum, and can be caused by infections, autoimmune disorders or paraneoplastic syndromes. The most common infective cause is the bacterium Listeria monocytogenes. Listeria monocytogenes is the predominant species to cause human listeriosis, and is commonly due to the ingestion of contaminated foods. Symptoms include a mild gastroenteritis, fever (often with extreme temperature variations), headache, and myalgia. In more severe cases, invasive disease may lead to bacteraemia and neurolisteriosis. Pregnant women are more susceptible to listeriosis, which is believed to be due to pregnancy-related immune modulation. Maternal-neonatal infection with adverse pregnancy outcomes include neonatal listeriosis, spontaneous miscarriage and intrauterine fetal demise. Diagnosis may be challenging due to initial nonspecific symptoms and low sensitivity and specificity of confirmatory diagnostic laboratory tests. Here, we describe a case of rhombencephalitis in pregnancy, attributed to Listeria, and review the clinical features, diagnosis and multidisciplinary management. Lastly, we describe the immunological response to Listeria monocytogenes and show in vitro pro-inflammatory effects of Listeria monocytogenes on peripheral blood mononuclear cells and placental explants.

Euglycaemic ketoacidosis in pregnant women with COVID-19: two case reports.

BACKGROUND: Euglycaemic ketoacidosis (EKA) is an infrequent but serious condition which usually follows a period of starvation, severe vomiting or illness in individuals with or without diabetes. Ketoacidosis is associated with materno-fetal morbidity and mortality necessitating prompt diagnosis and management. Physiological increases in insulin resistance render pregnancy a diabetogenic state with increased susceptibility to ketosis. COVID-19 is associated with worse clinical outcomes in patients with diabetes and is an independent risk factor for ketoacidosis in normoglycaemic individuals. CASE PRESENTATIONS: We describe two cases of SARS-CoV-2 positive pregnant women presenting with normoglycaemic metabolic ketoacidosis. Both cases were associated with maternal and fetal compromise, requiring aggressive fluid and insulin resuscitation and early delivery. CONCLUSION: We discuss possible physiology and propose a management strategy for euglycaemic ketoacidosis in pregnancy.

Second-trimester uterine artery Doppler in the prediction of stillbirths.

OBJECTIVE: To examine the role of second-trimester uterine artery Doppler in the prediction of stillbirths. METHODS: Uterine artery pulsatility index (PI) was measured at 20-24 weeks' gestation in 65,819 singleton pregnancies. The PI was converted to multiples of median (MoM) and compared in live births and stillbirths. Regression analysis was used to determine the significance of association between log(10) uterine artery PI MoM and gestational age (GA) at delivery in cases of stillbirths. RESULTS: There were 306 (0.46%) stillbirths and in 159 (52.0%) of these there was pre-eclampsia (PE), placental abruption and/or birthweight below the 10th percentile (small for gestational age, SGA). In the stillbirths, the uterine artery PI MoM was significantly higher than in live births and was inversely associated with GA at delivery. The uterine artery PI MoM was above the 90th percentile in 80.6% of stillbirths with PE, abruption and/or SGA delivering at <32 weeks' gestation, in 41.9% at 33-36 weeks and in 34.3% at ≥37 weeks, and the respective percentages for stillbirths without PE, abruption or SGA were 15.8, 25.0 and 12.4%. CONCLUSION: Second-trimester uterine artery PI is effective in identifying early stillbirths in association with PE, abruption or SGA but not late deaths in the absence of PE, abruption or SGA.

Maternal serum vitamin D at 11-13 weeks in pregnancies delivering small for gestational age neonates.

OBJECTIVES: To determine if maternal serum levels of 25(OH)D at 11-13 weeks' gestation are altered in pregnancies that subsequently deliver small for gestational age (SGA) neonates and whether the levels are related to placental function reflected in serum concentration of pregnancy-associated plasma protein-A (PAPP-A). METHODS: Serum 25(OH)D and PAPP-A were measured at 11-13 weeks in 150 singleton pregnancies that delivered SGA neonates and 1,000 appropriate for gestational age (AGA) controls. The median 25(OH)D and PAPP-A multiple of the unaffected median (MoM) in the outcome groups were compared. RESULTS: In the SGA, the median serum 25(OH)D and PAPP-A were significantly decreased (0.78 vs. 1.00 MoM, p < 0.0001 and 0.78 vs. 1.00 MoM, p < 0.0001, respectively). The incidence of 25(OH)D levels below the 10th percentile was significantly higher in the SGA than the AGA group in Caucasian women (p = 0.002) but not in those of African racial origin (p = 0.183). There was no significant association between 25(OH)D MoM and PAPPA MoM in either the SGA or the AGA groups. CONCLUSION: Serum 25(OH)D levels at 11-13 weeks are decreased in pregnancies of Caucasian women that deliver SGA neonates but not in those of African racial origin. The decrease in 25(OH)D levels is unrelated to placental function.

Normal range of maternal serum vitamin d at 11-13 weeks' gestation.

OBJECTIVE: To establish a normal range of maternal serum levels of total vitamin D at 11-13 weeks' gestation and examine factors from maternal characteristics and obstetric history affecting these levels. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] was measured by liquid chromatography-tandem mass spectrometry in 1,000 singleton pregnancies with normal outcome. Multiple regression analysis was used to determine the factors from maternal characteristics and obstetric history affecting the measured 25(OH)D levels and the regression model was used to convert each measurement into a multiple of the median (MoM). RESULTS: Serum 25(OH)D increased with maternal age, decreased with body mass index (BMI), it was higher in the summer than other months and when conception was assisted than spontaneous and it was lower in cigarette smokers and in women of African and Asian racial origin compared to Caucasians. In Caucasian, non-smoking women, with BMI below 25, conceiving spontaneously and sampled in the summer months the estimated 5th, 10th, 50th, 90th and 95th percentiles of 25(OH)D were 10.8, 14.7, 30.7, 48.2 and 55.7 ng/ml, respectively. CONCLUSION: Maternal serum 25(OH)D concentration at 11-13 weeks is affected by season of blood sampling and maternal characteristics.

Maternal serum adiponectin at 11-13 weeks of gestation in preeclampsia.

OBJECTIVE: To determine whether the maternal serum levels of adiponectin in the first trimester of pregnancy are altered in cases that develop preeclampsia (PE) and whether the levels are related to pregnancy-associated plasma protein-A (PAPP-A) and uterine artery pulsatility index (PI). METHODS: Serum adiponectin, PAPP-A and uterine artery PI were measured at 11-13 weeks in 90 cases that developed PE, including 30 that required delivery before 34 weeks (early PE) and 300 unaffected controls. The median adiponectin, PAPP-A and uterine artery PI multiple of the unaffected median (MoM) in the outcome groups were compared. RESULTS: In both early PE and late PE, compared to controls, uterine artery PI MoM was increased (1.32 and 1.05 vs. 1.02) and PAPP-A MoM was decreased (0.61 and 0.84 vs. 1.00), whereas adiponectin MoM was increased in early PE but not in late PE (1.32 and 1.05 vs. 1.02). In the PE group, there was no significant association between adiponectin and PAPP-A or uterine artery PI. Serum adiponectin did not improve the performance of screening for PE provided by a combination of the maternal factors, uterine artery PI and serum PAPP-A. CONCLUSION: Serum adiponectin levels at 11-13 weeks are increased in women that develop early PE by a mechanism unrelated to impaired placentation.

Maternal uterine artery Doppler flow velocimetry and the risk of stillbirth.

OBJECTIVE: We sought to relate the risk of antepartum stillbirth to uterine artery Doppler flow velocimetry at 22-24 weeks. METHODS: Data were available from 30,519 unselected women from seven units in the UK who had uterine artery Doppler performed between 22 and 24 weeks of gestation. The risk of stillbirth (n=109) was assessed using time to event and logistic regression analysis. Stillbirths were subdivided into placental (due to abruption, preeclampsia, or growth restriction) or unexplained. RESULTS: The risk of placental stillbirth was increased among women with a mean pulsatility index in the top decile (adjusted hazard ratio [HR] 5.5, 95% confidence interval [CI] 2.8-10.6) and those with a bilateral notch (adjusted HR 3.9, 95% CI 2.0-7.8). The relationship between a mean pulsatility index in the top decile and the risk of unexplained stillbirth was weaker (adjusted HR 2.5, 95% CI 1.1-5.6) and there was no association with a bilateral notch. Placental stillbirths occurred at earlier gestations than unexplained stillbirths (median [interquartile range] 30 [26-36] compared with 38 [36-40], P<.001). Consequently, being in the top 5% of predicted risk of stillbirth on the basis of the combination of mean pulsatility index and notching was a good predictor (sensitivity, specificity, and positive likelihood ratio) of all cause stillbirth up to 32 weeks (58%, 95%, and 12.1, respectively) but a poor predictor of stillbirth at later gestations (7%, 95%, and 1.3, respectively). CONCLUSION: Abnormal uterine artery Doppler was a better predictor of the risk of stillbirth due to placental causes than unexplained stillbirth. Consequently, abnormal uterine artery Doppler was a good predictor of stillbirth at extreme preterm gestations but a poor predictor of stillbirth at term. LEVEL OF EVIDENCE: II.

Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) and development of pre-eclampsia: a case-control study and a meta-analysis.

BACKGROUND: Pre-eclampsia is thought to have an important genetic component. Recently, pre-eclampsia has been associated in some studies with carriage of a common eNOS gene Glu298Asp polymorphism, a variant that leads to the replacement of glutamic acid by aspartic acid at codon 298. METHOD: Healthy women with singleton pregnancies were recruited from 7 district general hospitals in London, UK. Women at high risk of pre-eclampsia were screened by uterine artery Doppler velocimetry at 22-24 weeks of gestation and maternal blood was obtained to genotype the eNOS Glu298Asp polymorphism. Odds ratios (OR) and 95%CI, using logistic regression methods, were obtained to evaluate the association between the Glu298Asp polymorphism and pre-eclampsia. A meta-analysis was then undertaken of all published studies up to November 2005 examining the association of eNOS Glu298Asp genotype and pre-eclampsia. RESULTS: 89 women with pre-eclampsia and 349 controls were included in the new study. The Glu298Asp polymorphism in a recessive model was not significantly associated with pre-eclampsia (adjusted-OR: 0.83 [95%CI: 0.30-2.25]; p = 0.7). In the meta-analysis, under a recessive genetic model (1129 cases & 2384 controls) women homozygous for the Asp298 allele were not at significantly increased risk of pre-eclampsia (OR: 1.28 [95%CI: 0.76-2.16]; p = 0.34). A dominant model (1334 cases & 2894 controls) was associated with no increase of risk of pre-eclampsia for women carriers of the Asp298 allele (OR: 1.12 [95%CI: 0.84-1.49]; p = 0.42). CONCLUSION: From the data currently available, the eNOS Glu298Asp polymorphism is not associated with a significant increased risk of pre-eclampsia. However, published studies have been underpowered, much larger studies are needed to confirm or refute a realistic genotypic risk of disease, but which might contribute to many cases of pre-eclampsia in the population.

First trimester sex hormone-binding globulin and subsequent development of preeclampsia or other adverse pregnancy outcomes.

OBJECTIVE: To investigate whether first trimester maternal serum sex hormone-binding globulin (SHBG) concentrations are altered in women who subsequently develop preeclampsia or other pregnancy complications. POPULATION: Women undergoing first trimester combined ultrasound and biochemical screening for chromosomal anomalies. We searched the database and identified 32 pregnancies resulting in miscarriage, 64 pregnancies with preexisting or gestational diabetes mellitus, 107 with fetal growth restriction, 103 with preeclampsia, 64 with pregnancy-induced hypertension, and 26 with spontaneous preterm delivery. We also selected 400 controls from among the population of pregnancies that had a delivery of a normal baby with no pregnancy complications. METHODS: Maternal serum SHBG concentrations were measured retrospectively using a competitive chemiluminescent immunoassay. The levels between those with normal outcome and those resulting in adverse outcome were compared. RESULTS: The median maternal serum SHBG concentration was not significantly different from controls, in those that subsequently developed preeclampsia (median MoM 1.05), non-proteinuric hypertension (median MoM 0.94) or preterm delivery (median MoM 1.15). The levels were significantly lower in those with diabetes (median MoM, 0.81 p=0.0005) and those pregnancies resulting in miscarriage (median MoM 0.80, p=0.008). CONCLUSION: First trimester maternal serum SHBG concentrations are no different from controls in women who subsequently develop preeclampsia, pregnancy-induced hypertension, fetal growth restriction, or preterm delivery. Levels are reduced in those who subsequently miscarry or in those presenting with diabetes.

Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler.

BACKGROUND: Previous studies have shown an association between low first trimester maternal serum free beta-hCG and PAPP-A and subsequent development of pregnancy complications. Similarly, uterine artery Doppler in the late second trimester has shown that high impedance to flow is associated with increased risk for preeclampsia and fetal growth restriction. The objective of this study is to determine whether there is an association between the maternal serum concentration of PAPP-A and free beta-hCG at 11-13(+6) weeks with the uterine artery pulsatility index (PI) at 22-24 weeks, and secondly, to compare the screening characteristics of the two methods in the prediction of adverse pregnancy outcome. METHODS: Maternal serum PAPP-A and free beta-hCG at 11-13(+6) weeks and uterine artery PI at 22-24 weeks were measured in 4390 women with singleton pregnancies. Pregnancies with chromosomal defects or fetal anomalies were excluded. The biochemical and Doppler measurements were compared between those with normal outcome and those resulting in spontaneous preterm delivery, pre-eclampsia and fetal growth restriction (FGR). Detection rates using a combination of the biochemical and Doppler measurements were investigated. RESULTS: In the pregnancies resulting in pre-eclampsia (n = 64) and FGR (n = 172), the median PAPP-A was lower (0.844 and 0.813 MoM), the median uterine artery mean PI was higher (1.56 and 1.18) but the median free betahCG was not significantly different (0.923 and 0.933 MoM) than in the normal outcome group. In the preterm delivery group (n = 159), the median free beta-hCG (0.944 MoM) and uterine artery mean PI (1.06) were not significantly different from normal but the median PAPP-A (0.928 MoM) was significantly lower than normal. In screening for pre-eclampsia, the detection rate, for a 5% false-positive rate, was 14.1% for PAPP-A, 54.7% for uterine artery mean PI and 62.1% for a combination of PAPP-A and uterine artery mean PI. CONCLUSION: Maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes. The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia.

An integrated model for the prediction of preeclampsia using maternal factors and uterine artery Doppler velocimetry in unselected low-risk women.

OBJECTIVE: The purpose of this study was to develop a predictive model for preeclampsia. STUDY DESIGN: This was a prospective screening study for preeclampsia using uterine artery Doppler ultrasound in unselected low-risk singleton pregnancies at community hospitals in the UK (n = 32,157). Logistic regression models were developed and their predictive ability assessed using the area under the receiver operator curve (AROC). RESULTS: Six hundred twelve (2.0%) women developed preeclampsia, and 144 (0.5%) required early delivery (<34 weeks). A model using both maternal and ultrasound factors had an AROC of 0.798, which was higher than ultrasound alone (0.729, P < .0001) or maternal factors alone (0.712, P < .0001). In early onset disease, the ROC of ultrasound alone (0.922) was not significantly improved by adding maternal predictors (0.945, P = .27). In contrast, late onset disease was better predicted by the combined model (AROC 0.798) than ultrasound alone (AROC 0.729, P < .0001) or maternal factors alone (AROC 0.712, P < .0001). CONCLUSION: The combination of uterine artery Doppler ultrasound and maternal factors provided the best estimate of risk.

Assessment of risk for the development of pre-eclampsia by maternal characteristics and uterine artery Doppler.

OBJECTIVE: To develop a method for the estimation of patient-specific risk for the development of pre-eclampsia by combining maternal history and uterine artery Doppler. DESIGN: Prospective multicentre observational study. SETTING: Antenatal clinics in seven hospitals in the UK and three overseas centres. POPULATION: Unselected women with singleton pregnancies attending for routine antenatal care. METHODS: Doppler studies of the uterine arteries were performed using colour flow mapping and pulsed wave Doppler at 23 weeks of gestation. The mean pulsatility index (PI) of the two uterine arteries was calculated. Doppler and maternal history variables were combined to develop a model for risk assessment. The incidence of pre-eclampsia was used to derive the prior risk for this complication. The posterior risk was derived by multiplying the prior odds with likelihood ratios (LRs) derived from independent risk factors identified from the maternal history, and the LR estimated from the heights of the frequency distributions of mean PI in affected and unaffected pregnancies. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: There were 17,480 women recruited to the study, in which 17,319 (99.1%) of these Doppler examination of both uterine arteries were completed, and outcome data were available in 16,806 (97.0%). Pre-eclampsia occurred in 369 (2.20%) cases. Significant independent prediction of pre-eclampsia was provided by mean PI, ethnic origin, body mass index (BMI), parity, cigarette smoking, history of hypertension and family or personal history of pre-eclampsia. Models were derived allowing calculation of patient-specific risk for development of pre-eclampsia. For a false-positive rate of 25%, the detection rate of pre-eclampsia by screening using maternal history was 45.3%, with uterine artery Doppler it was 63.1% and with combined assessment it was 67.5%. CONCLUSIONS: Combining risk factors in the mother's history with Doppler of the uterine arteries allows calculation of patient-specific risk for the development of pre-eclampsia.

The role of uterine artery Doppler in predicting adverse pregnancy outcome.

The complications of placental insufficiency, pre-eclampsia and fetal growth restriction (FGR) are major causes of perinatal as well as maternal morbidity and mortality. In normal pregnancy, impedance to flow in the uterine arteries decreases with gestation, and histopathological studies suggest that this is due to trophoblastic invasion of the spiral arteries and their conversion into low-resistance vessels. Failure of trophoblastic invasion is associated with complications of uteroplacental insufficiency. Several Doppler screening studies, both in the second and more recently in the first trimester of pregnancy, have demonstrated an association between increased impedance to flow in the uterine arteries and subsequent development of pre-eclampsia, FGR and perinatal death.