Background

Pre-eclampsia is the hypertensive complications induced by a pregnancy.

OUTLINE

Epidemiology
Disease Associations	KIR2DL4 receptor Obesity Umbilical cord diameter
Pathogenesis	Cerebral perfusion pressure Chromosomal abnormalities Infection Neutrophil oxygen radical production Placental syncytin expression Superoxide Dismutase (SOD) T-helper cells Uteroplacental vascular dysfunction Vascular dysfunction
Laboratory/Radiologic/Other Diagnostic Testing	Beta2 glycoprotein 1 Fetal red blood cells Homocysteine Thrombophilia
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Prognosis and Treatment
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Pregnancy induced hypertension
INCIDENCE
The prevalence of pre-eclampsia and obstetric outcome in pregnancies of normotensive and hypertensive women attending a hospital specialist clinic. Lydakis C, Beevers M, Beevers DG, Lip GY. University Department of Medicine, City Hospital, Birmingham.	Int J Clin Pract 2001 Jul-Aug;55(6):361-7 Abstract quote To study the prevalence of pre-eclampsia (PE) and other obstetric outcomes (growth restriction and fetal mortality) in pregnancies of normotensive and hypertensive women attending an antenatal hypertension clinic, we studied a cohort of 372 pregnancies from 267 women. The prevalence of PE in the groups of pregnancies of normotensive and chronic hypertensive women was 11.9% (19/159 cases) and 16.0% (34/213 cases) respectively (chi 2 = 1.2, p = 0.27). There were no significant differences in respect of ethnicity, being primi- or multigravida and smoking status or age. Treatment with antihypertensive drugs during pregnancy did not decrease the prevalence of PE. In pregnancies with hypertensive complications (with or without PE) there was a trend towards higher rates of pre-term delivery (< 37 weeks), caesarean section, small for gestational age babies, stillbirth and lower baby birth weight and ponderal index values. Pregnancies in women with uncomplicated hypertension had an increased risk for emergency caesarean section, pre-term delivery (< 37 weeks), birth weight < 2500 g and stillbirth (relative risks [with confidence intervals] 2.5 [1.9-3.2], 2.3 [1.8-2.9], 3.1 [2.5-3.7] and 5.5 [2.6-11.9] respectively) compared with the general hospital obstetric population. After classification according to the type of hypertensive syndrome, a progressively higher risk for fetal growth restriction and adverse perinatal outcome was shown in the hypertensive and pre-eclamptic groups. In chronic hypertension, this was irrespective of superimposed pre-eclampsia or antihypertensive therapy. The high prevalence of PE in chronic hypertensive women (16.0%) was not statistically significant to that of normotensive women (11.9%), reflecting the referral selection of 'high risk' normotensive women to our clinic.
High intake of energy, sucrose, and polyunsaturated fatty acids is associated with increased risk of preeclampsia. Clausen T, Slott M, Solvoll K, Drevon CA, Vollset SE, Henriksen T. Department of Obstetrics and Gynecology, Aker University Hospital, Oslo, Norway.	Am J Obstet Gynecol 2001 Aug;185(2):451-8 Abstract quote OBJECTIVE: Preeclampsia is associated with high body mass index, insulin resistance, and hypertriglyceridemia. Our objective was to investigate prospectively whether diet in the first half of pregnancy is associated with the risk for preeclampsia. STUDY DESIGN: This prospective, population-based, cohort study of pregnant women investigated dietary intake early in the second trimester with a quantitative food frequency questionnaire. RESULTS: The questionnaire was completed by 3133 women (83%). Preeclampsia developed in 85 women. Adjusted odds ratio (95% CI) for preeclampsia was 3.7 (1.5-8.9) for energy intake of >3350 kcal/d compared with < or =2000 kcal/d. Adjusted odds ratio (95% CI) for preeclampsia was 3.6 (1.3-9.8) for sucrose intake (percent of total energy) of >25% compared with < or =8.5% and 2.6 (1.3-5.4) for polyunsaturated fatty acids intake (percent of total energy) of >7.5% compared with < or =5.2%. Other energy-providing nutrients were not associated with the risk for preeclampsia. CONCLUSION: The current study suggests that high intakes of energy, sucrose, and polyunsaturated fatty acids independently increase the risk for preeclampsia.
Smoking, sex of the offspring, and risk of placental abruption, placenta previa, and preeclampsia: a population-based cohort study. Mortensen JT, Thulstrup AM, Larsen H, Moller M, Sorensen HT. Department of Clinical Epidemiology, Aarhus University and Aalborg Hospitals, Aalborg, Denmark.	Acta Obstet Gynecol Scand 2001 Oct;80(10):894-8 Abstract quote BACKGROUND.: Placental abruption, placenta previa, and preeclampsia are serious pregnancy complications with an increased risk of perinatal death. Smoking during pregnancy is associated with increased risk of abruption and placenta previa, and it reduces the risk of preeclampsia. We examined the association between mothers' smoking habits during pregnancy, taking the sex of the offspring into consideration, and the risk and prognosis of placental abruption, placenta previa, and preeclampsia METHODS.: We conducted the study in the County of North Jutland, Denmark. Using the 10-digit personal identification number given to every Danish citizen at birth, we linked data from the Danish Medical Birth Registry, including information on mother and child, to data from the Pharmaco-Epidemiological Prescription Database with data on all reimbursed prescriptions to use selected drugs as a proxy measure for some maternal diseases, and data from the Regional Hospital Discharge Registry, including the discharge diagnoses. Among 47,932 singleton births we included only births for which we had information about the mothers' smoking habits, leaving 46,313 births for analysis. RESULTS.: Smoking was associated with the risk of placental abruption (OR=1.99 (95% CI 1.72-2.30)) and placenta previa (OR=1.88 (95% CI 1.15-3.07)). Smoking was inversely associated with the risk of preeclampsia (OR=0.55 (95% CI 0.48-0.62)). After stratification for the sex of the offspring the risk estimate of smoking as risk factor for placenta previa decreased for male fetuses (OR=1.63 (95% CI 0.75-3.51)) and increased for female fetuses (OR=4.82 (95% CI 1.69-13.75)). CONCLUSION.: Female fetuses are more vulnerable than male to the negative effect of maternal smoking on placenta previa.
Sex ratio and twinning in women with hyperemesis or pre-eclampsia. Basso O, Olsen J. The Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine- Aarhus University, DK 8000 Aarhus C, DK.	Epidemiology 2001 Nov;12(6):747-9 Abstract quote We examined twinning and fetal gender in births of women with a hospital diagnosis of pre-eclampsia or hyperemesis. We also investigated sex ratio in infants whose mothers had had hyperemesis or pre-eclampsia in a different pregnancy. From all the hospitalized cases in Denmark between 1980 and 1996 we extracted 6,227 births with hyperemesis and 24,764 with pre-eclampsia. Twins were more frequent in pregnancies with either condition. The male to female sex ratio was 1.04 (95%CI = 1.02-1.05) in the reference population, 0.87 (95% CI = 0.82-0.91) in births with hyperemesis, and 1.10 (95% CI = 1.07-1.12) in births with pre-eclampsia. Women with pre-eclampsia had slightly more males also in non-affected pregnancies
Higher risk of pre-eclampsia after change of partner. An effect of longer interpregnancy intervals? Basso O, Christensen K, Olsen J. The Danish Epidemiology Science Centre at the Department of Epidemiology and Social Medicine, Aarhus University, Denmark.	Epidemiology 2001 Nov;12(6):624-9 Abstract quote Epidemiologic studies have shown that pre-eclampsia is mainly a disease of first pregnancy, possibly associated with primipaternity. The interpregnancy interval, which is strongly associated with change of partner, has received little attention. In this study, based on Danish hospital records, we evaluated whether the interpregnancy interval may confound or modify the paternal effect on pre-eclampsia. We studied the outcome of the second birth in a cohort of Danish women with pre-eclampsia in the previous birth (8,401 women) and in all women with pre-eclampsia in second (but not first) birth together with a sample of women with two births (26,596 women). A long interpregnancy interval was associated with a higher risk of pre-eclampsia in women with no previous pre-eclampsia when the father was the same. We estimated the risk of pre-eclampsia in second birth according to paternal change in different models. Although partner change was associated with an increased risk of pre-eclampsia in women with no history of pre-eclampsia, this effect disappeared after adjustment for the interpregnancy interval. We saw, however, different results when we stratified on the length of the interval. Our results indicate that the interval between births should be taken into consideration when studying the effect of changing partner on pre-eclampsia.
Seasonal variation in the occurrence of pre-eclampsia. Magnu P, Eskild A. Section of Epidemiology, National Institute of Public Health, Oslo, Norway.	BJOG 2001 Nov;108(11):1116-9 Abstract quote OBJECTIVE: To obtain evidence for seasonal variability in pre-eclampsia using the assumption that environmental factors may have a role in the causal mechanisms. DESIGN: Cross sectional population-based study. POPULATION: All 1,869,388 deliveries in Norway in the years 1967 to 1998. METHOD: For each month, the percentage of births complicated by pre-eclampsia was calculated. The relative risks of pre-eclampsia by month of delivery were estimated as odds ratios using the month with lowest risk as the reference category. RESULTS: Mothers of children born in August had the lowest risk of pre-eclampsia, and the risk was highest in the winter months (for December adjusted OR: 1.26, 95% CI 1.20-1.31). This pattern was independent of parity. maternal age, year and place of living. CONCLUSION: The finding may provide a new clue for understanding the causes of pre-eclampsia. Environmental factors that show a similar seasonal variation should be investigated as possible causes.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
KIR2DL4 RECEPTOR
Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia. Witt CS, Whiteway JM, Warren HS, Barden A, Rogers M, Martin A, Beilin L, Christiansen FT. Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Western Australia.	Eur J Immunol 2002 Jan;32(1):18-29 Related Articles, Books, LinkOut Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia. Witt CS, Whiteway JM, Warren HS, Barden A, Rogers M, Martin A, Beilin L, Christiansen FT. Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Perth, Western Australia. A survey of KIR2DL4 polymorphism revealed seven common sequences in the Australian population. The seven sequences encode three different amino acid sequences of the immunoglobulin domains. Two of the sequences encoding different amino acid sequences in the immunoglobulin domains also occur on some chromosomes with a single nucleotide deletion at the end of exon 6, which encodes the transmembrane domain (DeltaTM mutation), resulting in exon 6 skipping during mRNA production. Due to alternate splicing, a fraction of the mRNA produced by these alleles includes the transmembrane region but is missing the cytoplasmic region. The remaining two sequences differed only by synonymous substitutions. All of the exonic polymorphisms of KIR2DL4 could be detected by single-stranded conformational polymorphism of individually amplified exons. The DeltaTM mutation is in linkage disequilibrium with the killer cell immunoglobulin-like receptor (KIR) A haplotype, and the wild-type sequence is in linkage disequilibrium with the B haplotype. The frequencies of alleles with the DeltaTM mutation or Ig-domain polymorphisms did not differ between women who experienced pre-eclampsia and normotensive controls. Similarly there was no difference in the KIR gene repertoire in pre-eclampsia and normotensive controls.
OBESITY
Obesity and preeclampsia: the potential role of inflammation. Wolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R. Renal Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.	Obstet Gynecol 2001 Nov;98(5 Pt 1):757-62 Abstract quote OBJECTIVE: Systemic inflammation might contribute to the pathogenesis of preeclampsia. In addition, the association between obesity and inflammation in preeclampsia has not been examined in detail. We determined whether first-trimester elevation of serum C-reactive protein, an index of systemic inflammation, was associated with preeclampsia. METHODS: We conducted a prospective, nested case-control study among women enrolled in the Massachusetts General Hospital Obstetrical Maternal Study cohort. High-resolution C-reactive protein assays were performed on first-trimester (11 +/- 2 weeks' gestation) serum samples in 40 women in whom preeclampsia developed (blood pressure [BP] greater than 140/90 mmHg, and proteinuria, either 2+ or more by dipstick or greater than 300 mg per 24 hours), and in 80 matched controls. This sample size had greater than 80% power to detect a difference in C-reactive protein levels between cases and controls. We used nonparametric tests to compare C-reactive protein levels and conditional logistic regression to control for confounding variables. RESULTS: First-trimester C-reactive protein levels were significantly higher among women in whom preeclampsia subsequently developed compared with controls (4.6 compared with 2.3 mg/L, P =.04). When women were subdivided into C-reactive protein quartiles, the odds ratio (OR) of being in the highest quartile of C-reactive protein was 3.2 (95% confidence interval [CI] 1.1, 9.3, P =.02) among cases of preeclampsia compared with controls. When body mass index (BMI) was added to the multivariable model, the highest quartile of C-reactive protein was no longer associated with increased risk of preeclampsia (OR 1.1, 95% CI.3, 4.3, P =.94). In the same model without BMI, the highest quartile of C-reactive protein was associated with increased risk of preeclampsia (OR 3.5, 95% CI 1.3, 9.5, P =.01). CONCLUSION: In women with preeclampsia, there was evidence of increased systemic inflammation in the first trimester. Inflammation might be part of a causal pathway through which obesity predisposes to preeclampsia.
UMBILICAL CORD DIAMETER
First-trimester sonographic umbilical cord diameter and the growth of the human embryo. Ghezzi F, Raio L, Di Naro E, Franchi M, Bruhwiler H, D'Addario V, Schneider H. Department of Obstetrics and Gynecology, University of Insubria, Varese, Italy.	Ultrasound Obstet Gynecol 2001 Oct;18(4):348-51 Abstract quote OBJECTIVES: Experimental and clinical evidence have shown that the morphometry of the umbilical cord in the second half of gestation might be useful in predicting adverse perinatal outcome. The purposes of this study were to generate a nomogram for the umbilical cord diameter in the first trimester and, in an observational study, to investigate whether the sonographic measurement of the umbilical cord diameter early in gestation has the same clinical value as that late in gestation. METHODS: The sonographic umbilical cord diameter, crown-rump length and biparietal diameter were measured in 439 fetuses at between 8 and 15 weeks of gestation. The perinatal outcome was recorded for all patients. RESULTS: The umbilical cord diameter increased steadily from 8 to 15 weeks of gestation. A significant correlation was found between umbilical cord diameter and gestational age (r = 0.78; P < 0.001), umbilical cord diameter and crown-rump length (r = 0.75; P < 0.001) and umbilical cord diameter and biparietal diameter (r = 0.81; P < 0.001). No correlation was found between umbilical cord diameter values and either birth weight or placental weight. Among patients who had a miscarriage (n = 7) and pre-eclampsia (n = 8) the umbilical cord diameter was below 2 standard deviations from the mean in three cases (42.9%) and three cases (37.5%), respectively. CONCLUSION: The measurement of the umbilical cord diameter in the first trimester is correlated with the growth of the embryo and may be a marker for identifying a subset of fetuses at risk of spontaneous miscarriage and pre-eclampsia.

 

PATHOGENESIS	CHARACTERIZATION
GENERAL
Recent Insights into the pathogenesis of pre-eclampsia. Roberts JM, Lain KY. Magee-Womens Research Institute and Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213-3180, USA.	Placenta 2002 May;23(5):359-72 Abstract quote Pre-eclampsia is more than pregnancy induced hypertension. The emerging view described in this presentation is that pre-eclampsia is secondary to the interactions of reduced placental perfusion with diverse maternal factors that alter endothelial function. The maternal contribution is from factors that antedate pregnancy and are influenced by the usual metabolic adaptations of pregnancy. The endothelium and other targets for the effects of these interactions are more sensitive to insults during pregnancy because of activation of the inflammatory cascade as a normal part of pregnancy. At least part of the response to reduced placental perfusion may be a fetal adaptive response to attempt to overcome the reduced delivery of nutrients. A reasonable convergence point for the interaction is at the level of oxidative stress. This hypothesis has both encouraging and discouraging corollaries. The diversity of maternal factors argues that there will be no single gene to explain the disorder and no single 'magic bullet' to treat the disorder. However, it is encouraging that the recognition of maternal predisposition to the disorder directs therapy to prevent pre-eclampsia at a specific target in subsets of women. Finally, the suggestion that some of the maternal alterations are due to fetal adaptive responses encourages careful choices of agents and meticulous infant follow up in well planned clinical trials.
CEREBRAL PERFUSION PRESSURE
Pregnant women with chronic hypertension and superimposed pre-eclampsia have high cerebral perfusion pressure. Belfort MA, Tooke-Miller C, Allen JC Jr, Varner MA, Grunewald C, Nisell H, Herd JA. Department of Obstetrics and Gynaecology, University of Utah School of Medicine, Salt Lake City, USA.	BJOG 2001 Nov;108(11):1141-7 Abstract quote OBJECTIVE: To determine any differences in cerebral perfusion pressure in patients with chronic hypertension compared with those with chronic hypertension and superimposed pre-eclampsia. DESIGN: A prospective observational study. SETTING: University hospital clinic and labour and delivery suite. PARTICIPANTS: Fifteen women with chronic hypertension and 15 with superimposed pre-eclampsia. METHODS: Transcranial Doppler ultrasound was used to measure blood velocity in the middle cerebral arteries of the patients. Systemic blood pressure in the brachial artery was measured simultaneously. Middle cerebral artery. resistance index, pulsatility index, and cerebral perfusion pressure were calculated and plotted on the same axes as data from normal pregnant women. Cerebral perfusion pressure values outside of the 5th and 95th centiles were regarded as abnormal. Cerebral perfusion pressure data from the chronic hypertension and superimposed pre-eclampsia groups were also expressed in terms of the number of normative standard deviations from the mean value for normal pregnancy (Multiples of the Standard Deviation: MOS). All studies were conducted before labour, under similar conditions, and before volume expansion or treatment. Statistical analysis was by Student's t test and Fisher's exact test as appropriate with significance set at a two-tailed P<0.05. RESULTS: Patient demographics and blood pressure were not significantly different between the two groups. The resistance index and pulsatility index were not significantly different (neither absolute nor multiples of the standard deviation values). The absolute cerebral perfusion pressure was significantly higher in the patients with superimposed pre-eclampsia. The group of women with superimposed pre-eclampsia had a significantly higher mean value of cerebral perfusion pressure measured as multiples of the standard deviation from the mean value for normal pregnancy, despite there being no blood pressure difference. CONCLUSIONS: Superimposed pre-eclampsia is associated with significantly higher cerebral perfusion pressure measurements compared with women with uncomplicated chronic hypertension. This is not directly related to a higher blood pressure. The difference in cerebral perfusion pressure may be used to speculate upon the pathophysiology of the increased risk for eclampsia seen in patients with superimposed pre-eclampsia.
CHROMOSOMAL ABNORMALITIES
A genome-wide scan for preeclampsia in the Netherlands. Lachmeijer AM, Arngrimsson R, Bastiaans EJ, Frigge ML, Pals G, Sigurdardottir S, Stefansson H, Palsson B, Nicolae D, Kong A, Aarnoudse JG, Gulcher JR, Dekker GA, ten Kate LP, Stefansson K. Department of Clinical Genetics and Human Genetics, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands, and Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands.	Eur J Hum Genet 2001 Oct;9(10):758-64 Abstract quote Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.
INFECTION
Is preeclampsia an infectious disease? Trogstad LI, Eskild A, Bruu AL, Jeansson S, Jenum PA. Department of Population Health, National Institute of Public Health, P.O. Box 4404 Nydalen, 0403 Oslo, Norway.	Acta Obstet Gynecol Scand 2001 Nov;80(11):1036-8 Abstract quote BACKGROUND: Studies have suggested a strong paternal factor in the etiology of preeclampsia. If preeclampsia is caused by an infectious agent transmitted by the woman's partner, seronegative women who may experience primary infection in pregnancy should be at increased risk of preeclampsia as compared to previously infected women. The aim of this study was to assess the impact of being seronegative for some viruses transmitted by close contact on the risk of developing preeclampsia. METHODS: Nine hundred and seventy-eight women were randomly drawn from a basic study population of 35,940 pregnant women in Norway. A serum sample drawn at the first antenatal visit was analyzed for specific IgG antibodies against herpes simplex virus type-2, cytomegalovirus and Epstein-Barr virus. For comparison, antibody status against Toxoplasma gondii was also assessed. Information on preeclampsia in pregnancy was obtained through linkage to the Medical Birth Registry of Norway. RESULTS: Thirty-three (3%) women developed preeclampsia. The risk of developing preeclampsia seemed to be increased for women who were seronegative for the viruses studied. Seronegativity for Toxoplasma gondii did not show such a pattern. INTERPRETATION: Women who are seronegative for antibodies against viral agents transmitted through close contact seem more likely to develop preeclampsia. This finding indicates that women who are seronegative to such agents may acquire primary infection in pregnancy, and subsequently be at increased risk of preeclampsia. This hypothesis could represent a new approach to the causes of preeclampsia, and encourage search for yet unidentified microbes as a possible causal factor.
NEUTROPHIL OXYGEN RADICAL PRODUCTION
Neutrophil oxygen radical production in pre-eclampsia with HELLP syndrome. Zusterzeel PL, Wanten GJ, Peters WH, Merkus HM, Steegers EA. Departments of Obstetrics and Gynaecology, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands	Eur J Obstet Gynecol Reprod Biol 2001 Dec 1;99(2):213-8 Abstract quote Objective: To determine whether severe pre-eclampsia complicated by hemolysis, elevated liver enzymes, low platelets (HELLP) -syndrome alters neutrophil oxygen radical production. Materials and Methods: Neutrophils were obtained from 10 healthy non-pregnant, 9 normal pregnant and 9 women with severe pre-eclampsia with concurrently HELLP syndrome. Oxygen radical production was evaluated using luminol-enhanced chemiluminescence and measured by cytochrome C reduction. Furthermore we incubated sera from cases and controls with isolated healthy neutrophils and measured their capacity to generate oxygen radicals. Results: Unstimulated neutrophil oxygen radical production was significantly lower in severe pre-eclamptics compared with healthy non-pregnant and pregnant subjects, whereas phorbol ester-induced oxygen radical production did not differ among categories. Cytochrome C reduction of unstimulated neutrophils showed similar results. Healthy neutrophils incubated with sera from pre-eclamptics enhanced the oxygen radical production significantly more than neutrophils incubated with sera from the healthy subjects. Conclusions: Severe pre-eclampsia is characterised by decreased unstimulated neutrophil oxygen radical production. This may be the result of an exhausted cellular response due to stimulation by a factor present in the serum of these patients.
PLACENTAL SYNCYTIN EXPRESSION
Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia. Lee X, Keith JC Jr, Stumm N, Moutsatsos I, McCoy JM, Crum CP, Genest D, Chin D, Ehrenfels C, Pijnenborg R, van Assche FA, Mi S. Wyeth/Genetics Institute, One Burtt Road, Andover, MA 01810, USA.	Placenta 2001 Nov;22(10):808-12 Abstract quote Development of placentation and successful pregnancy depend on co-ordinated interactions between the maternal decidua and myometrium, and the invasive properties of the fetal trophoblast. Syncytin, a protein encoded by the envelope gene of a recently identified human endogenous defective retrovirus, HERV-W, is highly expressed in placental tissue. Previously, we have shown that the major site of syncytin expression is the placental syncytiotrophoblast, a fused multinuclear syncytium originating from cytotrophoblast cells. Here we present the first evidence that in pre-eclampsia, syncytin gene expression levels are dramatically reduced. Additionally, immunohistochemical examination of normal placentae and placentae from women with pre-eclampsia reveals that the syncytin protein in placental tissue from women with pre-eclampsia is localized improperly to the apical syncytiotrophoblast microvillous membrane as opposed to its normal location on the basal syncytiotrophoblast cytoplasmic membrane. Our previous results suggest that syncytin may mediate placental cytotrophoblast fusion in vivo and may play an important role in human placental morphogenesis. The present study suggests that altered expression of the syncytin gene, and altered cellular location of its protein product, may contribute to the aetiology of pre-eclampsia.
SUPEROXIDE DISMUTASE (SOD)
Placental morphogenesis in pregnancies with Down's syndrome might provide a clue to pre-eclampsia. Banerjee S, Smallwood A, Nargund G, Campbell S. Department of Obstetrics and Gynaecology, St George's Hospital Medical School, Cranmer Terrace, London, SW17 0RE, UK.	Placenta 2002 Feb-Mar;23(2-3):172-4 Abstract quote Insufficient perfusion of placenta in pre-eclampsia is commonly associated with oxidative stress leading to increased superoxide formation and reduced invasion of uterine spiral arteries by differentiated migratory cytotrophoblasts. The superoxide dismutase (SOD) level, responsible for eliminating toxic superoxides, drops significantly in pre-eclampsia. On the contrary, the SOD synthesis increases dramatically, compared to that of normal placenta, in pregnancies with trisomy 21 (T21) fetus. However, despite a low level of placental hypoplasia, the overall perfusion of T21 placentae is comparable to that of normal pregnancy. In the light of recent reports on alternative modes of SOD function and factors regulating pathways of cytotrophoblast differentiation, here we have attempted to reconcile the two seemingly disparate pregnancy conditions and suggest that trisomy 21 pregnancies might provide new insight into our understanding of placental morphogenesis in pre-eclampsia.
T HELPER CELLS
Relation between plasma endothelin 1 levels and T helper 1: T helper 2 cell immunity in women with preeclampsia. Kuwajima T, Suzuki S, Yoneyama Y, Sawa R, Asakura H, Araki T. Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.	Gynecol Obstet Invest 2001;52(4):260-3 Abstract quote The aim of this study was to investigate the relationship between plasma endothelin 1 (ET-1) levels and T helper (Th)-1:Th2 cell immunity in women with preeclampsia. The percentage of Th1 and Th2 cells and the Th1:Th2 cell ratios in peripheral blood from 11 normal pregnant women and 11 patients with preeclampsia at 29-34 weeks of gestation were calculated using flow cytometry. The plasma ET-1 level was also determined using a modified radioimmunoassay. The plasma ET-1 concentrations and the Th1:Th2 cell ratios in normal pregnancies were significantly lower than those in patients with preeclampsia. Negative correlations were found between plasma ET-1 levels and Th2 cells in both the preeclamptic pregnancy groups and in the normal pregnant women. Our results indicate that elevated ET-1 levels are associated with a Th1:Th2 imbalance in preeclampsia.
UTEROPLACENTAL VASCULAR INSUFFICIENCY
Uteroplacental circulation development: Doppler assessment and clinical importance. Carbillon L, Challier JC, Alouini S, Uzan M, Uzan S. Department of Obstetrics and Gynecology, Assistance Publique, Hopitaux de Paris, Jean Verdier Hospital, 93143 BONDY, France.	Placenta 2001 Nov;22(10):795-9 Abstract quote In the first weeks of pregnancy, columns of endovascular cytotrophoblastic plugs develop in the lumen of spiral arteries. Morphologic data show that these plugs become loosened as soon as the end of the second month and the intervillous circulation of maternal blood is likely to be established progressively between the 8th and 12th weeks. The disorganization of the musculo-elastic layers of these vessels provokes a dramatic decrease in vascular tone in the uteroplacental circulation. These modifications appear to govern the establishment of a low-pressure blood flow in the placenta, and hence determine the quality of uteroplacental circulation and normal fetal growth. Placental bed biopsies in women with pre-eclampsia and in a proportion of pregnancies with intrauterine growth retardation have shown that these physiologic changes were absent in the myometrial segments of spiral arteries. Recently, colour Doppler was used to assess intervillous and spiral artery flow in early pregnancy, confirming in vivo free intervillous flow at 12 weeks and a progressive significant decrease in spiral artery resistance with advancing gestation during the first trimester. However, certain data at an earlier gestational age are still contradictory. Particularly, the exact nature of the contents of the intervillous space before 8 weeks, and whether or not this fluid can be considered maternal blood, remains controversial.
VASCULAR DYSFUNCTION
Cerebrovascular reactivity in normal pregnancy and preeclampsia. Riskin-Mashiah S, Belfort MA, Saade GR, Herd JA. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.	Obstet Gynecol 2001 Nov;98(5 Pt 1):827-32 Abstract quote OBJECTIVE: To compare cerebrovascular reactivity in normotensive and preeclamptic pregnant women. METHODS: Transcranial Doppler ultrasound was used to measure peak, end-diastolic, and mean velocities in the middle cerebral arteries of 45 normotensive and 36 preeclamptic women in the third trimester. All measurements were done in the left lateral position at baseline, during 5% carbon dioxide (CO2) inhalation, and during an isometric hand-grip test. Blood pressure (BP), heart rate, oxygen (O2) saturation, and end-tidal partial pressure of carbon dioxide (pCO2) were recorded with each Doppler measurement. The mean pulsatility index (PI), resistance index (RI), and cerebral perfusion pressure at each time was compared using two-way repeated measures analysis of variance. Cerebrovascular reactivity, calculated as the percentage change in response to each maneuver, was also compared using analysis of covariance. A post hoc power analysis was performed to evaluate the primary measures of the study (middle cerebral artery PI and RI). Using alpha error of 5%, the statistical power to identify a difference in PI and RI in women with preeclampsia compared with normotensive women was 90% and 67%, respectively. The statistical power to identify a difference in PI and RI in response to the two maneuvers was 69% and 53%, respectively. Statistical significance was set at P <.05. RESULTS: Preeclamptic women had higher baseline cerebral perfusion pressure (90.4 compared with 61.9 mmHg, P <.05) and lower PI (0.64 compared with 0.76, P <.05) and RI (0.46 compared with 0.51, P <.05) than normotensive pregnant women. In normotensive patients, both 5% CO2 inhalation and isometric hand-grip test caused a significant decrease in PI (-9.5% and -6.1%, respectively) and RI (-6.5% and -4.2%, respectively). In contrast, in preeclamptic patients there was no change in any of the middle cerebral artery parameters in response to either maneuver. CONCLUSION: Normotensive pregnant women had normal middle cerebral artery responses to both 5% CO2 inhalation and isometric hand-grip test. Preeclamptic patients had elevated baseline cerebral perfusion pressure and reduced vasodilatory responses to both tests. These findings are consistent with a state of vasoconstriction in preeclamptic women that is unresponsive to stimuli that under normal circumstances result in vasodilation.
The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia. Carr DB, McDonald GB, Brateng D, Desai M, Thach CT, Easterling TR. Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, Washington 98195-6460, USA.	Obstet Gynecol 2001 Dec;98(6):1109-16 Abstract quote OBJECTIVE: This study evaluated: 1) whether women with risk factors for preeclampsia had a hyperdynamic circulation and increased markers of endothelial and inflammatory activation; and 2) whether hemodynamically directed therapy was associated with a change in markers. METHODS: A controlled experimental study was performed for two groups: 1) women at risk for preeclampsia (high risk); and 2) women at low risk (controls). Tumor necrosis factor-alpha (TNF-alpha), TNF-alpha receptors 1 and 2, vascular cell adhesion molecule-1, cellular fibronectin, and cardiac output were measured at or before 24 weeks' gestation and at 6-8 week intervals. High-risk subjects with cardiac output greater than 7.4 L/minute were treated with atenolol. Atenolol therapy was not randomized. Therefore, the longitudinal data were descriptive. Data were analyzed by the t test, Wilcoxon rank sum test, chi(2) test, multivariable linear regression, and the standard two-stage test. RESULTS: There were 46 high-risk subjects and 25 controls. Maternal age, gestational age, and parity did not differ between the groups. Cardiac output (P <.001) and vascular cell adhesion molecule-1 (P =.02) at baseline were significantly increased in the high-risk group. A total of 42 women in the high-risk group received atenolol for high cardiac output. There was a slower rise in TNF-alpha receptor 1 in the treated group compared with the controls (P <.001). CONCLUSION :Women with risk factors for preeclampsia had a hyperdynamic circulation and endothelial activation. Hemodynamically directed therapy in women at risk was associated with a slower rise in TNF-alpha receptor 1 compared with low-risk women who were not treated, suggesting a relationship between hemodynamics and inflammatory activation.
Impaired vascular function in women with pre-eclampsia observed with orthogonal polarisation spectral imaging. Vollebregt KC, Boer K, Mathura KR, de Graaff JC, Ubbink DT, Ince C. Department of Obstetrics and Gynaecology, Academic Medical Centre, Amsterdam, The Netherlands.	BJOG 2001 Nov;108(11):1148-53 Abstract quote OBJECTIVE: To investigate in vivo the function of the microcirculation of the skin in pregnancy and pregnancy complicated with pre-eclampsia. DESIGN: Case-control study. SETTING: Academic Medical Centre. PARTICIPANTS: A group of 10 women with pre-eclampsia and a healthy control group of 10 pregnant women. METHODS: The microcirculation of the skin of the finger at rest and during venous occlusion was studied with laser Doppler fluxmetry and orthogonal polarisation spectral imaging. By inflating a cuff around the upper arm to a pressure of 50 mmHg, causing venous occlusion, the local sympathetic veno-arteriolar reflex was provoked. With laser Doppler fluxmetry the blood flow of the skin at a depth of 1-2mm was measured at rest and during venous occlusion. Orthogonal polarisation spectral imaging was used to assess red blood cell velocity at rest and during venous occlusion of the nutritive capillaries of the skin. RESULTS: Laser Doppler fluxmetry showed no significant difference between the normotensive group and the group with pre-eclampsia. Using orthogonal polarisation spectral imaging, venous occlusion produced a significantly greater decrease in red blood cell velocity in the control group than in the women with pre-eclampsia: (84% (81-88)(median and interquartile range) vs 58% (45-88), P = 0.0029). No differences in absolute red blood cell velocities were observed between groups either at rest or during venous occlusion. CONCLUSION: This study shows an impaired local veno-arteriolar reflex in pre-eclampsia at the nutritive, but not at the therrmoregulatory, level of the microcirculation of the skin.
Differential mechanisms of endothelium-dependent vasodilator responses in human myometrial small arteries in normal pregnancy and pre-eclampsia. Kenny LC, Baker PN, Kendall DA, Randall MD, Dunn WR. School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2RW, UK.	Clin Sci (Lond) 2002 Jul;103(1):67-73 Abstract quote Pre-eclampsia is a pregnancy-specific disorder associated with hypertension and proteinuria, characterized by alterations in endothelial cell function. In the present study we have compared responses to the endothelium-dependent vasodilator, bradykinin, in small myometrial arteries from normal pregnant and non-pregnant women and women with pre-eclampsia, in order to assess the relative contributions of nitric oxide, endothelium-derived hyperpolarizing factor (EDHF) and prostanoids in mediating endothelium-dependent vasodilatation. Bradykinin-induced concentration-dependent relaxation in arteries isolated from the three subject groups did not differ with regard to sensitivity or maximum response. Responses to bradykinin in all three groups were unaffected by cyclo-oxygenase inhibition alone, and were similarly unaffected by partial depolarization. The nitric oxide synthase (NOS) inhibitor, N-nitro-l-arginine methyl ester, significantly attenuated the responses to bradykinin in arteries from non-pregnant women and almost abolished responses in arteries from women with pre-eclampsia. However, in arteries from normal pregnant women, bradykinin-induced responses were maintained in the presence of NOS inhibition. Inhibition of NOS combined with partial depolarization abolished responses to bradykinin in these vessels. These results support the suggestion that, in the absence of NO, an EDHF can mediate vasodilator responses to bradykinin during normal pregnancy, an effect not apparent in arteries from non-pregnant women or women with pre-eclampsia. The up-regulation of EDHF-type function may represent a vascular adaptation to normal pregnancy that is absent in pre-eclampsia, and this might contribute to the clinical features of the disease.

 

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Serial assessment in eclampsia of cerebrohemodynamics by combined transcranial Doppler and magnetic resonance angiography. Ikeda T, Urabe H, Matsukage S, Sameshima H, Ikenoue T. Department of Obstetrics and Gynecology, Miyazaki Medical College, Miyazaki, Japan.	Gynecol Obstet Invest 2002;53(1):65-7 Abstract quote We used two different noninvasive methods, i.e., transcranial Doppler velocimetry and magnetic resonance angiography to serially assess cerebrohemodynamics in a patient with postpartum eclampsia. Five hours after an eclamptic seizure, a decrease in mean velocity in both middle cerebral arteries and slight angiographical spasms indicated cerebral hypoperfusion. On hospital day 8, the patient showed an increase in the mean velocity of the middle cerebral artery, accompanied by significant vasospasms. Abnormal findings were not observed on hospital day 20. These combined methods are useful in assessing cerebrohemodynamics in eclampsia.
LABORATORY MARKERS
BETA-2 GLYCOPROTEIN 1
Beta 2-glycoprotein I is a good indicator of certain adverse pregnancy conditions. Ulcova-Gallova Z, Bouse V, Krizanovska K, Balvin M, Rokyta Z, Netrvalova L. Department of Obstetrics and Gynecology, Charles University, Pilsen, Czech Republic.	Int J Fertil Womens Med 2001 Nov-Dec;46(6):304-8 Abstract quote OBJECTIVE: To compare levels of beta2-glycoprotein I antibodies with six different antiphospholipid antibodies (aPL) in sera from patients with certain adverse pregnancy conditions. PATIENTS AND METHODS: aPL levels were examined in pregnant women with anti-phospholipid syndrome (26), pre-eclampsia (32), autoimmune disease (12), or diabetes mellitus (23) and in a group with physiological pregnancy (38). A commercial ELISA was used to determine the serum levels of anti-beta2-GPI (Immunotech) in isotypes IgG and IgA, and anti-cardiolipin levels (Milenia) in IgG and IgM. aPL screening also included L-alpha-phosphatidic acid, L-alpha-phosphatidylethanolamine, L-alpha-phosphatidyl-DL-glycerol, L-alpha-phosphatidylinositol, and L-alpha-phosphatidyl-serine (Sigma, U.S.A.) in IgG and IgM. Statistical analysis of all aPL levels was made by cut-off levels for Ig isotypes by using 3 SD or 95th percentile calculated using STATGRAPHICS. RESULTS: Positive levels of antibodies against beta2-GPI in IgA are more frequently associated with a diagnosis of anti-phospholipid syndrome, pre-eclampsia, and autoimmune disease in pregnant women than with diabetes mellitus in pregnancy. Very high interindividual differences in aPLs (against inositol, L-serine, cardiolipin, and beta2-glycoprotein in IgG and IgA) were found in serum from women with pregnancy complicated by anti-phospholipid syndrome, pre-eclampsia, and autoimmune disease. Pregnant patients with diabetes mellitus had higher serum levels in aPLs to DL-glycerol, inositol, L-serine, and beta2-glycoprotein. Positive aPL levels predominate in isotype IgG. Very low levels of aPLs to phosphatidic acid and phosphatidyl-ethanolamine were detected in all groups studied. CONCLUSION: Serum levels of anti-beta2-GPI could serve as a better prognostic marker in complicated pregnancy than the panel of seven different anti-phospholipid antibodies. Detection of anti-beta2-GPI is proposed as a first step of the screening for aPLs.
FETAL RED BLOOD CELLS
Significantly higher number of fetal cells in the maternal circulation of women with pre-eclampsia. Jansen MW, Korver-Hakkennes K, van Leenen D, Visser W, in 't Veld PA, de Groot CJ, Wladimiroff JW. Department of Obstetrics and Gynecology, Erasmus University and University Hospital Dijkzigt, Rotterdam, The Netherlands.	Prenat Diagn 2001 Dec;21(12):1022-6 Abstract quote Although the pathophysiology of pre-eclampsia is unknown, several studies have indicated that abnormal placentation early in pregnancy might play a key role. It has recently been suggested that this abnormal placentation may result in transfusion of fetal cells (feto-maternal transfusion) in women with pre-eclampsia. In the present study, fetal nucleated red blood cells were isolated from 20 women with pre-eclampsia and 20 controls using a very efficient magnetic activated cell sorting (MACS) protocol. The number of male cells was determined using two-color fluorescence in situ hybridization (FISH) for X and Y chromosomes. Significantly more XY cells could be detected in women with pre-eclampsia (0.61+/-1.2 XY cells/ml blood) compared to women with uncomplicated pregnancies (0.02+/-0.04 XY cells/ml blood) (Mann-Whitney U-test, p<0.001). These results suggest that fetal cell trafficking is enhanced in women with pre-eclampsia, and this finding may contribute to the understanding of the pathophysiology of the disease.
HOMOCYSTEINE
Elevated plasma homocysteine in early pregnancy: a risk factor for the development of severe preeclampsia. Cotter AM, Molloy AM, Scott JM, Daly SF. Department of Biochemistry, Trinity College, Dublin, and Coombe Women's Hospital, Ireland.	Am J Obstet Gynecol 2001 Oct;185(4):781-5 Abstract quote OBJECTIVE: The aim of our study was to determine if an elevated plasma homocysteine level in early pregnancy is associated with the development of severe preeclampsia. STUDY DESIGN: Blood samples were obtained from patients attending their first antenatal visit. Cases were asymptomatic women who subsequently developed severe preeclampsia. Controls were matched for gestational age and date of sample collection. Plasma homocysteine level was measured by using fluorescence polarization immunoassay. RESULTS: There were 56 patients with severe preeclampsia from whom blood samples were obtained at a mean (+/-SD) gestation of 15.3 weeks (+/-4.04 weeks) and 112 controls at 14.9 weeks (+/-3.41 weeks). The preeclampsia cases had a mean (+/-SD) homocysteine level of 9.8 micromol/L (+/-3.3 micromol/L), whereas controls had a mean homocysteine level of 8.4 micromol/L (+/-1.9 micromol/L), P < or = .0001. CONCLUSION: Women who develop severe preeclampsia have higher plasma homocysteine levels in early pregnancy than women who remain normotensive throughout pregnancy. An elevated plasma homocysteine level in early pregnancy can increase the risk of developing severe preeclampsia by almost threefold.
IGF-1
IGF-I, osteocalcin, and bone change in pregnant normotensive and pre-eclamptic women. Sowers M, Scholl T, Grewal J, Chen X, Jannausch M. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan 48109-2029, USA.	J Clin Endocrinol Metab 2001 Dec;86(12):5898-903 Abstract quote Pre-eclampsia is a pregnancy disorder of uncertain etiology that affects 5-10% of all pregnancies, with symptoms typically presenting around or after 20 wk gestation. We hypothesized that IGF-I, osteocalcin, and bone loss would be different among women with pre-eclampsia compared with normotensive pregnant women. There were 962 pregnant healthy women, aged 12-35, who were assessed at entry to care, at 28 wk, and at delivery for osteocalcin and IGF-I concentrations. Bone ultrasound was measured at entry to care and at 6 wk postpartum, whereas bone mineral density was measured by dual x-ray densitometry at delivery. There were 64 women (6.7%) among the women being followed who developed pre-eclampsia. In women with pre-eclampsia, IGF-I concentrations were 74% greater in the third trimester compared with the first trimester, whereas there was little change in osteocalcin concentrations. In contrast, normotensive women had an average increase of 43% in IGF-I concentrations accompanied by a 63% decline in osteocalcin concentrations. In women with pre-eclampsia, IGF-I and osteocalcin concentrations were significantly correlated (r = 0.48 and 0.43) at both the first and third trimester time points, but only in the third trimester among normotensive women (r = 0.27). The bone change difference between the two groups was not statistically significant. Women with pre-eclampsia appear to have an exaggerated IGF-I responsiveness compared with women who are normotensive; however, the strong correlation between IGF-I and osteocalcin in women with pre-eclampsia suggests that the IGF-I is able to retain its role as a local regulator of bone remodeling, as indicated by the osteocalcin concentrations
THROMBOPHILIA
How strong is the association between maternal thrombophilia and adverse pregnancy outcome?. A systematic review. Alfirevic Z, Roberts D, Martlew V. Liverpool Women's Hospital, Crown Street, L8 7SS, Liverpool, UK	Eur J Obstet Gynecol Reprod Biol 2002 Feb 10;101(1):6-14 Abstract quote Objective: To determine whether inherited and acquired thrombophilias are associated with adverse obstetric complications. Study Design: A systematic review; studies where women with adverse obstetric complications were tested for one or more acquired and inherited thrombophilias were included. Main Outcome Measures: Prevalence of thrombophilia in women with severe pre-eclampsia/eclampsia, severe placental abruption, intrauterine growth restriction or unexplained stillbirth. Results: Compared with controls, placental abruption was more often associated with homozygous and heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homocysteinaemia, activated protein C resistance or anticardiolipin IgG antibodies. Women with pre-eclampsia/eclampsia were more likely to have heterozygous factor V Leiden mutation, heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T mutation, protein C deficiency, protein S deficiency or activated protein C resistance compared with controls. Unexplained stillbirth, when compared with controls, was more often associated with heterozygous factor V Leiden mutation, protein S deficiency, activated protein C resistance, anticardiolipin IgG antibodies or lupus anticoagulant. Women with intrauterine growth restriction had a higher prevalence of heterozygous G20210A prothrombin gene mutation, homozygous MTHFR C677T gene mutation, protein S deficiency or anticardiolipin IgG antibodies than controls. There was wide heterogeneity in the prevalence of thrombophilia between the studies. Conclusions: Women with adverse pregnancy outcome are more likely to have a positive thrombophilia screen but studies published so far are too small to adequately assess the true size of this association. Screening for thrombophilia should not become standard practice until clear evidence emerges that thromboprophylaxis during pregnancy improves perinatal outcome. Further research into the link between the observed association, causality and heterogeneity is required.

 

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
SPLENIC ARTERY ANEURYSM
Post-splenectomy splenic artery aneurysm rupture in an atypical presentation of pre-eclampsia. Lembet A, Saphier CJ, Gaddipati S, Divino C, Berkowitz RL. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Mount Sinai Medical Center, New York, USA.	J Matern Fetal Med 2001 Oct;10(5):360-2 Abstract quote Splenic artery aneurysm rupture in pregnancy is an uncommon catastrophic event. We report a patient who presented at 15 3/7 weeks with atypical pre-eclampsia. After termination was recommended, the patient chose to continue the pregnancy. Reversal of clinical and laboratory abnormalities occurred and the patient was discharged. The patient presented again at 24 weeks with severe pre-eclampsia and residual splenic artery aneurysm rupture, at the site of a splenectomy that had been performed 24 years previously.

 

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Doppler flow measurements and histomorphology of the placental bed in uteroplacental insufficiency. Voigt HJ, Becker V. Department of Obstetrics and Gynecology, University of Erlangen-Nuernberg, Fed. Rep. of Germany.	J Perinat Med 1992;20(2):139-47 Abstract quote For the first time histomorphological findings of the uteroplacental vessels were correlated with Doppler flow parameters of this vascular area in a combined study. The study group consisted of 58 women with a pregnancy-induced hypertension or an otherwise presumed uteroplacental perfusion impairment delivered by cesarean section. The control group included 50 healthy pregnancies, delivered by cesarean section due to presentation anomalies or failure to proceed. After removal of the placenta a placental bed biopsy containing the uteroplacental vessels of the decidual and inner myometrial layer was taken. The occurrence of accepted histological signs of low uteroplacental perfusion was compared to Doppler flow velocity wave forms in uteroplacental arteries. The accuracy of doppler-sonographic findings of uteroplacental circulatory impairment confirmed by the histomorphological results was high, even in cases not complicated by hypertension. The good accordance of Doppler flow parameters with morphological findings offers new perspectives for differentiated insights in pregnancy courses with and without signs of uteroplacental insufficiency.
Placental villi-decidua interactions in normal and hypertensive pregnancies: a morphological quantitative study. Biagini G, Pugnaloni A, Carboni V, Mazzanti L, Cester N, Romanini C, Toschi E, Castaldini C. Institute of Human Morphology, University of Ancona, Italy.	Gynecol Obstet Invest 1992;34(1):15-9 Abstract quote The decidual response to the implantation of the embryo is characterized by physical modifications to the uterine wall, with proliferation of the stromal cells which later change into decidual cells. We performed associated morphological and morphometrical studies to assess how the placental villi and decidua intersect, both in normal terminal pregnancy and in hypertensive patients in whom microenvironmental modifications induced by hypertension may cause significant alterations in mother-fetus relationships. In placentas of hypertensive women our morphometric analyses showed a higher number of chorionic villi-decidua interactions (p less than 0.05) with a more clumped distribution (p less than 0.05) and a smaller surface area of single interaction (p less than 0.001), in association with a higher number (p less than 0.005), and greater areas (p less than 0.01) of decidual cells. These data demonstrate how the placenta can enhance mother-fetus contacts impaired as the result of a hypertensive condition.
VARIANTS
CHRONIC VILLITIS
Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies. Labarrere C, Althabe O.	Eur J Obstet Gynecol Reprod Biol 1985 Jul;20(1):1-11 Abstract quote Placental lesions from 361 singleton full-term pregnancies were studied. T hese placentas were divided into two major groups: the study group consisting of 146 placentas from mothers with pregnancy-induced hypertension and a normotensive control group, which included 215 placentas from mothers with normal pregnancies. Each group was divided into three subgroups according to the allocation of infant's birthweight in the normal ponderal curve. A statistically significant higher incidence and severity of villous lesions was observed in placentas of mothers with pregnancy-induced hypertension when infants were over the 25th centile of the ponderal curve. Vascular lesions, i.e., absence of physiological changes in spiral arteries of the placental bed, acute atherosis and chronic vasculitis-like lesions were also more frequently observed in the hypertensive group than in controls. These placental lesions have been described in placentas of small for gestational age infants with or without maternal hypertension and in those of preeclamptic women with appropriate for gestational age infants. Since acute atherosis-like lesions have been reported in placentas of pregnant women with systemic lupus erythematosus and in rejected renal transplants, a possible maternal immunological reaction against fetal tissues could be responsible for the pathogenesis of these entities.
MAGNESIUM TREATED CHANGES
Magnesium supplement in pregnancy-induced hypertension. A clinicopathological study. Rudnicki M, Junge J, Frolich A, Ornvold K, Fischer-Rasmussen W. Department of Obstetrics and Gynecology, Hvidovre Hospital, University of Copenhagen, Denmark.	APMIS 1990 Dec;98(12):1123-7 Abstract quote The placenta and the umbilical cord obtained from 18 women with pregnancy-induced hypertension were investigated by light microscopy. The umbilical artery was studied by electron microscopy. 10 placentae and umbilical cords from normal pregnancies served as controls. The study was performed as a double-blind randomized controlled study in which 11 women were allocated to magnesium and 7 to placebo treatment. The treatment comprised a 48-hour intravenous magnesium/placebo infusion followed by daily oral magnesium/placebo intake until one day after delivery. Magnesium supplement increased birth weight and placental weight significantly. Light microscopic study of the placentae and the umbilical cord arteries showed no difference between the three groups concerning the occurrence of infarctions, cytotrophoblastic hyperplasia, vasculo-syncytial membranes, basement membrane thickening, stromal fibrosis or intervillous fibrin. Ultrastructurally, the endothelial cells of the umbilical arteries from women with pregnancy-induced hypertension showed a significant increase in the amount of dilated endoplasmic reticulum and basal laminae thickness when all 18 cases were compared with the controls. There was no significant difference when the magnesium group, the placebo group and the control group were compared separately. The present study suggests that magnesium supplement has a beneficial effect on fetal growth in pregnancy-induced hypertension. With regard to the light and electron microscopic changes we were unable to demonstrate any significant difference between the magnesium, placebo and control groups.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
PROGNOSTIC FACTORS
GENERAL
Obstetrical intervention rates and maternal and neonatal outcomes of women with gestational hypertension. Gofton EN, Capewell V, Natale R, Gratton RJ. Department of Obstetrics and Gynecology, St. Joseph's Health Care, Lawson Health Research Institute, University of Western Ontario, London, ON, Canada.	Am J Obstet Gynecol 2001 Oct;185(4):798-803 Abstract quote OBJECTIVE: The purpose of this study was to determine the obstetrical intervention rates and maternal and neonatal outcomes of women with gestational hypertension. STUDY DESIGN: Induction and operative delivery rates and indices of maternal and neonatal morbidity were determined in women (37-41 completed weeks) with gestational hypertension (n = 979), preeclampsia (n = 165), chronic hypertension (n = 187), and control subjects (n = 11,434) in a retrospective review of St. Joseph's Health Care Perinatal Database from November 1, 1995, to October 31, 1999. Data were analyzed by chi-square test, analysis of variance, Dunnett's t -test, and pairwise chi-square tests with Bonferroni correction. RESULTS: The induction and cesarean delivery rates in gestational hypertension were similar to preeclampsia and chronic hypertension groups and almost double of control subjects. The length of labor and postpartum stays and the incidence of operative vaginal delivery, postpartum hemorrhage, and neonatal intensive care involvement were greater in the gestational hypertension group than in the control subjects. CONCLUSION: Women with gestational hypertension had obstetrical intervention rates much higher than control subjects and similar to those with preeclampsia and chronic hypertension.
Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Medical Birth Registry of Norway, Locus for Registry Based Epidemiology, Department of Public Health, University of Bergen, Haukeland Hospital, N5021 Bergen, Norway.	BMJ 2001 Nov 24;323(7323):1213-7 Abstract quote OBJECTIVE: To assess whether mothers and fathers have a higher long term risk of death, particularly from cardiovascular disease and cancer, after the mother has had pre-eclampsia. DESIGN: Population based cohort study of registry data. SUBJECTS: Mothers and fathers of all 626 272 births that were the mothers' first deliveries, recorded in the Norwegian medical birth registry from 1967 to 1992. Parents were divided into two cohorts based on whether the mother had pre-eclampsia during the pregnancy. Subjects were also stratified by whether the birth was term or preterm, given that pre-eclampsia might be more severe in preterm pregnancies. MAIN OUTCOME MEASURES: Total mortality and mortality from cardiovascular causes, cancer, and stroke from 1967 to 1992, from data from the Norwegian registry of causes of death. RESULTS: Women who had pre-eclampsia had a 1.2-fold higher long term risk of death (95% confidence interval 1.02 to 1.37) than women who did not have pre-eclampsia. The risk in women with pre-eclampsia and a preterm delivery was 2.71-fold higher (1.99 to 3.68) than in women who did not have pre-eclampsia and whose pregnancies went to term. In particular, the risk of death from cardiovascular causes among women with pre-eclampsia and a preterm delivery was 8.12-fold higher (4.31 to 15.33). However, these women had a 0.36-fold (not significant) decreased risk of cancer. The long term risk of death was no higher among the fathers of the pre-eclamptic pregnancies than the fathers of pregnancies in which pre-eclampsia did not occur. CONCLUSIONS: Genetic factors that increase the risk of cardiovascular disease may also be linked to pre-eclampsia. A possible genetic contribution from fathers to the risk of pre-eclampsia was not reflected in increased risks of death from cardiovascular causes or cancer among fathers.
INFANT OUTCOME
Tall or short? Twenty years after preeclampsia exposure in utero: comparisons of final height, body mass index, waist-to-hip ratio, and age at menarche among women, exposed and unexposed to preeclampsia during fetal life. Ros HS, Lichtenstein P, Ekbom A, Cnattingius S. Department of Medical Epidemiology, Karolinska Institute, SE-171 77 Stockholm, Sweden	Pediatr Res 2001 Jun;49(6):763-9 Abstract quote Women exposed to preeclampsia during fetal life have lower risk of breast cancer, compared with unexposed women, possibly through fetal programming. Hypothetically, preeclampsia exposure could affect well-known risk factors for breast cancer, such as pubertal development or adult anthropometry. Women born in a defined geographic area of Sweden from 1973 through 1978, with verified preeclampsia exposure (n = 230) and nonexposure (n = 359) during fetal life, answered questions about anthropometric measures, smoking, parity, and age at menarche in a telephone interview in early adulthood. Compared with unexposed offspring, female offspring of women who had preeclampsia were lighter and shorter for gestational age, but in young adulthood there were no differences in height, body mass index, waist-to-hip ratio, or age at menarche. When analyzing the effects of other maternal and fetal characteristics, the results indicate that approximately 50% of the variance in final height was explained by parental heights and birth length for gestational age. Young-adult body mass index was weakly associated with maternal body mass index, maternal smoking, and birth weight for gestational age, which together explained 12% of the variance. Neither of the assessed maternal or fetal characteristics were significantly associated with age at menarche or waist-to-hip ratio. These data indicate that neither adult anthropometry nor age at menarche is in the causal pathway between intrauterine preeclampsia exposure and the reduced risk of breast cancer.
Outcome of infants delivered between 24 and 28 weeks' gestation in women with severe pre-eclampsia. Hiett AK, Brown HL, Britton KA. Department of Obstetrics and Gynecology, St Vincent Hospital and Health Services and Indiana University School of Medicine, Indianapolis, Indiana, USA	J Matern Fetal Med 2001 Oct;10(5):301-4 Abstract quote OBJECTIVE: To determine whether there are differences in neonatal outcome between infants born to mothers with severe pre-eclampsia and those born to normotensive mothers with preterm labor and intact membranes between 24 and 28 weeks' gestation. MATERIALS AND METHODS: Over a 4-year period between 1991 and 1995, neonates of women with severe pre-eclampsia delivering between 24 and 28 weeks were matched for maternal age, antenatally assigned gestational age and mode of delivery to normotensive women delivering during the same period. RESULTS: Fifty-eight women with severe pre-eclampsia were matched to 58 normotensive controls who delivered as a result of preterm labor. Antenatal steroids were used more often in pre-eclamptic women (75% vs. 47%, p < 0.01). The mean birth weight of pre-eclamptic neonates was significantly lower than that of controls, 767 g vs. 989 g, respectively. Other neonatal complications were similar for both groups. Neonates of pre-eclamptics required longer ventilator support (21 vs. 16 median days, p = 0.03). Neonatal survival was similar for both groups (72% and 79% for pre-eclamptics and normotensives, respectively). CONCLUSIONS: Neonates born to patients with severe pre-eclampsia have similar survival but a lower birth weight and require longer ventilator support than neonates born to women with preterm labor.
TIMING OF PREGNANCIES
The interval between pregnancies and the risk of preeclampsia. Skjaerven R, Wilcox AJ, Lie RT. Section for Medical Statistics, Department of Public Health and Primary Health Care, and the Medical Birth Registry of Norway, Locus for Registry-Based Epidemiology, University of Bergen, Bergen, Norway.	N Engl J Med 2002 Jan 3;346(1):33-8 Abstract quote BACKGROUND: The risk of preeclampsia is generally lower in second pregnancies than in first pregnancies, but not if the mother has a new partner for the second pregnancy. One explanation is that the risk is reduced with repeated maternal exposure and adaptation to specific antigens from the same partner. However, the difference in risk might instead be explained by the interval between births. A longer interbirth interval may be associated with both a change of partner and a higher risk of preeclampsia. METHODS: We used data from the Medical Birth Registry of Norway, a population-based registry that includes births that occurred between 1967 and 1998. We studied 551,478 women who had two or more singleton deliveries and 209,423 women who had three or more singleton deliveries. RESULTS: Preeclampsia occurred during 3.9 percent of first pregnancies, 1.7 percent of second pregnancies, and 1.8 percent of third pregnancies when the woman had the same partner. The risk in a second or third pregnancy was directly related to the time that had elapsed since the preceding delivery, and when the interbirth interval was 10 years or more, the risk approximated that among nulliparous women. After adjustment for the presence or absence of a change of partner, maternal age, and year of delivery, the odds ratio for preeclampsia for each one-year increase in the interbirth interval was 1.12 (95 percent confidence interval, 1.11 to 1.13). In unadjusted analyses, a pregnancy involving a new partner was associated with higher risk of preeclampsia, but after adjustment for the interbirth interval, the risk of preeclampsia was reduced (odds ratio for preeclampsia with a change of partner, 0.73; 95 percent confidence interval, 0.66 to 0.81). CONCLUSIONS: The protective effect of previous pregnancy against preeclampsia is transient. After adjustment for the interval between births, a change of partner is not associated with an increased risk of preeclampsia.
TREATMENT
ANGIOPLASTY
Angioplasty for cerebral vasospasm from eclampsia. Ringer AJ, Qureshi AI, Kim SH, Fessler RD, Guterman LR, Hopkins LN. Department of Neurosurgery and Toshiba Stroke Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.	Surg Neurol 2001 Dec;56(6):373-8 Abstract quote BACKGROUND: Neurological deterioration in eclampsia is considered to be secondary to cerebral vasospasm. Magnesium sulfate therapy improves symptoms and controls seizures, possibly related to its vasorelaxive effects in spastic arteries. Some cases, however, are refractory to magnesium therapy. To our knowledge, there is no report of angioplasty for vasospasm from eclampsia in the literature. METHODS: A 27-year-old woman presented 10 days postpartum with severe mental status changes and left arm and bilateral leg weakness that were refractory to magnesium therapy. Cerebral angiography demonstrated diffuse, severe vasospasm. We treated her with angioplasty of the bilateral middle and posterior cerebral arteries, basilar artery, and bilateral internal carotid arteries. RESULTS: Angioplasty resulted in excellent angiographic improvement. The patient immediately became responsive and appropriate with improved strength in all extremities. She continued to improve throughout her hospital stay and was discharged 10 days postangioplasty. CONCLUSIONS: Cerebral angioplasty is an effective treatment for vasospasm from eclampsia refractory to magnesium therapy. Angiography should be considered early in the course of neurological deterioration, but delayed therapy may also be effective.
ANTICONVULSANTS
Anticonvulsants for women with pre-eclampsia. Duley L, Gulmezoglu AM, Henderson-Smart DJ. Resource Centre for Randomised Trials, Institute of Health Sciences, Old Road, Headington, Oxford, UK, OX3 7LF.	Cochrane Database Syst Rev 2000;(2):CD000025 Abstract quote BACKGROUND: Pre-eclampsia is a relatively common complication of pregnancy. Anticonvulsants are used in the belief they help prevent eclamptic fits and subsequent poor outcomes for mother and infant. OBJECTIVES: The objective of this review was to assess the effects of anticonvulsants for women with pre-eclampsia on the women and their children. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register, and the Cochrane Controlled Trials Register, 1999 Issue 3. SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsants or comparisons of different anticonvulsants in women with pre-eclampsia. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. MAIN RESULTS: Nine studies were included. Comparing magnesium sulphate with placebo/no anticonvulsant the relative risk (RR) of eclampsia was 0.33, 95% confidence interval (CI) 0.11 to 1.02. There was no significant difference detected in the risk of caesarean section (RR 1.04, 95% CI 0.92 to 1.17). Magnesium sulphate appeared to be better than phenytoin at reducing the risk of eclampsia (RR 0.05, 95% CI 0.00 to 0.84). However there was an increased risk of caesarean section with magnesium sulphate compared to phenytoin (RR 1.21, 95% CI 1.05 to 1. 41). No statistically significant differences were reported for any other clinically important outcomes. Studies comparing magnesium sulphate and diazepam were too small for any reliable conclusions. REVIEWER'S CONCLUSIONS: There is not enough evidence to establish the benefits and hazards of anticonvulsants for women with pre-eclampsia. If an anticonvulsant is used, magnesium sulphate appears to be the best choice.
ANTIHYPERTENSIVE THERAPY
Antihypertensive drug therapy for mild to moderate hypertension during pregnancy (Cochrane Review). Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Centro Rosarino de Estudios Perinatales, Pueyrredon 985, Rosario, Santa Fe, ARGENTINA, 2000.	Cochrane Database Syst Rev 2001;2:CD002252 Abstract quote BACKGROUND: Mild-moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve outcome. OBJECTIVES: To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. SEARCH STRATEGY: Relevant trials were identified in the register of trials maintained by the Cochrane Pregnancy and Childbirth Group. In addition, the Cochrane Controlled Trial Register, MEDLINE, and EMBASE were searched. Date of last search: October 2000. SELECTION CRITERIA: All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy, defined whenever possible as systolic blood pressure 140-169 mmHg and diastolic blood pressure 90-109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. MAIN RESULTS: Overall, this review includes 40 studies (3797 women), 24 of which compared an antihypertensive drug with placebo/no antihypertensive drug (2815 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) [17 trials, 2155 women; relative risk (RR) 0.52 (95% confidence interval (CI) 0.41 to 0.64); risk difference (RD) -0.09 (-0.12 to -0.06); number needed to treat (NNT) 12 (9 to 17)] but little evidence of a difference in the risk of pre-eclampsia [19 trials, 2402 women; RR 0.99 (0.84 to 1.18)]. Similarly, there is no clear effect on the risk of the baby dying [23 trials, 2727 women; RR 0.71(0.46 to 1.09)], preterm birth [12 trials, 1738 women; RR 0.98 (0.85 to 1.13)], or small for gestational age babies [17 trials, 2159 women; RR 1.13 (0.91 to 1.42)]. There were no clear differences in any other outcomes. Seventeen trials (1182 women) compared one antihypertensive drug with another. There is no clear difference between any of these drugs in the risk of developing severe hypertension, and proteinuria/pre-eclampsia. Other antihypertensive agents seem better than methyldopa for reducing the risk of the baby dying [14 trials, 1010 subjects, RR 0.49 (0.24 to 0.99); RD -0.02 (-0.04 to 0.00); NNT 45 (22 to 1341)]. Other outcomes were only reported by a small proportion of studies, and there were no clear differences. REVIEWER'S CONCLUSIONS: It remains unclear whether antihypertensive drug therapy for mild-moderate hypertension during pregnancy is worthwhile.
ASPIRIN
Antiplatelet agents for preventing and treating pre-eclampsia. Knight M, Duley L, Henderson-Smart DJ, King JF. Resource Centre for Randomised Trials, Institute of Health Sciences, Old Road, Headington, Oxford, UK, OX3 7LF.	Cochrane Database Syst Rev 2000;(2):CD000492 Abstract quote BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, and low dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia, and to those with established pre-eclampsia. SEARCH STRATEGY: This review drew on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The Cochrane Controlled Trials Register was also searched, The Cochrane Library 1999 Issue 1, Embase was searched from 1994-1999 and hand searches were performed of the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia, and those with pre-eclampsia before delivery. Women treated postpartum were excluded. Interventions were any comparisons of an antiplatelet agent (such as low dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Assessment of trials for inclusion in the review and extraction of data was performed independently and unblinded by two reviewers. Data were entered into the Review Manager software and double checked. MAIN RESULTS: Forty two trials involving over 32,000 women were included in this review, with 30,563 women in the prevention trials. There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents [32 trials with 29,331 women; relative risk (RR) 0.85, 95% confidence interval (0.78, 0.92); Number needed to treat (NNT) 89, (59, 167)]. This reduction is regardless of risk status at trial entry or whether a placebo was used, and irrespective of the dose of asprin or gestation at randomisation. Twenty three trials (28,268 women) reported preterm delivery. There is a small (8%) reduction in the risk of delivery before 37 completed weeks [RR 0.92, (0.88, 0.97); NNT 72 (44, 200)]. Baby deaths were reported in 30 trials (30,093 women). Overall there is a 14% reduction in baby deaths in the antiplatelet group [RR 0.86, (0. 75, 0.98); NNT 250 (125, >10000)]. Small for gestational age babies were reported in 25 trials (20,349 women), with no overall difference between the groups, RR 0.92, (0.84, 1.01). There were no significant differences between treatment and control groups in any other measures of outcome. Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. REVIEWER'S CONCLUSIONS: Antiplatelet agents, in this review largely low dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment should be started, and at what dose.
Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review. Duley L, Henderson-Smart D, Knight M, King J. Resource Centre for Randomised Trials, Institute of Health Sciences, Oxford OX3 7LF.	BMJ 2001 Feb 10;322(7282):329-33 Abstract quote OBJECTIVE: To assess the effectiveness and safety of antiplatelet drugs for prevention of pre-eclampsia and its consequences. DESIGN: Systematic review. DATA SOURCES: Register of trials maintained by Cochrane Pregnancy and Childbirth Group, Cochrane Controlled Trials Register, and Embase. INCLUDED STUDIES: Randomised trials involving women at risk of pre-eclampsia, and its complications, allocated to antiplatelet drug(s) versus placebo or no antiplatelet drug. MAIN OUTCOME MEASURES: Pre-eclampsia, preterm birth, fetal or neonatal death, and small for gestational age baby. Studies were assessed for quality of concealment of allocation and losses to follow up. RESULTS: 39 trials (30 563 women) were included, and 45 trials (>3000 women) excluded. Use of antiplatelet drugs was associated with a 15% reduction in the risk of pre-eclampsia (32 trials, 29 331 women; relative risk 0.85, 95% confidence interval 0.78 to 0.92; number needed to treat 100, 59 to 167). There was also an 8% reduction in the risk of preterm birth (23 trials, 28 268 women; 0.92, 0.88 to 0.97; 72, 44 to 200), and a 14% reduction in the risk of fetal or neonatal death (30 trials, 30 093 women; 0.86, 0.75 to 0.98; 250, 125 to >10 000) for women allocated antiplatelet drugs. Small for gestational age babies were reported in 25 trials (20 349 women), with no overall difference between the groups (relative risk 0.92, 0.84 to 1.01). There were no significant differences in other measures of outcome. CONCLUSIONS: Antiplatelet drugs, largely low dose aspirin, have small to moderate benefits when used for prevention of pre-eclampsia.
Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: a meta-analysis. Coomarasamy A, Papaioannou S, Gee H, Khan KS. Birmingham Women's Hospital, Birmingham, United Kingdom.	Obstet Gynecol 2001 Nov;98(5 Pt 1):861-6 Abstract quote OBJECTIVE: To determine the effectiveness of aspirin to prevent preeclampsia in women identified as high risk for preeclampsia by an abnormal second-trimester uterine artery Doppler examination. DATA SOURCES: Searches were conducted in MEDLINE, Embase, the Cochrane Controlled Trials Register, and Science Citation Index for randomized trials published from 1966 to 2000, using the following medical subject headings and key words: "aspirin," "antiplatelet*," "salicyl*," "acetylsalicyl*," "platelet aggregation inhibitors," "ultrasonography," "ultraso*," and "Doppler." STUDY SELECTION: We included all randomized trials that evaluated the effectiveness of aspirin compared with placebo or no treatment in women with an abnormal uterine artery Doppler and that reported clinically relevant perinatal and maternal outcomes. Study selection, quality assessment, and data extraction were performed in duplicate. TABULATION, INTEGRATION, AND RESULTS: There were five relevant trials. Pooling of results from these trials showed a significant benefit of aspirin in reducing preeclampsia (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.32, 0.95). The baseline risk of preeclampsia in women with abnormal uterine artery Doppler was 16%, and the number of women needed to be treated with aspirin to prevent one case of preeclampsia was 16 (95% CI 8, 316). Women on aspirin had babies who were on average 82 g heavier than controls, but this result did not reach statistical significance (weighted mean difference 81.5, 95% CI 40.27, 203.27). CONCLUSION: Uterine artery Doppler assessment identifies high-risk women in whom aspirin therapy results in a significant reduction in preeclampsia.
CALCIUM
Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Atallah AN, Hofmeyr GJ, Duley L. Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Rue Pedro de Toledo 598, Sao Paulo, Brazil, 04024 900.	Cochrane Database Syst Rev 2000;(2):CD001059 Abstract quote BACKGROUND: Calcium supplementation may prevent high blood pressure through a number of mechanisms and may help to prevent preterm labour. OBJECTIVES: The objective of this review was to assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child adverse outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register and we contacted study authors. SELECTION CRITERIA: Randomised trials comparing at least one gram daily of calcium during pregnancy compared to placebo. DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed. Data extraction was carried out independently by two reviewers. MAIN RESULTS: Nine studies were included, all of good quality. There was a modest reduction in high blood pressure with calcium supplementation (relative risk 0.80, 95% confidence interval 0.73 to 0.88). The effect was greatest for women at high risk of hypertension (relative risk 0.35, 95% confidence interval 0.21 to 0.57) and those with low baseline dietary calcium (relative risk 0.49, 95% confidence interval 0.38 to 0.62). There was also a modest reduction in the risk of pre-eclampsia with calcium supplementation (relative risk 0. 72, 95% confidence interval 0.60 to 0.86). The effect was greatest for women at high risk of hypertension (relative risk 0.22, 95% confidence interval 0.11 to 0.43) and those with low baseline calcium intake (relative risk 0.32, 95% confidence interval 0.21 to 0.49). There was no overall effect on the risk of preterm delivery, although there was a reduction in risk amongst women at high risk of hypertension (relative risk 0.42, 95% confidence interval 0.23 to 0. 78). There was no evidence of any effect of calcium supplementation on stillbirth or death before discharge from hospital. REVIEWER'S CONCLUSIONS: Calcium supplementation appears to be beneficial for women at high risk of gestational hypertension and in communities with low dietary calcium intake. Optimum dosage requires further investigation.
MAGNESIUM
Magnesium supplementation in pregnancy (Cochrane Review). Makrides M, Crowther CA. Child Nutrition Research Centre, Child Health Research Institute, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA, AUSTRALIA, 5006.	Cochrane Database Syst Rev 2001;4:CD000937 Abstract quote BACKGROUND: Many women, especially those from disadvantaged backgrounds, have intakes of magnesium below recommended levels. Magnesium supplementation during pregnancy may be able to reduce fetal growth retardation and pre-eclampsia, and increase birth weight. OBJECTIVES: The objective of this review was to assess the effects of magnesium supplementation during pregnancy on maternal, neonatal and paediatric outcomes. SEARCH STRATEGY: We searched the Cochrane Cochrane Controlled Trials Register. The date of the last search was June 2001. SELECTION CRITERIA: Randomised and quasi-randomised trials of dietary magnesium supplementation during pregnancy. DATA COLLECTION AND ANALYSIS: Suitability for inclusion and methodological quality were separately assessed by each reviewer. Data were independently extracted by the two reviewers. MAIN RESULTS: Seven trials involving 2689 women were included. Six of these trials randomly allocated women to either an oral magnesium supplement or a control group, whist the largest trial with 985 women had a cluster design where randomisation was according to study centre. The analysis was conducted with and without the cluster trial. In the analysis of all trials, oral magnesium treatment from before the 25th week of gestation was associated with a lower frequency of preterm birth, (relative risk (RR) 0.73, 95% confidence interval (CI) 0.57 to 0.94), a lower frequency of low birth weight (RR 0.67, 95% CI 0.46 to 0.96) and fewer small for gestational age infants (RR 0.70, 95% CI 0.53 to 0.93) compared with placebo. In addition, magnesium treated women had less hospitalisations during pregnancy (RR 0.66, 95% CI 0.49 to 0.89) and fewer cases of antepartum haemorrhage (RR 0.38, 95% CI 0.16 to 0.90) than placebo treated women. In the analysis excluding the cluster randomised trial, the effects of magnesium treatment on the frequencies of preterm birth, low birth weight and small for gestational age were not different from placebo. Of the seven trials included in the review, only one was judged to be of high quality. Poor quality trials are likely to have resulted in a bias favouring magnesium supplementation. REVIEWER'S CONCLUSIONS: There is not enough high quality evidence to show that dietary magnesium supplementation during pregnancy is beneficial.

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Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.

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