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The pre-eclampsia conundrum

The evidence that pre-eclampsia is not a single disease entity, but two different conditions with different times of onset, pathophysiology and maternal and fetal effects continues to accumulate. The early form, with onset before 34 weeks of gestation, is more severe and is associated with worse perinatal and maternal outcomes during the pregnancy. The risk of recurrence of early-onset pre-eclampsia in the next pregnancy is higher than with late-onset disease. Early-onset pre-eclampsia is also linked to an increased risk of longer-term maternal hypertension, heart disease and associated metabolic disturbances, including higher insulin levels and evidence of endothelial dysfunction, so it is quite possible that factors related to early-onset disease remain after the pregnancy is over. Even if hypertension does not occur in a future pregnancy, are there other adverse outcomes? A report in this issue asks what happens in women who have early-onset disease in later pregnancies that are not complicated by hypertension. In a population-based retrospective cohort study of 12 835 women Chang et al. page 946 report that in women who had early-onset pre-eclampsia (before 34 weeks of gestation) and who went on to have a normotensive second pregnancy, there was an increased incidence of small-for-gestational-age infants, preterm births, fetal death, caesarean section and placental abruption relative to women in their second pregnancy who had late-onset pre-eclampsia, after controlling for confounders. Women who had early-onset pre-eclampsia in the first pregnancy had more than twice the odds of fetal death in the next pregnancy compared with women who had late-onset pre-eclampsia in the first pregnancy. Early-onset pre-eclampsia in a first pregnancy increased the odds of placental abruption by 140% in a normotensive second pregnancy. Interestingly, in the second normotensive pregnancies of women with late-onset pre-eclampsia, the incidence of small-for-gestational-age babies was less than in those with early-onset pre-eclampsia (7.6% versus 14.1%) and the incidence of large-for-gestational-age babies was greater (12.6% versus 8.1%). This is entirely in keeping with the concept that late-onset pre-eclampsia is associated with normal or even accelerated fetal growth and normal placental function whereas in early-onset disease there is fetal growth restriction secondary to placental dysfunction. Regardless of the uncertainties about the mechanisms of these effects, women with previous early-onset pre-eclampsia clearly need careful monitoring throughout a subsequent pregnancy even if they remain normotensive throughout.

Guessing who will have a premature delivery

There is increasing evidence that multiple courses of antenatal steroids may have adverse effects on fetal growth (Murphy et al., Lancet 2008;372:2143–51; Wapner et al., N Engl J Med 2007;357:1190–8; Crowther et al., Cochrane Database Syst Rev 2007; issue 3) and some data suggest that even a single course of antenatal steroids may have harmful effects on insulin resistance in the offspring 30 years later (Dalziel et al., Lancet 2005;365(9474):1856–62). Deciding if a women who appears to be at risk of delivering significantly preterm (e.g. before 34 weeks of gestation) needs steroids is clearly crucial.

The difficulties in predicting preterm delivery using history and basic clinical examination alone are confirmed in the study of Mahony et al. page 963. in which neither fetal fibronectin nor transvaginal ultrasound estimation of closed cervical length was used to assist the decision as to whether to give steroids.

In this prospective cohort study of 414 women, 67% received antenatal corticosteroids. Among women delivering before 34 weeks of gestation only about two-thirds received a complete course of steroids. The ratio of women given a complete corticosteroid course to the number who delivered before 34 weeks was 15:1 in suspected preterm labour, 8:1 in antepartum haemorrhage, and 2:1 in preterm prelabour rupture of membranes and medically indicated preterm birth. If this reflects what happens on the average labour ward in the developed world then clearly a lot of steroids are being given unnecessarily.

The evidence for or against the use of fibronectin or cervical ultrasound for most important outcomes in symptomatic women remains inconclusive (Berghella et al., Cochrane Database Syst Rev 2008; Berghella et al., Cochrane Database Syst Rev 2009, issue 3) although using either or both methods has been advocated. Both are the subject of recently completed or ongoing trials, the results of which we await with interest.

Yet another reason to stop smoking in pregnancy?

The effects of smoking on pregnancy outcome are now well established, with an increased risk of a number of adverse outcomes, such as fetal growth restriction and preterm birth, with small decrements in academic performance of offspring that continue into adolescence. Smokers in general are more likely to experience deep vein thrombosis, stroke, pulmonary embolus, myocardial infarction, influenza, pneumonia and bronchitis, asthma, gastrointestinal ulcers and back pain. Can we now add pelvic pain in pregnancy to this long list? On page 1019 we publish the results of a nested case–control study from the Danish National Birth Cohort which suggest that self-reported pelvic pain is more common in smokers and most common in women who smoke the most. It is very difficult to disentangle lifestyle factors associated with smoking and heavy smoking, but the effect may be genuine and a manifestation of smoking-induced vasoconstriction and ischaemia.

Ovarian failure after uterine artery embolisation

There have been several reports of premature ovarian failure following uterine artery embolisation (UAE), with figures ranging between 1% and 14%. This variation may be partly because ovarian failure after UAE seems to be more common in women who are closest to the menopause.

This is a factor that Rashid et al. page 985 sought to investigate when they examined ovarian function and menstrual characteristics of women following UAE or surgery for the treatment of fibroids in a subgroup of 95 women from the REST trial (Randomised controlled trial comparing Embolisation to Surgery as a Treatment for fibroids. N Engl J Med 2007;356:360–70). Seventy-three women who had UAE and 23 women who had surgery with conservation of the ovaries had serum follicle-stimulating hormone measurements made before treatment and at 6 and 12 months. There was no significant difference in the rate of ovarian failure at 12 months between women undergoing UAE (11%) and those undergoing surgery (18%). In women aged under 45 years (48 subjects), in whom ovarian failure has the most relevant effect on fertility, two women in the UAE group showed signs of ovarian failure at 6 months and one women at 12 months. There was no evidence of ovarian failure in any woman under 45 years in the surgery group. These data indicate that women under 45 years old should be informed that there is about a 5% risk of ovarian failure and subsequent reduction in fertility following UAE for fibroids.

Obesity and depression

My late father always maintained that whatever changes happen in the population of the USA, the UK will follow a few years later. He was certainly right about obesity. The recent relentless rise of obesity in the UK mirrors the changes that have occurred in the USA over the last 25 years (http://www.nao.org.uk/publications/0001/tackling_obesity_in_england.aspx, http://www.cdc.gov/obesity/). Although there is some evidence that the rate of increase in obesity in the USA is slowing (Prevalence and Trends in Obesity Among US Adults, 1999–2008. JAMA 2010;303(3):235–41), there are no data to suggest that this is happening in the UK.

The prevalence of obesity in pregnancy in the UK has shown corresponding increases, rising from 9–10% in the early 1990s to 16–19% in the 2000s (Heslehurst et al., BJOG 2007;114(2):187–94; Kanagalingam et al., BJOG 2005;112(10):1431–3.) The recent publication by the Centre for Maternal and Child Enquiries/Royal College of Obstetricians and Gynaecologists (RCOG) Guidelines for the Management of Obesity is timely (http://www.rcog.org.uk/womens-health/clinical-guidance/management-women-obesity-pregnancy) and a National Institute for Clinical Excellence report is due to appear later this year. The RCOG report outlines measures to try and reduce the effects of the known serious problems associated with obesity in pregnancy, including thromboembolism, gestational diabetes, pre-eclampsia, dysfunctional labour, postpartum haemorrhage, wound infections, stillbirth and neonatal death. In this issue (LaCoursiere et al., page 1011) we present data that strengthen the argument that obesity is also associated with postpartum depression (PPD), and that this association is independent of the other obstetric adverse outcomes that can occur with obesity in pregnancy. In previous studies of this purported association crude measures of depressive symptoms were used, or samples were self-selected or small. In the present cohort study of 1053 women, all subjects were recruited immediately postpartum and screened for depression using the Edinburgh Postnatal Depression Scale 6–8 weeks later.

Among the women of normal weight, 14.4% screened positive, whereas the proportions for PPD in women with BMIs in the ranges 30–34.9 (n = 16), 35–39.9 (n = 11) and 40 (n = 8) or more were around 19%, 32% and 40%, respectively. After controlling for demographic, psychological and medical/obstetric factors the association between women with a BMI of 35–39.9 remained strongly associated with screening positive for PPD. It appears that a BMI above 35 is an important independent risk factor for PPD, with around a 30–40% risk. The association between obesity and depression in nonpregnant women is well established. What is not clear from this study or from other published data is what proportion of obese pregnant women has antenatal or pre-pregnancy depression, and what are the best time and method for screening women with a high BMI to allow timely and effective intervention. Failure to diagnose and treat such depression is likely to lead to impaired functioning in the mother and consequent behavioural and cognitive delays in her child.

Super-obesity and late-onset and early-onset pre-eclampsia

Moving up the weight divisions, super-obesity describes those with a BMI > 50. The prevalence in the USA seems to be rising faster than for lesser degrees of obesity and if interventions in the UK are unsuccessful then the UK can expect the same changes. Mbah et al., page 997 in a study of 854 085 singleton births, have examined the relationship between obesity, weight gain in pregnancy and late- and early-onset pre-eclampsia. This appears to be the first study to include significant numbers of women with super-obesity. Of the births, 21.4% were to obese women. 12.4% of the women had a BMI in the range 30–34.9, 5.5% had a BMI in the range 35–39.9, 3.1% in the range 40–49.9 and 0.4% were super-obese (n = 3001). When compared with women of normal weight, obese pregnant women had about a three-fold increased risk of pre-eclampsia even after adjusting for confounders, and the risk increased in a dose-dependent manner with increasing BMI. Super-obese women had the highest incidence at 13.4%. Weight gain in pregnancy was also important. The risk for pre-eclampsia in obese women with high weight gain compared with obese women with moderate weight gain was almost doubled, and super-obese women who gained the most weight during pregnancy were at the greatest risk of all groups. When the pre-eclampsia was subdivided into late-onset and early-onset the BMI/pre-eclampsia relationship was found in both types, but the increase in risk of pre-eclampsia with increasing BMI was more pronounced for the early-onset form. The management of the obese pregnant woman is clearly a great challenge. Perhaps the time has come to set the minimum standard of care for every maternity unit at a similar level to that which we already have for diabetes; an obstetrician who is the designated lead for their care.

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