Hein W. Bruinse

Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies

Anti-phospholipid antibodies are associated with first trimester abortions and late intra-uterine fetal death. The histopathology of 47 placentae from 45 women with intra-uterine fetal death, including 16 patients with anti-phospholipid antibodies, was studied in order to detect potential differences between placentae from women with and without these antibodies. Thirteen patients had systemic lupus erythematosus or lupus-like disease, including 6 women with anti-phospholipid antibodies. In placentae from patients with anti-phospholipid antibodies, a decrease in vasculo-syncytial membranes, fibrosis mainly in infarcted areas, hypovascular villi and thrombosis or infarction was seen significantly more often than in placentae from women without these antibodies. Of 17 placentae from 16 patients with anti-phospholipid antibodies, only 3 did not demonstrate signs of thrombosis or infarction. Thrombosis/infarction was significantly associated with a decrease in vasculo-syncytial membranes, fibrosis, hypovascular villi and an increase in syncytial knots. These findings are most likely to be the result of prolonged hypoxia due to thrombosis or infarction. It is concluded that thrombosis or infarctions are prominent features in placenta from patients with anti-phospholipid antibodies and intra-uterine fetal death. Consequently, antithrombotic treatment during pregnancy forms a rational approach in these patients.

A prospective, controlled multicenter study on the obstetric risks of pregnant women with antiphospholipid antibodies

OBJECTIVES A prospective, controlled multicenter study was performed to estimate the obstetric risks of antiphospholipid antibodies (the lupus anticoagulant and anticardiolipin antibodies). In addition, the risks of prior thrombosis, obstetric history, systemic lupus erythematosus, and high-dose prednisone treatment were evaluated. STUDY DESIGN After screening for antiphospholipid antibodies in patients with lupus erythematosus or women with prior fetal loss(es), 59 subsequent pregnancies with and 54 without these antibodies were followed. RESULTS The presence of the lupus anticoagulant and a history of at least three spontaneous abortions could predict fetal loss (p = 0.032 and 0.001, respectively). In live born infants, a low birth weight could be predicted by the presence of anticardiolipin antibodies (p = 0.034), prior intrauterine fetal death (p = 0.025), and treatment with high-dose prednisone (p = 0.002). No relationships were seen between antiphospholipid antibodies and small-for-gestational-age newborns and pregnancy-induced hypertension or preeclampsia. The disappearance of antiphospholipid antibodies during pregnancy was not correlated with live birth. CONCLUSION It is concluded that the presence of antiphospholipid antibodies is a risk factor for adverse pregnancy outcome.

Cardiac output in normal pregnancy : a critical review

Objective To review the literature about the effect of normal pregnancy on cardiac output, with special attention to study design, measurement technique, position of the subject, and parity. Data Sources For studies from the period 1955–1987, we examined Cumulated Index Medicus (National Library of Medicine Cataloging in Publication. Chicago: American Medical Association). For studies from 1988 to May 1, 1994, we used Medline on Silver Platter (U.S. National Library of Medicine Silver Platter International, 1994). Methods of Study Selection Thirty-three cross-sectional and 19 longitudinal studies on cardiac output measurement in normal pregnancy were retrieved and reviewed. Thirteen longitudinal studies were excluded from analysis because an unvalidated technique was used or because not all subjects were measured at each study interval. The six remaining studies of genuine longitudinal design with at least two measurements throughout pregnancy were used for the definitive analysis. The results of the cross-sectional studies were included only to demonstrate a trend. Data Extraction and Synthesis By pooling data from cross-sectional studies, a tendency was shown toward a higher cardiac output in the second trimester compared with the first trimester, and a tendency toward lower cardiac output was found in the third trimester compared with the second trimester. After delivery, cardiac output was lower than at any time during pregnancy. Selected longitudinal studies showed that the rise in cardiac output occurred early in the first trimester, and a further rise occurred during the second trimester. During the third trimester, cardiac output rose, fell, or plateaued, irrespective of the method of measurement applied or conditions during measurement. Conclusions Cardiac output during the third trimester was widely divergent among the studies and probably dependent on individual factors. The tendency to report cardiac output as averages negated these inter-individual differences.

Perinatal mortality and severe morbidity in low and high risk term pregnancies in the Netherlands: prospective cohort study

Objective To compare incidences of perinatal mortality and severe perinatal morbidity between low risk term pregnancies supervised in primary care by a midwife and high risk pregnancies supervised in secondary care by an obstetrician. Design Prospective cohort study using aggregated data from a national perinatal register. Setting Catchment area of the neonatal intensive care unit (NICU) of the University Medical Center in Utrecht, a region in the centre of the Netherlands covering 13% of the Dutch population. Participants Pregnant women at 37 weeks’ gestation or later with a singleton or twin pregnancy without congenital malformations. Main outcome measures Perinatal death (antepartum, intrapartum, and neonatal) or admission to a level 3 NICU. Results During the study period 37 735 normally formed infants were delivered at 37 weeks’ gestation or later. Sixty antepartum stillbirths (1.59 (95% confidence interval 1.19 to 1.99) per 1000 babies delivered), 22 intrapartum stillbirths (0.58 (0.34 to 0.83) per 1000 babies delivered), and 210 NICU admissions (5.58 (4.83 to 6.33) per 1000 live births) occurred, of which 17 neonates died (0.45 (0.24 to 0.67) per 1000 live births). The overall perinatal death rate was 2.62 (2.11 to 3.14) per 1000 babies delivered and was significantly higher for nulliparous women compared with multiparous women (relative risk 1.65, 95% confidence interval 1.11 to 2.45). Infants of pregnant women at low risk whose labour started in primary care under the supervision of a midwife had a significant higher risk of delivery related perinatal death than did infants of pregnant women at high risk whose labour started in secondary care under the supervision of an obstetrician (relative risk 2.33, 1.12 to 4.83). NICU admission rates did not differ between pregnancies supervised by a midwife and those supervised by an obstetrician. Infants of women who were referred by a midwife to an obstetrician during labour had a 3.66 times higher risk of delivery related perinatal death than did infants of women who started labour supervised by an obstetrician (relative risk 3.66, 1.58 to 8.46) and a 2.5-fold higher risk of NICU admission (2.51, 1.87 to 3.37). Conclusions Infants of pregnant women at low risk whose labour started in primary care under the supervision of a midwife in the Netherlands had a higher risk of delivery related perinatal death and the same risk of admission to the NICU compared with infants of pregnant women at high risk whose labour started in secondary care under the supervision of an obstetrician. An important limitation of the study is that aggregated data of a large birth registry database were used and adjustment for confounders and clustering was not possible. However, the findings are unexpected and the obstetric care system of the Netherlands needs further evaluation.

Risk factors for cardiovascular disease in women with a history of pregnancy complicated by preeclampsia or intrauterine growth restriction.

Objective: Women with a history of preeclampsia or intrauterine growth restriction (IUGR) have an increased risk for cardiovascular disease in later life. We determined the presence of traditional and novel risk factors for cardiovascular disease in these women. Methods: We studied 256 women with a history of preeclampsia and 59 women with a history of intrauterine growth restriction. Fifty-three women with a history of uncomplicated pregnancy served as controls. We determined values for blood pressure, body mass index, concentrations of cholesterol, high-density lipoprotein cholesterol, triglycerides and lipoprotein (a), and insulin resistance. Results: Women with a history of preeclampsia exhibited more risk factors for future cardiovascular disease such as dyslipidemia, hypertension, obesity, and increased insulin resistance compared with women with a history of uncomplicated pregnancy. Women with a history of IUGR have higher concentrations of cholesterol and show a tendency to higher BMI, higher triglyceride concentrations, and increased insulin resistance as compared with women with a history of normal pregnancy. Conclusions: Preeclampsia or IUGR may represent an early marker for increased risk for early cardiovascular disease.

Prophylactic administration of clindamycin 2 % vaginal cream to reduce the incidence of spontaneous preterm birth in women with an increased recurrence risk: a randomised placebo-controlled double-blind trial

Objective To test the hypothesis that prophylactic administration of clindamycin 2% vaginal cream can reduce the incidence of preterm birth in a high risk population.

Fetal growth retardation as a cause of impaired ovarian development

Low birthweight has been associated with diseases and disorders later in life. It has been suggested that this is caused by the impaired development of abdominal organs, especially in cases of growth retardation. Besides general malnutrition of the fetus, preferential bloodflow to the heart and brain may further deprive organs, such as liver, pancreas and kidney, of nutrients. As a result these organs may not develop properly. Anatomically, the ovary is situated close to the kidney and it is very likely that, similar to the kidney, ovarian development can be negatively affected by intra-uterine growth retardation. Placental insufficiency, which is an important cause of severe intra-uterine growth retardation, was used as a model to investigate this hypothesis. In the present study, the volume percentages of primordial follicles in the ovaries of four severely growth-retarded fetuses of different gestational ages are compared to those of four age-matched controls. It is found that these volume percentage in growth-retarded fetuses were significantly lower than those observed in the age-matched controls. It can be concluded that ovarian development is impaired in intra-uterine growth-retarded fetuses. These findings further suggest that, as a result of the premature loss of follicles, females with low birthweights may encounter fertility problems later in life.

Doppler assessment of the fetoplacental circulation in normal and growth-retarded fetuses

The Pulsatility Index (PI) of Doppler flow signals from umbilical arteries was used to study flow resistance of the placental villous circulation. A preliminary reference curve of PI values in normal pregnancy was composed from 23 healthy women examined every 2 wk from the 16th postmenstrual week until delivery. The gestational age-related decrease of PI values reflects a reduction of flow resistance in the placental villous circulation. In small-for-date fetuses significantly increased PI values were found, indicating that this simple technique may permit an early diagnosis of compromised fetoplacental circulation, even several weeks to months before fetal growth retardation is clinically presumed.

Maternal and Infant Characteristics Associated With Perinatal Arterial Stroke in the Preterm Infant

Background and Purpose— Most perinatal arterial stroke (PAS) studies that investigated infant characteristics have excluded preterm infants from the study population. We sought to analyze the imaging findings and antenatal and perinatal risk factors in preterm infants with PAS. Methods— This was a hospital-based, case-control study of preterm infants. Case infants were confirmed by reviewing brain imaging scans and medical records (n=31). Three controls per case were individually matched with case infants from the study population. Results— Gestational age ranged between 27 and 36 weeks, and birth weight ranged between 580 and 3180 g. PAS was more common on the left side (61%), and 7% had bilateral PAS. The majority of strokes involved the middle cerebral artery distribution. Involvement of 1 or more lenticulostriate branches was most common among infants with a gestational age of 28 to 32 weeks, but main branch involvement was seen only in those with a gestational age of >32 weeks. Twin-to-twin-transfusion syndrome, fetal heart rate abnormality, and hypoglycemia were identified as independent risk factors for PAS. Conclusions— Preterm PAS is associated with prenatal, perinatal, and postpartum risk factors. We were unable to identify any maternal risk factors. Involvement of the different branches of the middle cerebral artery changed with an increase in gestational age.

Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome

Summary.  Background: HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome is a severe complication of pre‐eclampsia in pregnancy, characterized by microvascular platelet thrombi. Activation of the endothelium is thought to play a key role in pre‐eclampsia and HELLP syndrome. Activation of endothelial cells may lead to release of von Willebrand factor (VWF) multimers, which are highly reactive with platelets. Normally, newly released multimers are cleaved by ADAMTS13, resulting in less reactive derivatives. Objective: We hypothesized that HELLP syndrome is characterized by increased amounts of active VWF compared with healthy pregnancy and pre‐eclampsia, due to acute activation of endothelial cells. This might contribute to thrombocytopenia and thrombotic microangiopathy. Methods: Active VWF and ADAMTS13 activity were measured in healthy pregnant volunteers (n = 9), patients with pre‐eclampsia (n = 6) and patients with HELLP syndrome (n = 14) at similar gestational ages. To study the role of endothelial cell activation, the propeptide/mature VWF ratio was determined, and VWF released by cultured endothelial cells was analyzed. Results: Active VWF levels were increased 2.1‐fold in HELLP syndrome compared with healthy pregnant volunteers (P < 0.001) and 1.6‐fold compared with patients with pre‐eclampsia (P = 0.001). ADAMTS13 activity was moderately decreased in patients with HELLP syndrome compared with healthy pregnant volunteers (P < 0.004), but not compared with patients with pre‐eclampsia. The propeptide/mature VWF ratio was increased 1.7‐fold compared with healthy pregnant volunteers (P < 0.001) and 1.5‐fold compared with patients with pre‐eclampsia (P < 0.05). A significant correlation was found between this ratio and the activation factor of VWF (r = 0.68, P < 0.001). The amount of active VWF was increased 1.4‐fold in medium of stimulated endothelial cells when compared with non‐stimulated cells (P < 0.05). Conclusion: Acute endothelial cell activation in HELLP syndrome and decreased ADAMTS13 activity result in increased amounts of active VWF. This might explain the consumptive thrombocytopenia and thrombotic microangiopathy associated with HELLP syndrome. Inhibition of circulating active VWF could be a potential new approach in the treatment of patients with HELLP syndrome.