Metabolic syndrome and time to pregnancy: a retrospective study of nulliparous women.

OBJECTIVE: To determine: (1) the association between metabolic syndrome (MetS), time to pregnancy (TTP), and infertility; (2) associations between individual and an increasing number of MetS components, TTP, and infertility; and (3) whether these relationships differ by body mass index (BMI < 30 kg/m2 versus BMI ≥ 30 kg/m2 ). DESIGN: Retrospective cohort study. SETTING: Multiple centres (in Australia, Ireland, New Zealand, and the UK). POPULATION: Five thousand five hundred and nineteen low-risk nulliparous pregnant women. METHODS: Data on retrospectively reported TTP (number of months to conceive) and a blood sample to assess metabolic health were collected between 14 and 16 weeks of gestation. MetS was defined according to the International Diabetes Federation criteria. Accelerated failure time models with log-normal distribution were conducted to estimate time ratios (TRs) and 95% CIs. Differences in MetS on infertility (TTP > 12 months) were compared using a generalised linear model (Poisson distribution) with robust variance estimates (relative risks, RRs; 95% CIs). All analyses (entire cohort and split by BMI) were controlled for a range of maternal and paternal confounding factors. MAIN OUTCOME MEASURES: Time to pregnancy and infertility. RESULTS: Of the 5519 women included, 12.4% (n = 684) had MetS. Compared with women without MetS, women with MetS had a longer TTP (adjusted TR 1.30; 95% CI 1.15-1.46), which was similar in women who were obese and in women who were not obese. Marginal estimates for median TTP in women with MetS versus without MetS was 3.1 months (3.0-3.3 months) versus 4.1 months (3.6-4.5 months), respectively. Women with MetS were at a 62% greater risk for infertility and were at a greater risk for infertility whether they were obese (adjusted RR 1.62; 95% CI 1.15-2.29) or not (adjusted RR 1.73; 95% CI 1.33-2.23). Reduced high-density lipoprotein cholesterol (HDL-C) and raised triglycerides (TGs) were the main individual components associated with risk for infertility. CONCLUSION: Metabolic syndrome is associated with longer TTP and infertility, independent of obesity. Additional studies, before pregnancy, are required to support our findings and to determine the applicability of which combinations of metabolic abnormalities pose the greatest risk to delayed fertility, or whether individual components are amenable to modification. TWEETABLE ABSTRACT: Metabolic syndrome is associated with longer time to pregnancy and infertility, independent of obesity.

Antidepressant use in late gestation and risk of postpartum haemorrhage: a retrospective cohort study.

OBJECTIVE: To investigate the association between antidepressant use in late gestation and postpartum haemorrhage (PPH). DESIGN: Retrospective cohort study. SETTING: Tertiary teaching hospital in Adelaide, Australia. POPULATION: A total of 30 198 women delivering between 2002 and 2008. METHODS: Relative risks adjusted for maternal sociodemographics and comorbidities (aRRs) were calculated for PPH, comparing women with late-gestation exposure to antidepressants (n = 558), women with a psychiatric illness but no antidepressant use (n = 1292), and women with neither antenatal exposures (n = 28 348). Additional sensitivity analyses were undertaken, examining associations with severe PPH and postpartum anaemia. MAIN OUTCOME MEASURES: The primary outcome was PPH, defined as a recorded blood loss of ≥500 mL for vaginal deliveries and ≥1000 mL for caesarean sections. Secondary outcomes included severe PPH (≥1000 mL blood loss, irrespective of method of delivery), and the presence of postpartum anaemia (identified from hospital medical records). RESULTS: Compared with unexposed controls, women exposed to antidepressants had an increased risk of PPH (aRR 1.53; 95% confidence interval, 95% CI 1.25-1.86), whereas no increased risk was observed for women with a psychiatric illness but no antidepressant use (aRR 1.04; 95% CI 0.89-1.23). In sensitivity analyses, late gestation antidepressant exposure was associated with an increased risk of severe PPH (aRR 1.84; 95% CI 1.39-2.44), as well as postpartum anaemia (aRR 1.80; 95% CI 1.46-2.22). CONCLUSIONS: Exposure to antidepressants in late gestation was associated with a significantly increased risk of PPH. Although potential confounding by unmeasured factors cannot be ruled out, these findings suggest a direct effect of antidepressant exposure on PPH. TWEETABLE ABSTRACT: Late gestation antidepressant exposure is associated with a significantly increased risk of postpartum haemorrhage.

Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study.

OBJECTIVES: To assess the performance of clinical risk factors, uterine artery Doppler and angiogenic markers to predict preterm pre-eclampsia in nulliparous women. DESIGN: Predictive test accuracy study. SETTING: Prospective multicentre cohort study Screening for Pregnancy Endpoints (SCOPE). METHODS: Low-risk nulliparous women with a singleton pregnancy were recruited. Clinical risk factor data were obtained and plasma placental growth factor (PlGF), soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 14-16 weeks of gestation. Prediction models were developed using multivariable stepwise logistic regression. MAIN OUTCOME MEASURE: Preterm pre-eclampsia (delivered before 37(+0)  weeks of gestation). RESULTS: Of the 3529 women recruited, 187 (5.3%) developed pre-eclampsia of whom 47 (1.3%) delivered preterm. Controls (n = 188) were randomly selected from women without preterm pre-eclampsia and included women who developed other pregnancy complications. An area under a receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.67-0.84) was observed using previously reported clinical risk variables. The AUC improved following the addition of PlGF measured at 14-16 weeks (0.84; 95% CI 0.77-0.91), but no further improvement was observed with the addition of uterine artery Doppler or the other angiogenic markers. A sensitivity of 45% (95% CI 0.31-0.59) (5% false-positive rate) and post-test probability of 11% (95% CI 9-13) were observed using clinical risk variables and PlGF measurement. CONCLUSIONS: Addition of plasma PlGF at 14-16 weeks of gestation to clinical risk assessment improved the identification of nulliparous women at increased risk of developing preterm pre-eclampsia, but the performance is not sufficient to warrant introduction as a clinical screening test. These findings are marker dependent, not assay dependent; additional markers are needed to achieve clinical utility.

The impact of maternal body mass index on the phenotype of pre-eclampsia: a prospective cohort study.

OBJECTIVE: We hypothesised that among nulliparous women with pre-eclampsia, overweight or obese women would have a different phenotype of pre-eclampsia compared with normal weight women with pre-eclampsia. Specifically, they are more likely to develop term pre-eclampsia and less likely to have indicators of impaired placental perfusion, e.g. abnormal uterine artery Doppler or a small-for-gestational-age (SGA) infant. DESIGN: Prospective, multicentre, cohort SCOPE study (n = 3170). SETTING: New Zealand and Australia. POPULATION: Nulliparous women who developed pre-eclampsia. METHODS: Participants were interviewed at 14-16 weeks of gestation, uterine artery Doppler studies were performed at 19-21 weeks and pregnancy outcome was tracked prospectively. MAIN OUTCOME MEASURES: Rates of abnormal uterine artery Doppler indices, term/preterm birth and SGA infants were compared between normal, overweight and obese women with pre-eclampsia. Multivariable analysis was performed to examine the association between body mass index (BMI) and term pre-eclampsia. RESULTS: Of 178 women with pre-eclampsia, one underweight woman was excluded and 66 (37%) were normal weight, 52 (29%) were overweight and 59 (34%) were obese. Pre-eclampsia developed preterm in 26% of women and at term in 74% of women. There were no differences in the rates of term/preterm pre-eclampsia, abnormal uterine artery Doppler indices or SGA infants between BMI groups (P > 0.10). No independent association between BMI and term pre-eclampsia was found (P = 0.56). CONCLUSIONS: Among women with pre-eclampsia, those who are overweight or obese in early pregnancy are not more likely to have term pre-eclampsia compared with women with a normal BMI. Overweight and obese women require vigilant surveillance for the development of preterm as well as term pre-eclampsia.

Increased lymphocyte micronucleus frequency in early pregnancy is associated prospectively with pre-eclampsia and/or intrauterine growth restriction.

Genome stability is essential for normal foetal growth and development. To date, genome stability in human lymphocytes has not been studied in relation to late pregnancy diseases, such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR), which can be life-threatening to mother and baby and together affect >10% of pregnancies. We performed a prospective cohort study investigating the association of maternal chromosomal damage in mid-pregnancy (20 weeks gestation) with pregnancy outcomes. Chromosome damage was measured using the cytokinesis-block micronucleus cytome (CBMNcyt) assay in peripheral blood lymphocytes. The odds ratio for PE and/or IUGR in a mixed cohort of low- and high-risk pregnancies (N = 136) and a cohort of only high-risk pregnancies (N = 91) was 15.97 (P = 0.001) and 17.85 (P = 0.007), respectively, if the frequency of lymphocytes with micronuclei (MN) at 20 weeks gestation was greater than the mean + 2 SDs of the cohort. These results suggest that the presence of lymphocyte MN is significantly increased in women who develop PE and/or IUGR before the clinical signs or symptoms appear relative to women with normal pregnancy outcomes. The CBMNcyt assay may provide a new approach for the early detection of women at risk of developing these late pregnancy diseases and for biomonitoring the efficacy of interventions to reduce DNA damage, which may in turn ameliorate pregnancy outcome.

Risk of uterine rupture in Australian women attempting vaginal birth after one prior caesarean section: a retrospective population-based cohort study.

OBJECTIVE: Higher risks of uterine rupture have been reported among women attempting vaginal birth after caesarean (VBAC) particularly following induction with prostaglandins, compared with women who do not labour. This study aimed to estimate these risks as well as that associated with oxytocin use. DESIGN: Population-based retrospective cohort study involving all women who had their first births by caesarean. In their second birth, risks of uterine rupture among women without labour and women who had labour augmented or induced were compared with women who gave birth after spontaneous labour. SETTING: Four Australian states in 1998-2000. POPULATION: Women on pregnancy outcome databases with a second birth after a prior caesarean for their first birth. METHODS: From 29, 008 women identified from the databases, those with uterine rupture were identified and validated using hospital case records. MAIN OUTCOME MEASURE: Uterine rupture. RESULTS: The risk of complete uterine rupture among women without labour was 0.01%. The risk in spontaneous labour without augmentation was 0.15%, considerably higher when there was augmentation with oxytocin (1.91%). The risk with induction of labour was 0.54% for oxytocin alone, 0.68% for prostaglandin alone, 0.63% without either and 0.88% when they were combined. Compared with spontaneous labour, risks were increased three- to five-fold for any induction, six-fold for prostaglandin combined with oxytocin and 14-fold for augmentation with oxytocin. CONCLUSIONS: Careful consideration should be given to the use of oxytocin for augmentation of labour or induction by any method for women with a previous caesarean in view of increased risks of uterine rupture.

Risk factors for small-for-gestational-age infants by customised birthweight centiles: data from an international prospective cohort study.

OBJECTIVE: To identify clinical and ultrasound variables associated with the birth of small-for-gestational-age (SGA) infants by customised centiles, subclassified according to whether their mothers were normotensive or developed hypertensive complications. DESIGN: Prospective, multicentre cohort study. SETTING: Participating centres of the Screening for Pregnancy Endpoints (SCOPE) study in Auckland, New Zealand, Adelaide, Australia, Manchester and London, UK, and Cork, Ireland. POPULATION: The 3513 nulliparous participants of the SCOPE study. METHODS: Women were interviewed at 15 ± 1 weeks, and had ultrasound growth measurements and umbilical and uterine Doppler studies at 20 ± 1 weeks. Variables associated with SGA infants were identified using logistic regression. MAIN OUTCOME MEASURES: Small for gestational age (i.e. a birthweight of less than the tenth customised centile), normotensive-SGA and hypertensive-SGA. Comparison groups for statistical analyses were non-SGA, normotensive non-SGA and hypertensive non-SGA. RESULTS: Among 376 (10.7%) SGA infants, 281 (74.7%) were normotensive-SGA and 95 (25.3%) were hypertensive-SGA. Independent risk factors for normotensive-SGA were low maternal birthweight, low fruit intake pre-pregnancy, cigarette smoking, increasing maternal age, daily vigorous exercise, being a tertiary student, head and abdominal circumference of less than the tenth centile and increasing uterine artery Doppler indices at the 20-week scan. Protective factors were: high green leafy vegetable intake pre-pregnancy, and rhesus-negative blood group. Risk factors for hypertensive-SGA were conception by in vitro fertilisation, previous early pregnancy loss and femur length of less than tenth centile at the 20-week scan. CONCLUSIONS: Risk factors for infants who are SGA by customised centiles have been identified in a cohort of healthy nulliparous women. A number of these factors are modifiable; however, further studies are needed to replicate these findings.

Changes in Doppler flow velocity waveforms and fetal size at 20 weeks gestation among cigarette smokers.

OBJECTIVES: To compare umbilical and uterine artery Doppler waveforms and fetal size at 20 weeks between smokers and nonsmokers. DESIGN: Prospective cohort study. SETTING: Auckland, New Zealand and Adelaide, Australia. POPULATION: Nulliparous participants in the Screening for Pregnancy Endpoints (SCOPE) study. METHODS: Self-reported smoking status was determined at 15 +/- 1 weeks' gestation. At the 20 +/- 1 week anatomy scan, uterine and umbilical Doppler resistance indices (RI) and fetal measurements were compared between smokers and nonsmokers. MAIN OUTCOMES MEASURES: Umbilical and mean uterine artery Doppler RI values, abnormal umbilical and uterine Doppler (RI > 90th centile) and fetal biometry. RESULTS: Among the 2459 women, 248 (10%) were smokers. Smokers had higher umbilical RI [0.75 (SD 0.06) versus 0.73 (0.06), P < 0.0001] and mean uterine RI [0.59 (0.09) versus 0.56 (0.10), P < 0.0001]. They were twice as likely to have an abnormal umbilical Doppler at 20 weeks compared with nonsmokers [n = 35 (14.6%) versus n = 156 (7.2%), OR 2.21, 95% CI 1.49-3.27]. This effect remained significant after adjusting for age, ethnicity, marital status, employment and BMI (adjusted OR 1.62, 95% CI 1.03-2.54). Smokers were more likely to have an abnormal mean uterine RI [n = 33 (13.7%) versus n = 198 (9.2%), OR 1.57, 95% CI 1.06-2.33], but this association was not significant after adjusting for confounders. Fetuses of women who smoked had a small reduction in femur length and estimated weight compared with nonsmokers. CONCLUSIONS: At 20 weeks' gestation, women who smoke have higher umbilical artery RI, a surrogate measure for an abnormal placental villous vascular tree. This may contribute to later fetal growth restriction among smokers. Further research is needed to explore the clinical significance of these findings.

Paternal contributions to large-for-gestational-age term babies: findings from a multicenter prospective cohort study.

We assessed whether paternal demographic, anthropometric and clinical factors influence the risk of an infant being born large-for-gestational-age (LGA). We examined the data on 3659 fathers of term offspring (including 662 LGA infants) born to primiparous women from Screening for Pregnancy Endpoints (SCOPE). LGA was defined as birth weight >90th centile as per INTERGROWTH 21st standards, with reference group being infants ⩽90th centile. Associations between paternal factors and likelihood of an LGA infant were examined using univariable and multivariable models. Men who fathered LGA babies were 180 g heavier at birth (P<0.001) and were more likely to have been born macrosomic (P<0.001) than those whose infants were not LGA. Fathers of LGA infants were 2.1 cm taller (P<0.001), 2.8 kg heavier (P<0.001) and had similar body mass index (BMI). In multivariable models, increasing paternal birth weight and height were independently associated with greater odds of having an LGA infant, irrespective of maternal factors. One unit increase in paternal BMI was associated with 2.9% greater odds of having an LGA boy but not girl; however, this association disappeared after adjustment for maternal BMI. There were no associations between paternal demographic factors or clinical history and infant LGA. In conclusion, fathers who were heavier at birth and were taller were more likely to have an LGA infant, but maternal BMI had a dominant influence on LGA.

Fetal exposure to herpesviruses may be associated with pregnancy-induced hypertensive disorders and preterm birth in a Caucasian population.

OBJECTIVE: To investigate the role of fetal viral infection in the development of a range of adverse pregnancy outcomes (APOs), including pregnancy-induced hypertensive disorders (PIHD), antepartum haemorrhage (APH), birthweight <10th percentile (small for gestational age, SGA) and preterm birth (PTB). DESIGN: Population-based case-control study. SETTING: Laboratory-based study. POPULATION: The newborn screening cards of 717 adverse pregnancy cases and 609 controls. METHODS: Newborn screening cards were tested for RNA from enteroviruses and DNA from herpesviruses using polymerase chain reaction (PCR). The herpesviruses were detected using two PCRs, one detecting nucleic acids from herpes simplex virus (HSV)-1, HSV-2, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus (HHV)-8, hereafter designated Herpes PCR group A viruses, and the other detecting nucleic acids from varicella-zoster virus (VZV), HHV-6 and HHV-7, hereafter designated Herpes PCR group B viruses. MAIN OUTCOME MEASURE: Odds ratios and 95% CIs for specific APOs. RESULTS: For both term and PTBs, the risk of developing PIHD was increased in the presence of DNA from Herpes PCR group B viruses (OR 3.57, 95% CI 1.10-11.70), CMV (OR 3.89, 95% CI 1.67-9.06), any herpesvirus (OR 5.70, 95% CI 1.85-17.57) and any virus (OR 5.17, 95% CI 1.68-15.94). The presence of CMV was associated with PTB (OR 1.61, 95% CI 1.14-2.27). No significant association was observed between SGA or APH and exposure to viral infection. CONCLUSIONS: Fetal exposure to herpesvirus infection was associated with PIHD for both term and PTBs in this exploratory study. Exposure to CMV may also be associated with PTB. These findings need confirmation in future studies.

Risk factors for stillbirth in a socio-economically disadvantaged urban Australian population.

INTRODUCTION: Several risk factors for stillbirth have been extensively investigated. Some risk factors are more common in socio-economically disadvantaged regions. The aim of this study was to identify risk factors for stillbirth in the Northern suburbs of Adelaide, one of the most socio-economically disadvantaged urban areas in Australia. MATERIAL AND METHODS: A retrospective case control study (two controls per case) of all women with a singleton pregnancy resulting in a stillbirth during the decade 2002-2012. RESULTS: One hundred and thirty stillbirths were registered over these 10 years. Using univariate analysis, the following risk factors were identified: obesity ≥40 body mass index (BMI) (OR 4.75), non-Caucasian ethnicity (odds ratio [OR] 2.737), pre-existing diabetes (p <0.000), polycystic ovary syndrome (PCOS) (OR 5.250), in vitro fertilisation (IVF) (OR 4.000), booking systolic blood pressure (SBP) ≥ 140 (OR 5.000) and booking diastolic blood pressure (DBP) ≥ 80 (OR 3.111). Many of these factors have complex interrelationships. Multivariate analysis identified the following independent risk factors: BMI ≥40 (OR 3.940), ethnic minorities (mainly indigenous Australians) (OR 2.255) and social issues (OR 3.079). PCOS had an independent effect to some extent, but this was clearly confounded by BMI. CONCLUSION: These Australian data confirm the presence of several potentially modifiable risk factors for stillbirth, within this socio-economically disadvantaged region. Modifying these risk factors, in particular obesity, is a big challenge not only for maternity and primary care providers, but for overall society.

An observational study of the impact of an antenatal asthma management service on asthma control during pregnancy.

OBJECTIVE: We sought to investigate the impact of introducing an antenatal asthma management service (AMS) on asthma control during pregnancy and subsequent perinatal outcomes. STUDY DESIGN: Prospective, observational cohort study of pregnant asthmatic women attending a tertiary hospital antenatal clinic. Asthmatic women were recruited from the antenatal clinic and were followed prospectively with visits at 12, 20, 28 and 36 weeks gestation. A new nurse-led AMS was introduced offering asthma self-management education and support. Outcomes were compared between women recruited before and after the AMS was introduced (n=89 and 80, respectively) and included; prevalence of exacerbations during pregnancy, asthma control throughout pregnancy and perinatal outcomes, including preterm birth and small-for-gestational-age (SGA). RESULTS: The relative risk for exacerbations (0.69; CI: 0.33-1.42), loss of control (0.67; CI 0.46-0.99) and persistent uncontrolled asthma (0.48; CI 0.26-0.9) were all reduced with attendance to AMS during pregnancy. AMS was associated with non-statistically significant reductions in asthma exacerbations (19.1-15.0%; p=0.480) and uncontrolled asthma at ≥ 2 study visits (21.3-11.3%; p=0.078). CONCLUSIONS: These findings demonstrate the potential impact of an AMS in improving asthma control during pregnancy, supporting the need for an adequately powered RCT to determine its clinical- and cost-effectiveness.

Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study.

BACKGROUND: Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. METHODS: Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. RESULTS: Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16-3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. LIMITATIONS: 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. CONCLUSIONS: Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category.

A five century evolution of cervical incompetence as a clinical entity.

Since cervical incompetence was introduced in the English literature in 1678, our understanding and obstetric management of this clinical entity, have changed tremendously over the years. This review shows the historical perspective of the development of cervical incompetence as a distinct clinical entity and an all or nothing phenomenon to cervical incompetence as part of a spectrum leading to preterm delivery, which can express differently in subsequent pregnancies. These changes in our understanding imply consequences for the obstetric management of cervical incompetence. This review focuses on the obstetric management of women considered to be at high risk of preterm delivery due to cervical incompetence, by transvaginal ultrasonographic follow-up of cervical length and transvaginal cervical cerclage.

Preeclampsia: a couple's disease with maternal and fetal manifestations.

Preeclampsia still ranks as one of obstetrics major problems. Clinicians typically encounter preeclampsia as maternal disease with variable degrees of fetal involvement. More and more the unique immunogenetic maternal-paternal relationship is appreciated, and as such also the specific 'genetic conflict' that is characteristic of haemochorial placentation. From that perspective preeclampsia can also been seen as a disease of an individual couple with primarily maternal and fetal manifestations. Factors that are unique to a specific couple would include the length and type of sexual relationship, the maternal (decidual natural killer cells) acceptation of the invading cytotrophoblast (paternal HLA-C), and seminal levels of transforming growth factor-beta and probably other cytokines. The magnitude of the maternal response would be determined by factors including a maternal set of genes determining her characteristic inflammatory responsiveness, age, quality of her endothelium, obesity/insulin resistance and probably a whole series of susceptibility genes amongst which the thrombophilias received a lot of attention in recent years.

A genome-wide scan for preeclampsia in the Netherlands.

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.

Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid?

The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis.

Change in paternity: a risk factor for preeclampsia in multiparous women?

BACKGROUND: Preeclampsia is often thought of as being a disease of first pregnancies. The incidence of preeclampsia in subsequent pregnancies, after a previous normal pregnancy is lower. However, it has been reported that this beneficial effect of multiparity is lost with a change in paternity. The aim of this study was to assess the impact of change in paternity on the incidence of preeclampsia in Dutch multiparous pregnant women. METHODS: 364 Multiparous patients with hypertension (diastolic blood pressure > or = 100 mmHg) were identified in the obstetric database of the Academic Hospital Vrije Universiteit Amsterdam for the period 1989-1996. The diagnosis in their obstetrical history (Preeclampsia, HELLP-syndrome, chronic hypertension) was defined in a pragmatic way in view of the retrospective nature of the study. The control group consisted of 281 multiparous women from a midwife clinic, with normotensive pregnancies in the same period. Patients and controls were asked, by telephone, if the index pregnancy was from the same partner as the previous pregnancy and what the sex of the newborns had been in each pregnancy. Fisher's Exact test was used for statistical analysis and P < 0.05 was considered significant. RESULTS: The final study group consisted of 333 multiparous patients with hypertension. The control group consisted of 182 multiparous women without hypertension. The prevalence of new paternity was significantly higher (P < 0.0001) both for preeclamptic and HELLP patients in comparison with the controls, with an odds ratio of 8.6 (95%CI: 3.1-23.5) and 10.9 (95%CI: 3.7-32.3), respectively. CONCLUSION: This study confirms that change of partner raises the risk for preeclampsia in subsequent pregnancies. Immune maladaptation on the fetal maternal interface could be an underlying mechanism. Multiparous women with a new partner should be approached as being primigravid women.

Fetal plasma levels of cellular fibronectin as a measure of fetal endothelial involvement in preeclampsia.

OBJECTIVE: To determine the degree of fetal endothelial involvement in preeclampsia by measuring fetal plasma concentrations of cellular fibronectin. METHODS: In a prospective cohort study, fetal plasma was collected at delivery from the chorionic plate arteries and veins in a convenience sample of 28 pregnancies complicated by preeclampsia and in 28 normal pregnancies. Stored plasma was assayed for cellular fibronectin using a sensitive and specific enzyme immunoassay. On the basis of a desired power of 0.8, alpha of .05, and expected fetal plasma cellular fibronectin values of 4 +/- 2 micrograms/mL, 26 women were required in each group to detect a 40% difference between the groups. Results were compared using the unpaired Student t test, chi 2 analysis with Yates correction, and linear regression. RESULTS: There was no statistically significant difference in fetal plasma concentrations of cellular fibronectin in women with preeclampsia compared with normal pregnant women, either in arteries (3.2 +/- 1.1 and 2.9 +/- 1.5 micrograms/mL; P = .33) or veins (3.3 +/- 1.5 and 2.8 +/- 1.6 micrograms/mL; P = .18). Plasma cellular fibronectin concentrations in fetal arteries correlated significantly with those in fetal veins (r = 0.45, P < .001), but not with those in maternal veins (r = 0.15, P = .27). CONCLUSION: Fetal plasma cellular fibronectin concentrations are similar in preeclamptic and normal pregnancies. We found no evidence that factors responsible for maternal endothelial involvement in preeclampsia are operative in the fetal circulation.