Andrée Gruslin

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Less-Tight versus Tight Control of Hypertension in Pregnancy

BACKGROUND The effects of less-tight versus tight control of hypertension on pregnancy complications are unclear. METHODS We performed an open, international, multicenter trial involving women at 14 weeks 0 days to 33 weeks 6 days of gestation who had nonproteinuric preexisting or gestational hypertension, office diastolic blood pressure of 90 to 105 mm Hg (or 85 to 105 mm Hg if the woman was taking antihypertensive medications), and a live fetus. Women were randomly assigned to less-tight control (target diastolic blood pressure, 100 mm Hg) or tight control (target diastolic blood pressure, 85 mm Hg). The composite primary outcome was pregnancy loss or high-level neonatal care for more than 48 hours during the first 28 postnatal days. The secondary outcome was serious maternal complications occurring up to 6 weeks post partum or until hospital discharge, whichever was later. RESULTS Included in the analysis were 987 women; 74.6% had preexisting hypertension. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35), as were the rates of serious maternal complications (3.7% and 2.0%, respectively; adjusted odds ratio, 1.74; 95% CI, 0.79 to 3.84), despite a mean diastolic blood pressure that was higher in the less-tight-control group by 4.6 mm Hg (95% CI, 3.7 to 5.4). Severe hypertension (≥160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001). CONCLUSIONS We found no significant between-group differences in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a significantly higher frequency of severe maternal hypertension. (Funded by the Canadian Institutes of Health Research; CHIPS Current Controlled Trials number, ISRCTN71416914; ClinicalTrials.gov number, NCT01192412.).

Maternal–Fetal Nutrient Transport in Pregnancy Pathologies: The Role of the Placenta

Appropriate in utero growth is essential for offspring development and is a critical contributor to long-term health. Fetal growth is largely dictated by the availability of nutrients in maternal circulation and the ability of these nutrients to be transported into fetal circulation via the placenta. Substrate flux across placental gradients is dependent on the accessibility and activity of nutrient-specific transporters. Changes in the expression and activity of these transporters is implicated in cases of restricted and excessive fetal growth, and may represent a control mechanism by which fetal growth rate attempts to match availability of nutrients in maternal circulation. This review provides an overview of placenta nutrient transport with an emphasis on macro-nutrient transporters. It highlights the changes in expression and activity of these transporters associated with common pregnancy pathologies, including intrauterine growth restriction, macrosomia, diabetes and obesity, as well as the potential impact of maternal diet. Molecular signaling pathways linking maternal nutrient availability and placenta nutrient transport are discussed. How sexual dimorphism affects fetal growth strategies and the placenta’s response to an altered intrauterine environment is considered. Further knowledge in this area may be the first step in the development of targeted interventions to help optimize fetal growth.

Obesity in Pregnancy: Pre-Conceptional to Postpartum Consequences

OBJECTIVE To review the effects of obesity on reproduction and pregnancy outcome. METHODS A search of the literature was performed using key word searching and citation snowballing to identify English language articles published between January 1, 2000, and December 31, 2006, on the subject of obesity and its effects on pregnancy. Once the articles were identified, a thorough review of all results was conducted. Results and conclusions were compiled and summarized. RESULTS Obesity during pregnancy was linked with maternal complications ranging from effects on fertility to effects on delivery and in the postpartum period, as well as many complications affecting the fetus and newborn. The maternal complications associated with obesity included increased risks of infertility, hypertensive disorders, gestational diabetes mellitus, and delivery by Caesarean section. Fetal complications included increased risks of macrosomia, intrauterine fetal death and stillbirth, and admission to the neonatal intensive care unit. CONCLUSION Obesity causes significant complications for the mother and fetus. Interventions directed towards weight loss and prevention of excessive weight gain must begin in the pre-conception period. Obstetrical care providers must counsel their obese patients regarding the risks and complications conferred by obesity and the importance of weight loss. Maternal and fetal surveillance may need to be heightened during pregnancy; a multidisciplinary approach is useful. Women need to be informed about both maternal and fetal complications and about the measures that are necessary to optimize outcome, but the most important measure is to address the issue of weight prior to pregnancy.

Current CHS and NHBPEP Criteria for Severe Preeclampsia Do Not Uniformly Predict Adverse Maternal or Perinatal Outcomes

Objective: To determine the association between adverse maternal/perinatal outcomes and Canadian and U.S. preeclampsia severity criteria. Methods: Using PIERS data (Preeclampsia Integrated Estimate of RiSk), an international continuous quality improvement project for women hospitalized with preeclampsia, we examined the association between preeclampsia severity criteria and adverse maternal and perinatal outcomes (univariable analysis, Fishers exact test). Not evaluated were variables performed in <80% of pregnancies (e.g., 24-hour proteinuria). Results: Few of the evaluated variables were associated with adverse maternal (chest pain/dyspnea, thrombocytopenia, ‘elevated liver enzymes’, HELLP syndrome, and creatinine >110 μM) or perinatal outcomes (dBP >110 mm Hg and suspected abruption) (at p < 0.01). Conclusions: In the PIERS cohort, most factors used in the Canadian or American classifications of severe preeclampsia do not predict adverse maternal and/or perinatal outcomes. Future classification systems should take this into account.

The Prediction of Adverse Maternal Outcomes in Preeclampsia

OBJECTIVES (1) To evaluate whether clinical variables reflecting the multiorgan dysfunctions of preeclampsia can predict adverse maternal outcomes of preeclampsia; (2) to determine the usefulness of the mean platelet volume (MPV):platelet ratio as a novel measure of platelet consumption in predicting the severity of preeclampsia. METHOD A retrospective chart review was conducted of cases of preeclampsia seen in 3 tertiary level units from January 2001 to December 2001. Candidate predictors of adverse maternal outcome were gestational age (GA) on admission to hospital, blood pressure, proteinuria, urine output, uric acid, creatinine, aspartate transaminase (AST), lactate dehydrogenase, bilirubin, albumin, fraction of inspired oxygen:oxygen saturation (FIO2:SaO2) ratio, platelet count, MPV, MPV:platelet ratio, fibrinogen, and seizures. The combined adverse maternal outcomes included maternal death; 1 or more of hepatic failure, hematoma, or rupture; Glasgow coma scale <13; stroke; 2 or more seizures; cortical blindness; positive inotrope support; myocardial infarction; infusion of any third antihypertensive; dialysis; renal transplantation; > or =50% FIO2 for >1 hour; intubation; or transfusion of > or =10 units of blood products. Descriptive, univariable, and multivariable analyses were performed, with significance set at P < .05. RESULTS Of a total of 594 women with preeclampsia, 60 (10.1%) developed at least 1 element of the combined adverse outcome; 1 of these 60 women died. The most common outcomes were increased oxygen requirements, the use of a third infused antihypertensive, and transfusion >10 units. In women who developed an adverse outcome, GA and fibrinogen were lower, and total leukocyte count, creatinine, and AST were greater. Multivariable logistic regression revealed that admission GA (odds ratio [OR], 0.91), dipstick protein (OR, 1.31), and MPV:platelet ratio (OR, 391.0) independently predicted the outcome. CONCLUSIONS Several promising markers were identified: admission GA, dipstick proteinuria, and the MPV:platelet ratio. MPV:platelet ratio also showed promise as a marker of platelet consumption. A prospective study is required to develop a clinical prediction model for preeclampsia.

Cytomegalovirus Infection in Pregnancy

OBJECTIVES To review the principles of prenatal diagnosis of congenital cytomegalovirus (CMV) infection and to describe the outcomes of the affected pregnancies. OUTCOMES Effective management of fetal infection following primary and secondary maternal CMV infection during pregnancy. Neonatal signs include intrauterine growth restriction (IUGR), microcephaly, hepatosplenomegaly, petechiae, jaundice, chorioretinitis, thrombocytopenia and anemia, and long-term sequelae consist of sensorineural hearing loss, mental retardation, delay of psychomotor development, and visual impairment. These guidelines provide a framework for diagnosis and management of suspected CMV infections. EVIDENCE Medline was searched for articles published in English from 1966 to 2009, using appropriate controlled vocabulary (congenital CMV infection) and key words (intrauterine growth restriction, microcephaly). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated into the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. RECOMMENDATIONS The quality of evidence reported in this document has been assessed using the evaluation of evidence criteria in the Report of the Canadian Task Force on Preventive Health Care (Table 1). 1. Diagnosis of primary maternal cytomegalovirus (CMV) infection in pregnancy should be based on de-novo appearance of virus-specific IgG in the serum of a pregnant woman who was previously seronegative, or on detection of specific IgM antibody associated with low IgG avidity. (II-2A) 2. In case of primary maternal infection, parents should be informed about a 30% to 40% risk for intrauterine transmission and fetal infection, and a risk of 20% to 25% for development of sequelae postnatally if the fetus is infected. (II-2A) 3. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis, which should be done at least 7 weeks after presumed time of maternal infection and after 21 weeks of gestation. This interval is important because it takes 5 to 7 weeks following fetal infection and subsequent replication of the virus in the kidney for a detectable quantity of the virus to be secreted to the amniotic fluid. (II-2A) 4. The diagnosis of secondary infection should be based on a significant rise of IgG antibody titre with or without the presence of IgM and high IgG avidity. In cases of proven secondary infection, amniocentesis may be considered, but the risk-benefit ratio is different because of the low transmission rate. (III-C) 5. Following a diagnosis of fetal CMV infection, serial ultrasound examinations should be performed every 2 to 4 weeks to detect sonographic abnormalities, which may aid in determining the prognosis of the fetus, although it is important to be aware that the absence of sonographic findings does not guarantee a normal outcome. (II-2B) 6. Quantitative determination of CMV DNA in the amniotic fluid may assist in predicting the fetal outcome. (II-3B) 7. Routine screening of pregnant women for CMV by serology testing is currently not recommended. (III-B) 8. Serologic testing for CMV may be considered for women who develop influenza-like illness during pregnancy or following detection of sonographic findings suggestive of CMV infection. (III-B) 9. Seronegative health care and child care workers may be offered serologic monitoring during pregnancy. Monitoring may also be considered for seronegative pregnant women who have a young child in day care. (III-B).

Pre-eclampsia: Fetal assessment and neonatal outcomes

Pre-eclampsia is associated with a number of short- and long-term perinatal and neonatal complications, including death. These are mostly related to birth weight and gestational age at delivery, and therefore are most relevant to severe or early onset pre-eclamptic toxaemia. Currently, little information is available on the optimal antenatal testing modality to be used for pre-eclampsia. Significant limitations are associated with fetal movement counts and the biophysical profile. Evidence is accumulating, however, to support the incorporation of umbilical artery and venous Doppler velocimetry in the evaluation of such fetuses, especially in cases of associated placental insufficiency. Pre-eclampsia might confer some survival advantage to small gestational age infants and prematurely born infants compared with infants born after spontaneous preterm labour. The degree of intrauterine growth restriction also has a negative effect on early morbidity. Longer term outcomes for prematurely born infants are dependent on gestational age, and it is unclear whether the survival advantage conferred by pre-eclampsia translates into better long-term neurodevelopmental outcomes. Abnormal umbilical artery flows might predict poorer cognitive outcomes, although evidence for this is not strong.

The Control of Hypertension In Pregnancy Study pilot trial

Objective  To determine whether ‘less tight’ (versus ‘tight’) control of nonsevere hypertension results in a difference in diastolic blood pressure (dBP) between groups.

X-Linked Inhibitor of Apoptosis Protein Expression and the Regulation of Apoptosis During Human Placental Development

Abstract In this study, we have examined the expression and potential role of X-linked inhibitor of apoptosis protein (XIAP), Fas, and Fas ligand (FasL) in the regulation of apoptosis throughout placental development. Protein expression was determined by Western blot analysis and immunohistochemistry, whereas apoptotic cell death was assessed by DNA fragmentation analysis and TUNEL. The XIAP was present in trophoblast throughout placental development, but its content significantly decreased during late pregnancy, when apoptosis was maximal. The FasL content was low during early placental development but increased coincidentally to the decrease in XIAP during the third trimester. Our data also suggest that placental apoptosis is the culmination of the relative expression of these cell-death and -survival proteins, a phenomenon that is cell type-specific and dependent on cytodifferentiation and the stage of placental development. Moreover, the induction of syncytiotrophoblast apoptosis may involve the concomitant up-regulation of FasL for Fas activation and the removal of downstream inhibition of the apoptotic cascade by XIAP.