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Preterm pre-eclampsia: What every neonatologist should know
Early Human Development 114 (2017) 26–30
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Review
Preterm pre-eclampsia: What every neonatologist should know Lisa Story a b
a,b
, Lucy C. Chappell
MARK
b,⁎
Centre for the Developing Brain, Faculty of Life Sciences and Medicine, King's College London, SE1 7EH, United Kingdom Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London SE1 7EH, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Keywords: Pre-eclampsia Hypertension Pregnancy Fetal growth restriction
Although pre-eclampsia affects 5–10% of pregnancies globally and is responsible for substantial maternal and perinatal morbidity and mortality, currently there is no cure other than delivery of the baby. Predictive screening tests based on clinical risk factors, with or without the addition of biomarkers and imaging, have been developed, but adoption into clinical practice is limited by suboptimal test performance. Once established preeclampsia is diagnosed, a woman is usually managed expectantly prior to 37 weeks' gestation to reduce perinatal morbidity and mortality associated with iatrogenic prematurity until maternal or fetal triggers for delivery mean that risks of pregnancy prolongation outweigh the benefits. Associated fetal growth restriction is a common feature of pre-eclampsia, particularly with early-onset disease, and will influence decisions for delivery and subsequent neonatal course. Prematurity and fetal growth restriction both have potential short and long-term consequences for the infant and child.
1. Introduction The decision for iatrogenic preterm delivery of a baby is never straightforward. Prematurity can be associated with considerable mortality and morbidity involving multiple organ systems particularly at gestations prior to 32 weeks. Very preterm birth is associated with an increased incidence of multisystem pathology encompassing bronchopulmonary dysplasia, neurodevelopmental sequelae including cerebral palsy and gastrointestinal disorders such as necrotizing enterocolitis [1]. However, where there are substantial concerns regarding the maternal or fetal condition, these risks may be outweighed by the immediate threat to the life of the mother or baby and preterm delivery becomes unavoidable. Pre-eclampsia is a pregnancy-specific, multisystem syndrome that can pose such a clinical dilemma, as delivery of the fetus and placenta is currently the only definitive treatment. The condition is characterised by new onset hypertension in the mother (defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg) after 20 weeks' gestation together with other features of maternal disease (proteinuria, thrombocytopenia, deranged liver or renal function, pulmonary oedema or cerebral complications) or fetal growth restriction [2]. Maternal and fetal manifestations represent a clinical spectrum ranging from mild hypertension and proteinuria in the mother with an appropriately grown fetus near term to early-onset disease causing severe complications including eclampsia and pulmonary oedema in the mother and severe growth restriction in the fetus. ⁎
If disease onset is early, expectant management with careful control of blood pressure and monitoring of fetal wellbeing is possible but iatrogenic preterm delivery is still often warranted. Prolongation of the pregnancy at early gestations is purely to confer benefit for the fetus and reduce complications associated with prematurity as definitive treatment remains delivery of the baby. This review discusses the implications of pre-eclampsia from the perspective of the health of the fetus, with regards to prevention, management and long-term consequences. 2. Pathophysiology Although extensive research into the pathophysiology of preeclampsia has been undertaken, the exact mechanisms remain uncertain and are likely to be multifactorial. Pre-eclampsia is usually characterised by abnormal placentation. In normal pregnancy, the villous cytotrophoblast invades into the inner third of the myometrium and the maternal spiral arteries are converted into low resistance vessels by loss of their endothelium and muscle fibres. In pre-eclampsia, the invasion of cytotrophoblast cells into the maternal spiral arteries does not occur to the same extent. Hypo-perfusion of the fetoplacental unit and associated hypoxia results in the release of reactive oxygen species and cytokines from the placenta that lead to endothelial dysfunction and inflammation, together with the downstream clinical manifestations of the disease which usually become apparent in the third (or less frequently the late second) trimester.
Corresponding author at: Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London SE1 7EH, United Kingdom. E-mail addresses: [email protected] (L. Story), [email protected] (L.C. Chappell).
http://dx.doi.org/10.1016/j.earlhumdev.2017.09.010
0378-3782/ © 2017 Elsevier B.V. All rights reserved.
Early Human Development 114 (2017) 26–30
L. Story, L.C. Chappell
maternal vasculature, particularly uterine artery Doppler flow velocity waveforms. Over 70 risk prediction models have been published and systematically reviewed, but internal and external validations of these models have been limited, hampering demonstration of adequate performance sufficient for recommendation into clinical practice by a national guideline body. This largely reflects the challenge of predicting a disease as heterogeneous as described above; screening tests have better performance for early onset pre-eclampsia with associated fetal growth restriction, where placentation is impaired, abnormal placental biomarkers and/or flow velocity waveforms to the placenta can be identified and the interval between a screening test (e.g. at 12 or 22 weeks of pregnancy) and onset of the disease is short. Prediction of late onset pre-eclampsia (e.g. developing after 37 weeks' gestation) remains elusive. Screening tests that incorporate serum biomarkers such as placental growth factor, pregnancy associated plasma protein A (PAPP-A), uterine artery pulsatility index and multiple maternal clinical risk factors have reported detection rates of 54% for all pre-eclampsia cases, and 96% of those requiring delivery before 34 weeks' gestation [7]. This screening algorithm has been validated by the same group in other populations [8,9] but test performance has often diminished when applied by other researchers into different populations (reviewed by Kane [10]) usually due to overfitting of the model highlighting discrepancies between the cohort in whom the model was developed and the ‘real-world’ environment. Although a comparison of clinical risk factors and multi-parameter screening tests has reported enhanced performance of the latter, identifying 75% of women with pre-eclampsia requiring delivery before 37 weeks (compared to 39% with clinical risk factors alone) [11], adoption by national screening committees has not yet occurred in the UK or the US, particularly related to concern over the high false-positive rate associated with such screening tests.
Alterations in both innate and adaptive immune processes may also be implicated in the pathophysiology of the disease and a genetic predisposition to pre-eclampsia may result from polymorphisms in genes such as those encoding inflammatory modulators which are activated by placental insufficiency or hypoxia resulting in alteration of transcriptional function of downstream cytokines or anti-angiogenic proteins [3]. Research over recent decades has characterised an imbalance of circulating angiogenic and antiangiogenic factors [4] including increased concentrations of anti-angiogenic proteins soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased concentrations of the pro-angiogenic vascular endothelial growth factor and placental growth factor (PlGF). It remains unclear the extent to which this imbalance is a cause or consequence of the rest of the disease process [3]. 3. Risk factors and screening for pre-eclampsia Although there is a good understanding of the risk factors for preeclampsia, this has not yet translated into a widely adopted screening test, as these currently have limited performance for introduction into clinical practice. For the neonatologist, this is relevant for two reasons as it provides an understanding of the possible comorbidities associated with the disease, and an appreciation of why introduction of a screening test has been elusive. A recent systematic review and meta-analysis of early pregnancy clinical risk factors reported that those most strongly associated with a high rate of pre-eclampsia include antiphospholipid antibody syndrome (pooled incidence 17.3%, 95% confidence interval 6.8% to 31.4%), chronic hypertension (16.0%, 12.6% to 19.7%), prior pre-eclampsia (12.0%, 10.4% to 13.7%) and pre-gestational diabetes (11.0%, 8.4% to 13.8%. [5] However, the population attributable fraction (i.e. the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to ideal) showed that different risk factors contributed most: nulliparity (32.3%, 27.4% to 37.0%), pre-pregnancy body mass index > 25 (23.8%, 22.0% to 25.6%) and prior pre-eclampsia (22.8%, 19.6% to 26.3%). These need to be interpreted, though, in the light of those risk factors that are modifiable (e.g. raised body mass index) and those that are not (e.g. nulliparity). A woman with pre-eclampsia may have one of a number of comorbidities that are relevant to the fetus and newborn (e.g. diabetes) and that in addition, these may make identification of complications such as fetal growth restriction more challenging if the co-existent diseases drive fetal growth in opposing directions. Identification of these risk factors has informed current screening within the National Institute for Health and Care Excellence guidelines [6] for management of Hypertension in Pregnancy (Table 1). However, the recognition that screening through clinical risk factors alone is imperfect has led other groups to explore the incorporation of additional biomarker-based tests and/or sonographic imaging of the
4. Prevention of pre-eclampsia The main purpose of screening is to enable prophylactic treatment to be given (either in clinical practice or within a research setting), and/ or appropriate surveillance for higher-risk women. Development of preventative treatments has continued over recent decades. The only treatment with a high-quality evidence base for demonstrating benefit is the administration of low-dose aspirin from the second trimester. One of its proposed mechanisms of action is by inhibition of thromboxane A2 synthesis (increased in women who develop pre-eclampsia) resulting in vasodilation and improved blood flow and implantation. In individual patient data meta-analyses, low dose aspirin has been shown to have a moderate effect in reducing the relative risk (0.90 95% CI 0.84–0.97) of pre-eclampsia [12]. More recently, work has indicated a dose-response relationship up to 150 mg of aspirin, with higher doses potentially conferring increased benefit for early onset disease [13]. The recent ASPRE trial confirmed that this higher dose of aspirin was associated with a marked reduction in preterm pre-eclampsia (odds ratio 0.38; 95% CI 0.20 to 0.74) [9] but concerns have been expressed over remaining uncertainty over the effect on perinatal and other safety outcomes. Other innovative therapies are currently being evaluated, based on the pathophysiological pathways identified in pre-eclampsia, including alpha-1-microglobulin, recombinant antithrombin, angiogenic factors and proton pump inhibitors [14]; although several are being trialled, none are close to introduction to routine clinical practice. The challenges of drug development in pregnancy including regulatory hurdles have been detailed elsewhere [15] and continue to present a major obstacle to the introduction of novel prophylactic treatments.
Table 1 Screening for pre-eclampsia based on clinical risk factors [22]. Risk factor One or more risk factors present
Two or more risk factors present
Chronic kidney disease Autoimmune disease Type 1 or type 2 diabetes Chronic hypertension Hypertensive disease during a previous pregnancy First pregnancy Age ≥ 40 years Pregnancy interval > 10 years BMI ≥ 35 kg/m2 Family history of pre-eclampsia Multi-fetal (e.g. twin) pregnancy
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of the circulation or ‘brain sparing’, whereby blood is diverted preferentially to supply essential organs such as the brain and heart often at the expense of organs such as the kidney, gastrointestinal tract and the lower limbs, where vasoconstriction is assumed to occur. Consequently, ultrasound assessment of fetal growth may indicate a reduction in abdominal circumference and femur length with relative conservation of head growth. Estimation of fetal weight using biometry is routinely used for counselling women and planning care; for women with an estimated fetal weight < 500 g and/or a gestational age prior to 24 weeks' gestation, counselling should be undertaken by experienced obstetricians and neonatologists to provide realistic estimations of prognosis. More detailed clinical assessment of the fetal state encompasses Doppler velocimetry of three fetal vessels: the umbilical and middle cerebral arteries and the ductus venosus to provide information on downstream peripheral vascular impedance of the placenta. There is a strong correlation between absent or reversed end diastolic flow in the umbilical artery and poor perinatal outcome [22]. The middle cerebral arteries are used to assess the extent of redistribution of the circulation within the fetus. When brain sparing occurs there is a reduction in cerebral flow resistance, reflected by a reduction in the Doppler indices of the middle cerebral arteries. In severe and terminal cases of fetal growth restriction, this adaptive mechanism is lost and normalisation of these parameters occurs. When the compensatory mechanisms of arterial blood flow redistribution have occurred, and it is no longer possible to maintain oxygen delivery to the myocardium, characteristic changes in the venous flow velocity waveforms occur, including loss of the a-wave in the ductus venosus and pulsatility in the umbilical vein.
5. Management of established pre-eclampsia and its complications 5.1. Management of maternal hypertension Delivery of the fetus is the only cure for pre-eclampsia but blood pressure control is the mainstay of maternal treatment. Although it does not modify the disease process, adequate blood pressure control is imperative to reduce risk of maternal cerebrovascular events, known to be associated with increasing systolic hypertension (particularly above 160 mm Hg) and may facilitate prolongation of the pregnancy to viable gestations in early onset disease. The exact thresholds at which to instigate antihypertensive therapy are uncertain; concerns have previously been raised that tight control may compromise the uteroplacental circulation and hence adversely affect fetal growth. The CHIPS trial, however, reported that treating women with pregnancy hypertension to a target of tight control (diastolic blood pressure of 85 mm Hg) compared to less tight control (diastolic blood pressure of 100 mm Hg) resulted in no difference in the primary perinatal outcome (pregnancy loss or high-level neonatal care for > 48 h during the first 28 postnatal days) but resulted in a lower incidence of maternal hypertension [16]. Commonly used antihypertensive agents include labetalol (a combined alpha and beta blocker), nifedipine (a calcium channel blocker) and methyldopa (a competitive inhibitor of aromatic L-amino acid decarboxylase and an alpha-2-adrenergic receptor agonist). The choice, formulation and administration of antihypertensive agent may affect fetal and neonatal parameters. Although results of studies have been conflicting, beta-blockers (including labetalol) have been associated with neonatal hypoglycaemia and bradycardia in a large cohort of 2,292,116 completed pregnancies even after controlling for confounders [17]. The use of atenolol, in particular, has been associated with fetal growth restriction [18] and is now rarely used. Only labetalol has a license for use in pregnancy in the UK, but nifedipine and methyldopa are also widely used for treating hypertension in pregnancy and are considered to have minimal fetal or neonatal side-effects. Fetal bradycardia can result from rapid decreases in maternal blood pressure and care should be taken to avoid this. Although some studies have reported that methyldopa affects fetal heart rate characteristics (typically showing reduced baseline variability), a systematic review in 2004 of commonly used oral antihypertensives in pregnancy concluded that there were inadequate data to assess whether methyldopa, nifedipine or labetalol affected the fetal or neonatal heart rate [19].
5.4. Intrauterine death Fetal growth restriction is a common feature of early-onset preeclampsia and is associated with a 15-fold increased risk of intrauterine death [23], related to the severity of the Doppler velocimety abnormalities [24] and independent of gestational age [25]. 5.5. Placental abruption Women with pre-eclampsia are also at increased risk of placental abruption, occurring when there is premature separation of the placenta. It is likely that a shared pathophysiological mechanism, uteroplacental ischaemia, is responsible for this association. Placental abruption, independent of pre-eclampsia, can be responsible for preterm birth but it may also be an indication for iatrogenic preterm delivery as a significant placental abruption can result in catastrophic maternal haemorrhage. Although published data are limited, a study of 29 neonates delivered following a placental abruption (median gestation of 29 weeks), reported a 10-fold increased risk of cystic periventricular leukomalacia [26] and severe abruption has also been found to increase the risk of cerebral palsy [27].
5.2. Perinatal therapies to improve neonatal outcome Pre-eclampsia is often associated with iatrogenic preterm delivery for maternal or fetal indications; once diagnosed, antenatal therapies to improve neonatal outcomes are limited. Steroids such as dexamethasone or betamethasone cross the placenta and decrease the incidence of respiratory distress syndrome, intraventricular haemorrhage and necrotizing enterocolitis, having their maximum effect between 24 h and seven days [20] and are routinely administered when delivery is anticipated between 23 and 34 completed weeks of gestation. In addition, magnesium sulfate was found to improve neurodevelopmental sequelae in preterm infants, following subgroup analysis of women receiving magnesium sulfate as part of treatment protocols for severe pre-eclampsia. This was further investigated with three randomised controlled trials (ACTOMgSO4, PREMAG and BEAM); results pooled in a number of meta-analyses found that magnesium sulfate reduced the incidence of cerebral palsy and gross motor dysfunction [21].
6. Timing of delivery The only cure for pre-eclampsia is delivery. When disease onset is early, prolongation of the pregnancy is usually attempted in order to avoid neonatal deaths or long-term complications from prematurity. Current national guidance recommends expediting delivery once 37 weeks' gestation is reached [6], following the results of HYPITAT-1, a multicentre randomised trial that demonstrated improved maternal outcomes compared to expectant management, with no difference in neonatal outcomes [28]. Between 34 and 37 weeks the optimal timing of delivery is uncertain and the benefit and risks of pregnancy prolongation versus immediate delivery are not well defined [29]. This uncertainty is being addressed by the PHOENIX trial in the UK, in which 900 women with
5.3. Fetal growth restriction Traditionally it has been reported that the fetal circulation responds to hypoxemia associated with suboptimal placentation by centralisation 28
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abnormal umbilical artery Doppler or middle cerebral artery Doppler delivery should be no later than 37 weeks' gestation [33].
late pre-term pre-eclampsia are being enrolled into a randomised controlled trial of planned delivery vs. expectant management (ISRCTN01879376), with both maternal and perinatal outcomes being considered. Prior to 34 weeks' gestation an expectant approach is recommended for women with early onset pre-eclampsia as a systematic review has found this to be associated with reduced neonatal morbidity (intraventricular haemorrhage, hyaline membrane disease) and decreased neonatal intensive care admission and length of stay [30]. Whilst gestation is the primary determinant of plans for delivery or expectant management, there are maternal and fetal indications for delivery prior to 37 weeks' gestation as continuation of the pregnancy is considered to have greater risks than the benefit afforded to the fetus of prolonging gestation [28].
7. Mode of delivery For many women with pre-eclampsia, particularly at later gestations, planned vaginal delivery by induction of labour is the usual option if there is no urgent indication for delivery or significant fetal compromise. However, Caesarean section as a mode of delivery becomes more likely with decreasing gestation and presence of fetal growth restriction, and often reflects the background readiness of that maternity setting to perform operative deliveries. A recent trial of timing of delivery in the Netherlands reported Caesarean section rates around 30% in women with pre-eclampsia between 34 and 37 weeks gestation [34], whilst a retrospective cohort study of women with mild and superimposed pre-eclampsia from the US found Caesarean section rates of 61% and 80% respectively [35]. The presence of fetal growth restriction increases this likelihood: the TRUFFLE study reported Caesarean section rates of 97% [32]. A retrospective cohort study described the success of induction of labour in 491 women with severe early-onset pre-eclampsia and reported vaginal delivery rates of 6.7%, 47.5% and 68.8% for women delivering at 24–28 weeks, 28–32 and 32–34 weeks of pregnancy respectively regardless of suspected fetal growth restriction [36]. They concluded that induction was not associated with an increase in neonatal morbidity or mortality rate after controlling for gestational age and other confounders and it can thus be considered as an option for appropriate women. The Royal College of Obstetricians and Gynaecologists' guidelines for the diagnosis and management of small for gestational age fetuses recommends delivery by Caesarean section with absent or reversed end diastolic flow on umbilical artery Doppler velocimetry. If the Dopplers are normal or have raised pulsatility index, induction of labour can be considered with continuous fetal heart rate monitoring advised [33].
6.1. Maternal indications The maternal manifestations of the disease reflect the multi-system heterogeneous disorder, but are variable with regards to timing, severity and progression of its features. Maternal indications for delivery include - Uncontrolled blood pressure despite appropriate antihypertensive agents (usually maximal dose of three agents) - Persistent deterioration in liver (rise in transaminases) or kidney (increase in creatinine) function or coagulation (decrease in platelet count) - Eclampsia - HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome - Other severe complications (e.g. cerebral haemorrhage, cortical blindness, pulmonary oedema, renal failure, hepatic rupture) - Placental abruption with maternal haemodynamic compromise 6.2. Fetal indications
8. Neonatal consequences of pre-eclampsia Fetal indications for delivery associated with pre-eclampsia are usually attributable to concomitant fetal growth restriction. Where early onset disease is present, there has been considerable uncertainty regarding the optimal timing of delivery. The use of Doppler velocimetry has been shown to be beneficial in improving perinatal outcomes in high-risk pregnancies. The ductus venosus is the most useful predictor of short-term adverse outcome, as its deterioration is late in disease progression. Abnormalities in the ductus venosus or pulsatility in the umbilical vein are considered sufficient to instigate delivery (after the completion of a course of steroids). Changes usually precede alterations in the fetal heart rate on cardiotocogram [31]. The TRUFFLE study demonstrated that there were no significant differences in the proportion of infants surviving without neuro-impairment whether women with early-onset fetal growth restriction were randomised to delivery being based either on abnormal short-term variation on cardiotocogram, early or late changes of the ductus venosus waveform. Perinatal death occurred in 8% of cases and 70% survived without severe neonatal morbidity. Death and severe morbidity were significantly related to gestational age and the concomitant diagnosis of maternal hypertension as this shortened the interval from antenatal diagnosis of fetal growth restriction to delivery [32]. Current guidelines from the Royal College of Obstetricians and Gynaecologists advise that in the presence of fetal growth restriction, prior to 32 weeks, venous changes should trigger delivery, provided the fetus is viable and after completion of steroids. Even when the venous Doppler waveforms are normal, delivery is recommended by 32 weeks' gestation in the presence of reversed or absent end diastolic flow in the umbilical artery, and should be considered from 30 weeks. If fetal growth restriction is detected after 32 weeks' gestation with an
8.1. Consequences of preterm growth restriction Preterm growth restricted neonates face an increased risk of multiple complications: intracranial haemorrhage, sepsis, necrotising enterocolitis and respiratory distress syndrome, hypoglycaemia and polycythaemia compared with appropriately grown preterm neonates [37]. A meta-analysis assessed short-term neonatal outcomes associated with fetal growth restriction, reporting that for all perinatal outcomes the risk of adverse events decreased as gestation increased. Table 2 shows the increased risk compared with appropriately grown fetuses at comparable gestations [37]. Neonatal thrombocytopaenia has an also been reported to have an increased incidence in babies of women with pre-eclampsia, and is usually identified within the first three days of delivery with resolution by day 10 [38], but the exact pathogenesis for this finding is uncertain. 8.2. Long term health consequences Although the association between pre-eclampsia and long-term maternal cardiovascular and metabolic disease in later life is well documented, associated aberrant placentation can also have a significant impact on the long-term health of the child. Many studies evaluating long-term child health outcomes have focussed on the outcomes of pre-eclampsia associated with fetal growth restriction. Children of women with pre-eclampsia are at increased risk of high blood pressure, stroke, cognitive delay and depression [3]. This may be related to the malnourished fetus being programmed to exhibit a thrifty phenotype with increased fat deposition and possibly decreased energy 29
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Table 2 Predicted risk of outcomes with 95% confidence intervals for complications associated with fetal growth restriction (FGR) in comparison with appropriately grown neonates (AGA), stratified for gestation. All comparisons were statistically significant: p < 0.01 in all cases. Table adapted from Damodaram et al. [37]. Complication
Neonatal death Intracranial haemorrhage Necrotising enterocolitis Respiratory complications
24–28 weeks
28–32 weeks
32–37 weeks
FGR
AGA
FGR
AGA
FGR
AGA
21.8% (19.7–24) 32% (29.5–34.6) 20.5% (18.1–23.1) 75.6% (71.7–79.2)
6.1% (5.8–6.3) 19.6% (19.1–20.2) 8.1% (7.7–8.5) 41.3% (40.6–42)
15.5% (13.6–17.4) 14.8% (12.9–16.7) 11.6% (9.7–13.7) 53.4% (49.0–57.7)
2.8% (2.7–2.9) 6.2% (6.1–6.4) 2.8% (2.7–2.9) 20.0% (19.7–20.2)
9.5% (8.0–11.1) 2.1% (1.4–3.0) 4.1% (3.0–5.5) 26.7% (23.0–30.6)
0.6% (0.5–0.7) 0% (0.0–0.0) 0.1% (0.0–0.1) 3.5% (3.3–3.6)
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Broekhuijsen, G.J. van Baaren, M.G. van Pampus, et al., Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial, Lancet 385 (9986) (2015) 2492–2501. [35] A.M. Valent, E.A. DeFranco, A. Allison, et al., Expectant management of mild preeclampsia versus superimposed preeclampsia up to 37 weeks, Am. J. Obstet. Gynecol. 212 (4) (2015) 515 e1–8. [36] M.C. Alanis, C.J. Robinson, T.C. Hulsey, M. Ebeling, D.D. Johnson, Early-onset severe preeclampsia: induction of labor vs elective cesarean delivery and neonatal outcomes, Am. J. Obstet. Gynecol. 199 (3) (2008) 262 e1–6. [37] M. Damodaram, L. Story, E. Kulinskaya, M. Rutherford, S. Kumar, Early adverse perinatal complications in preterm growth-restricted fetuses, Aust. N. Z. J. Obstet. Gynaecol. 51 (3) (2011) 204–209. [38] R.F. Burrows, M. Andrew, Neonatal thrombocytopenia in the hypertensive disorders of pregnancy, Obstet. Gynecol. 76 (2) (1990) 234–238. [39] D.J. Barker, J.G. Eriksson, T. Forsen, C. Osmond, Fetal origins of adult disease: strength of effects and biological basis, Int. J. Epidemiol. 31 (6) (2002) 1235–1239.
output in later life. When calories become ample postnatally altered homeostatic mechanisms lead to manifestations of adult disease such as the metabolic syndrome [39]. 9. Conclusions Pre-eclampsia is a significant health burden and although maternal effects both during pregnancy and in the long term are well reported, the same underlying mechanisms of abnormal placentation can result in significant consequences for the baby both in utero and beyond. Currently the only cure is delivery but this needs to be carefully balanced with the risks of iatrogenic prematurity. Funding sources LS is supported by Tommy's Charity. LC is supported by a National Institute for Health Research Professorship. The views expressed in this publication are those of the author and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Conflict of interest statement Both authors declare no conflicts of interest. References [1] R.M. Ward, J.C. Beachy, Neonatal complications following preterm birth, BJOG 110 (Suppl. 20) (2003) 8–16. [2] A.L. Tranquilli, G. Dekker, L. Magee, et al., The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP, Pregnancy Hypertens. 4 (2) (2014) 97–104. [3] J. Hakim, M.K. Senterman, A.M. Hakim, Preeclampsia is a biomarker for vascular disease in both mother and child: the need for a medical alert system, Int. J. Pediatr. 2013 (2013) 953150. [4] R. Mustafa, S. Ahmed, A. Gupta, R.C. Venuto, A comprehensive review of hypertension in pregnancy, J. Pregnancy 2012 (2012) 105918. [5] E. Bartsch, K.E. Medcalf, A.L. Park, J.G. Ray, High risk of pre-eclampsia identification G. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies, BMJ 353 (2016) i1753. [6] National Institute for Health and Clinical Excellence, Hypertension in pregnancy: the management of hypertensive disorders during pregnancy, CG107, 2010. [7] R. Akolekar, A. Syngelaki, L. Poon, D. Wright, K.H. Nicolaides, Competing risks model in early screening for preeclampsia by biophysical and biochemical markers, Fetal Diagn. Ther. 33 (1) (2013) 8–15. [8] N. O'Gorman, D. Wright, L.C. Poon, et al., Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks' gestation, Ultrasound Obstet. Gynecol. 49 (6) (2017) 751–755. [9] D.L. Rolnik, D. Wright, L.C.Y. Poon, et al., ASPRE trial: performance of screening for preterm pre-eclampsia, Ultrasound Obstet. Gynecol. (Jul 25 2017), http://dx.doi.org/10. 1002/uog.18816 [Epub ahead of print]. [10] S.C. Kane, First trimester screening for pre-eclampsia, Obstet. Med. 9 (3) (2016) 106–112. [11] N. O'Gorman, D. Wright, L.C. Poon, et al., Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11–13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations, Ultrasound Obstet. Gynecol. 49 (6) (2017) 756–760. [12] L.M. Askie, L. Duley, D.J. Henderson-Smart, L.A. Stewart, Group PC, Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data, Lancet 369
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Contents lists available at ScienceDirect
Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Review
Preterm pre-eclampsia: What every neonatologist should know Lisa Story a b
a,b
, Lucy C. Chappell
MARK
b,⁎
Centre for the Developing Brain, Faculty of Life Sciences and Medicine, King's College London, SE1 7EH, United Kingdom Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London SE1 7EH, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Keywords: Pre-eclampsia Hypertension Pregnancy Fetal growth restriction
Although pre-eclampsia affects 5–10% of pregnancies globally and is responsible for substantial maternal and perinatal morbidity and mortality, currently there is no cure other than delivery of the baby. Predictive screening tests based on clinical risk factors, with or without the addition of biomarkers and imaging, have been developed, but adoption into clinical practice is limited by suboptimal test performance. Once established preeclampsia is diagnosed, a woman is usually managed expectantly prior to 37 weeks' gestation to reduce perinatal morbidity and mortality associated with iatrogenic prematurity until maternal or fetal triggers for delivery mean that risks of pregnancy prolongation outweigh the benefits. Associated fetal growth restriction is a common feature of pre-eclampsia, particularly with early-onset disease, and will influence decisions for delivery and subsequent neonatal course. Prematurity and fetal growth restriction both have potential short and long-term consequences for the infant and child.
1. Introduction The decision for iatrogenic preterm delivery of a baby is never straightforward. Prematurity can be associated with considerable mortality and morbidity involving multiple organ systems particularly at gestations prior to 32 weeks. Very preterm birth is associated with an increased incidence of multisystem pathology encompassing bronchopulmonary dysplasia, neurodevelopmental sequelae including cerebral palsy and gastrointestinal disorders such as necrotizing enterocolitis [1]. However, where there are substantial concerns regarding the maternal or fetal condition, these risks may be outweighed by the immediate threat to the life of the mother or baby and preterm delivery becomes unavoidable. Pre-eclampsia is a pregnancy-specific, multisystem syndrome that can pose such a clinical dilemma, as delivery of the fetus and placenta is currently the only definitive treatment. The condition is characterised by new onset hypertension in the mother (defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg) after 20 weeks' gestation together with other features of maternal disease (proteinuria, thrombocytopenia, deranged liver or renal function, pulmonary oedema or cerebral complications) or fetal growth restriction [2]. Maternal and fetal manifestations represent a clinical spectrum ranging from mild hypertension and proteinuria in the mother with an appropriately grown fetus near term to early-onset disease causing severe complications including eclampsia and pulmonary oedema in the mother and severe growth restriction in the fetus. ⁎
If disease onset is early, expectant management with careful control of blood pressure and monitoring of fetal wellbeing is possible but iatrogenic preterm delivery is still often warranted. Prolongation of the pregnancy at early gestations is purely to confer benefit for the fetus and reduce complications associated with prematurity as definitive treatment remains delivery of the baby. This review discusses the implications of pre-eclampsia from the perspective of the health of the fetus, with regards to prevention, management and long-term consequences. 2. Pathophysiology Although extensive research into the pathophysiology of preeclampsia has been undertaken, the exact mechanisms remain uncertain and are likely to be multifactorial. Pre-eclampsia is usually characterised by abnormal placentation. In normal pregnancy, the villous cytotrophoblast invades into the inner third of the myometrium and the maternal spiral arteries are converted into low resistance vessels by loss of their endothelium and muscle fibres. In pre-eclampsia, the invasion of cytotrophoblast cells into the maternal spiral arteries does not occur to the same extent. Hypo-perfusion of the fetoplacental unit and associated hypoxia results in the release of reactive oxygen species and cytokines from the placenta that lead to endothelial dysfunction and inflammation, together with the downstream clinical manifestations of the disease which usually become apparent in the third (or less frequently the late second) trimester.
Corresponding author at: Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London SE1 7EH, United Kingdom. E-mail addresses: [email protected] (L. Story), [email protected] (L.C. Chappell).
http://dx.doi.org/10.1016/j.earlhumdev.2017.09.010
0378-3782/ © 2017 Elsevier B.V. All rights reserved.
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maternal vasculature, particularly uterine artery Doppler flow velocity waveforms. Over 70 risk prediction models have been published and systematically reviewed, but internal and external validations of these models have been limited, hampering demonstration of adequate performance sufficient for recommendation into clinical practice by a national guideline body. This largely reflects the challenge of predicting a disease as heterogeneous as described above; screening tests have better performance for early onset pre-eclampsia with associated fetal growth restriction, where placentation is impaired, abnormal placental biomarkers and/or flow velocity waveforms to the placenta can be identified and the interval between a screening test (e.g. at 12 or 22 weeks of pregnancy) and onset of the disease is short. Prediction of late onset pre-eclampsia (e.g. developing after 37 weeks' gestation) remains elusive. Screening tests that incorporate serum biomarkers such as placental growth factor, pregnancy associated plasma protein A (PAPP-A), uterine artery pulsatility index and multiple maternal clinical risk factors have reported detection rates of 54% for all pre-eclampsia cases, and 96% of those requiring delivery before 34 weeks' gestation [7]. This screening algorithm has been validated by the same group in other populations [8,9] but test performance has often diminished when applied by other researchers into different populations (reviewed by Kane [10]) usually due to overfitting of the model highlighting discrepancies between the cohort in whom the model was developed and the ‘real-world’ environment. Although a comparison of clinical risk factors and multi-parameter screening tests has reported enhanced performance of the latter, identifying 75% of women with pre-eclampsia requiring delivery before 37 weeks (compared to 39% with clinical risk factors alone) [11], adoption by national screening committees has not yet occurred in the UK or the US, particularly related to concern over the high false-positive rate associated with such screening tests.
Alterations in both innate and adaptive immune processes may also be implicated in the pathophysiology of the disease and a genetic predisposition to pre-eclampsia may result from polymorphisms in genes such as those encoding inflammatory modulators which are activated by placental insufficiency or hypoxia resulting in alteration of transcriptional function of downstream cytokines or anti-angiogenic proteins [3]. Research over recent decades has characterised an imbalance of circulating angiogenic and antiangiogenic factors [4] including increased concentrations of anti-angiogenic proteins soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased concentrations of the pro-angiogenic vascular endothelial growth factor and placental growth factor (PlGF). It remains unclear the extent to which this imbalance is a cause or consequence of the rest of the disease process [3]. 3. Risk factors and screening for pre-eclampsia Although there is a good understanding of the risk factors for preeclampsia, this has not yet translated into a widely adopted screening test, as these currently have limited performance for introduction into clinical practice. For the neonatologist, this is relevant for two reasons as it provides an understanding of the possible comorbidities associated with the disease, and an appreciation of why introduction of a screening test has been elusive. A recent systematic review and meta-analysis of early pregnancy clinical risk factors reported that those most strongly associated with a high rate of pre-eclampsia include antiphospholipid antibody syndrome (pooled incidence 17.3%, 95% confidence interval 6.8% to 31.4%), chronic hypertension (16.0%, 12.6% to 19.7%), prior pre-eclampsia (12.0%, 10.4% to 13.7%) and pre-gestational diabetes (11.0%, 8.4% to 13.8%. [5] However, the population attributable fraction (i.e. the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to ideal) showed that different risk factors contributed most: nulliparity (32.3%, 27.4% to 37.0%), pre-pregnancy body mass index > 25 (23.8%, 22.0% to 25.6%) and prior pre-eclampsia (22.8%, 19.6% to 26.3%). These need to be interpreted, though, in the light of those risk factors that are modifiable (e.g. raised body mass index) and those that are not (e.g. nulliparity). A woman with pre-eclampsia may have one of a number of comorbidities that are relevant to the fetus and newborn (e.g. diabetes) and that in addition, these may make identification of complications such as fetal growth restriction more challenging if the co-existent diseases drive fetal growth in opposing directions. Identification of these risk factors has informed current screening within the National Institute for Health and Care Excellence guidelines [6] for management of Hypertension in Pregnancy (Table 1). However, the recognition that screening through clinical risk factors alone is imperfect has led other groups to explore the incorporation of additional biomarker-based tests and/or sonographic imaging of the
4. Prevention of pre-eclampsia The main purpose of screening is to enable prophylactic treatment to be given (either in clinical practice or within a research setting), and/ or appropriate surveillance for higher-risk women. Development of preventative treatments has continued over recent decades. The only treatment with a high-quality evidence base for demonstrating benefit is the administration of low-dose aspirin from the second trimester. One of its proposed mechanisms of action is by inhibition of thromboxane A2 synthesis (increased in women who develop pre-eclampsia) resulting in vasodilation and improved blood flow and implantation. In individual patient data meta-analyses, low dose aspirin has been shown to have a moderate effect in reducing the relative risk (0.90 95% CI 0.84–0.97) of pre-eclampsia [12]. More recently, work has indicated a dose-response relationship up to 150 mg of aspirin, with higher doses potentially conferring increased benefit for early onset disease [13]. The recent ASPRE trial confirmed that this higher dose of aspirin was associated with a marked reduction in preterm pre-eclampsia (odds ratio 0.38; 95% CI 0.20 to 0.74) [9] but concerns have been expressed over remaining uncertainty over the effect on perinatal and other safety outcomes. Other innovative therapies are currently being evaluated, based on the pathophysiological pathways identified in pre-eclampsia, including alpha-1-microglobulin, recombinant antithrombin, angiogenic factors and proton pump inhibitors [14]; although several are being trialled, none are close to introduction to routine clinical practice. The challenges of drug development in pregnancy including regulatory hurdles have been detailed elsewhere [15] and continue to present a major obstacle to the introduction of novel prophylactic treatments.
Table 1 Screening for pre-eclampsia based on clinical risk factors [22]. Risk factor One or more risk factors present
Two or more risk factors present
Chronic kidney disease Autoimmune disease Type 1 or type 2 diabetes Chronic hypertension Hypertensive disease during a previous pregnancy First pregnancy Age ≥ 40 years Pregnancy interval > 10 years BMI ≥ 35 kg/m2 Family history of pre-eclampsia Multi-fetal (e.g. twin) pregnancy
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of the circulation or ‘brain sparing’, whereby blood is diverted preferentially to supply essential organs such as the brain and heart often at the expense of organs such as the kidney, gastrointestinal tract and the lower limbs, where vasoconstriction is assumed to occur. Consequently, ultrasound assessment of fetal growth may indicate a reduction in abdominal circumference and femur length with relative conservation of head growth. Estimation of fetal weight using biometry is routinely used for counselling women and planning care; for women with an estimated fetal weight < 500 g and/or a gestational age prior to 24 weeks' gestation, counselling should be undertaken by experienced obstetricians and neonatologists to provide realistic estimations of prognosis. More detailed clinical assessment of the fetal state encompasses Doppler velocimetry of three fetal vessels: the umbilical and middle cerebral arteries and the ductus venosus to provide information on downstream peripheral vascular impedance of the placenta. There is a strong correlation between absent or reversed end diastolic flow in the umbilical artery and poor perinatal outcome [22]. The middle cerebral arteries are used to assess the extent of redistribution of the circulation within the fetus. When brain sparing occurs there is a reduction in cerebral flow resistance, reflected by a reduction in the Doppler indices of the middle cerebral arteries. In severe and terminal cases of fetal growth restriction, this adaptive mechanism is lost and normalisation of these parameters occurs. When the compensatory mechanisms of arterial blood flow redistribution have occurred, and it is no longer possible to maintain oxygen delivery to the myocardium, characteristic changes in the venous flow velocity waveforms occur, including loss of the a-wave in the ductus venosus and pulsatility in the umbilical vein.
5. Management of established pre-eclampsia and its complications 5.1. Management of maternal hypertension Delivery of the fetus is the only cure for pre-eclampsia but blood pressure control is the mainstay of maternal treatment. Although it does not modify the disease process, adequate blood pressure control is imperative to reduce risk of maternal cerebrovascular events, known to be associated with increasing systolic hypertension (particularly above 160 mm Hg) and may facilitate prolongation of the pregnancy to viable gestations in early onset disease. The exact thresholds at which to instigate antihypertensive therapy are uncertain; concerns have previously been raised that tight control may compromise the uteroplacental circulation and hence adversely affect fetal growth. The CHIPS trial, however, reported that treating women with pregnancy hypertension to a target of tight control (diastolic blood pressure of 85 mm Hg) compared to less tight control (diastolic blood pressure of 100 mm Hg) resulted in no difference in the primary perinatal outcome (pregnancy loss or high-level neonatal care for > 48 h during the first 28 postnatal days) but resulted in a lower incidence of maternal hypertension [16]. Commonly used antihypertensive agents include labetalol (a combined alpha and beta blocker), nifedipine (a calcium channel blocker) and methyldopa (a competitive inhibitor of aromatic L-amino acid decarboxylase and an alpha-2-adrenergic receptor agonist). The choice, formulation and administration of antihypertensive agent may affect fetal and neonatal parameters. Although results of studies have been conflicting, beta-blockers (including labetalol) have been associated with neonatal hypoglycaemia and bradycardia in a large cohort of 2,292,116 completed pregnancies even after controlling for confounders [17]. The use of atenolol, in particular, has been associated with fetal growth restriction [18] and is now rarely used. Only labetalol has a license for use in pregnancy in the UK, but nifedipine and methyldopa are also widely used for treating hypertension in pregnancy and are considered to have minimal fetal or neonatal side-effects. Fetal bradycardia can result from rapid decreases in maternal blood pressure and care should be taken to avoid this. Although some studies have reported that methyldopa affects fetal heart rate characteristics (typically showing reduced baseline variability), a systematic review in 2004 of commonly used oral antihypertensives in pregnancy concluded that there were inadequate data to assess whether methyldopa, nifedipine or labetalol affected the fetal or neonatal heart rate [19].
5.4. Intrauterine death Fetal growth restriction is a common feature of early-onset preeclampsia and is associated with a 15-fold increased risk of intrauterine death [23], related to the severity of the Doppler velocimety abnormalities [24] and independent of gestational age [25]. 5.5. Placental abruption Women with pre-eclampsia are also at increased risk of placental abruption, occurring when there is premature separation of the placenta. It is likely that a shared pathophysiological mechanism, uteroplacental ischaemia, is responsible for this association. Placental abruption, independent of pre-eclampsia, can be responsible for preterm birth but it may also be an indication for iatrogenic preterm delivery as a significant placental abruption can result in catastrophic maternal haemorrhage. Although published data are limited, a study of 29 neonates delivered following a placental abruption (median gestation of 29 weeks), reported a 10-fold increased risk of cystic periventricular leukomalacia [26] and severe abruption has also been found to increase the risk of cerebral palsy [27].
5.2. Perinatal therapies to improve neonatal outcome Pre-eclampsia is often associated with iatrogenic preterm delivery for maternal or fetal indications; once diagnosed, antenatal therapies to improve neonatal outcomes are limited. Steroids such as dexamethasone or betamethasone cross the placenta and decrease the incidence of respiratory distress syndrome, intraventricular haemorrhage and necrotizing enterocolitis, having their maximum effect between 24 h and seven days [20] and are routinely administered when delivery is anticipated between 23 and 34 completed weeks of gestation. In addition, magnesium sulfate was found to improve neurodevelopmental sequelae in preterm infants, following subgroup analysis of women receiving magnesium sulfate as part of treatment protocols for severe pre-eclampsia. This was further investigated with three randomised controlled trials (ACTOMgSO4, PREMAG and BEAM); results pooled in a number of meta-analyses found that magnesium sulfate reduced the incidence of cerebral palsy and gross motor dysfunction [21].
6. Timing of delivery The only cure for pre-eclampsia is delivery. When disease onset is early, prolongation of the pregnancy is usually attempted in order to avoid neonatal deaths or long-term complications from prematurity. Current national guidance recommends expediting delivery once 37 weeks' gestation is reached [6], following the results of HYPITAT-1, a multicentre randomised trial that demonstrated improved maternal outcomes compared to expectant management, with no difference in neonatal outcomes [28]. Between 34 and 37 weeks the optimal timing of delivery is uncertain and the benefit and risks of pregnancy prolongation versus immediate delivery are not well defined [29]. This uncertainty is being addressed by the PHOENIX trial in the UK, in which 900 women with
5.3. Fetal growth restriction Traditionally it has been reported that the fetal circulation responds to hypoxemia associated with suboptimal placentation by centralisation 28
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abnormal umbilical artery Doppler or middle cerebral artery Doppler delivery should be no later than 37 weeks' gestation [33].
late pre-term pre-eclampsia are being enrolled into a randomised controlled trial of planned delivery vs. expectant management (ISRCTN01879376), with both maternal and perinatal outcomes being considered. Prior to 34 weeks' gestation an expectant approach is recommended for women with early onset pre-eclampsia as a systematic review has found this to be associated with reduced neonatal morbidity (intraventricular haemorrhage, hyaline membrane disease) and decreased neonatal intensive care admission and length of stay [30]. Whilst gestation is the primary determinant of plans for delivery or expectant management, there are maternal and fetal indications for delivery prior to 37 weeks' gestation as continuation of the pregnancy is considered to have greater risks than the benefit afforded to the fetus of prolonging gestation [28].
7. Mode of delivery For many women with pre-eclampsia, particularly at later gestations, planned vaginal delivery by induction of labour is the usual option if there is no urgent indication for delivery or significant fetal compromise. However, Caesarean section as a mode of delivery becomes more likely with decreasing gestation and presence of fetal growth restriction, and often reflects the background readiness of that maternity setting to perform operative deliveries. A recent trial of timing of delivery in the Netherlands reported Caesarean section rates around 30% in women with pre-eclampsia between 34 and 37 weeks gestation [34], whilst a retrospective cohort study of women with mild and superimposed pre-eclampsia from the US found Caesarean section rates of 61% and 80% respectively [35]. The presence of fetal growth restriction increases this likelihood: the TRUFFLE study reported Caesarean section rates of 97% [32]. A retrospective cohort study described the success of induction of labour in 491 women with severe early-onset pre-eclampsia and reported vaginal delivery rates of 6.7%, 47.5% and 68.8% for women delivering at 24–28 weeks, 28–32 and 32–34 weeks of pregnancy respectively regardless of suspected fetal growth restriction [36]. They concluded that induction was not associated with an increase in neonatal morbidity or mortality rate after controlling for gestational age and other confounders and it can thus be considered as an option for appropriate women. The Royal College of Obstetricians and Gynaecologists' guidelines for the diagnosis and management of small for gestational age fetuses recommends delivery by Caesarean section with absent or reversed end diastolic flow on umbilical artery Doppler velocimetry. If the Dopplers are normal or have raised pulsatility index, induction of labour can be considered with continuous fetal heart rate monitoring advised [33].
6.1. Maternal indications The maternal manifestations of the disease reflect the multi-system heterogeneous disorder, but are variable with regards to timing, severity and progression of its features. Maternal indications for delivery include - Uncontrolled blood pressure despite appropriate antihypertensive agents (usually maximal dose of three agents) - Persistent deterioration in liver (rise in transaminases) or kidney (increase in creatinine) function or coagulation (decrease in platelet count) - Eclampsia - HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome - Other severe complications (e.g. cerebral haemorrhage, cortical blindness, pulmonary oedema, renal failure, hepatic rupture) - Placental abruption with maternal haemodynamic compromise 6.2. Fetal indications
8. Neonatal consequences of pre-eclampsia Fetal indications for delivery associated with pre-eclampsia are usually attributable to concomitant fetal growth restriction. Where early onset disease is present, there has been considerable uncertainty regarding the optimal timing of delivery. The use of Doppler velocimetry has been shown to be beneficial in improving perinatal outcomes in high-risk pregnancies. The ductus venosus is the most useful predictor of short-term adverse outcome, as its deterioration is late in disease progression. Abnormalities in the ductus venosus or pulsatility in the umbilical vein are considered sufficient to instigate delivery (after the completion of a course of steroids). Changes usually precede alterations in the fetal heart rate on cardiotocogram [31]. The TRUFFLE study demonstrated that there were no significant differences in the proportion of infants surviving without neuro-impairment whether women with early-onset fetal growth restriction were randomised to delivery being based either on abnormal short-term variation on cardiotocogram, early or late changes of the ductus venosus waveform. Perinatal death occurred in 8% of cases and 70% survived without severe neonatal morbidity. Death and severe morbidity were significantly related to gestational age and the concomitant diagnosis of maternal hypertension as this shortened the interval from antenatal diagnosis of fetal growth restriction to delivery [32]. Current guidelines from the Royal College of Obstetricians and Gynaecologists advise that in the presence of fetal growth restriction, prior to 32 weeks, venous changes should trigger delivery, provided the fetus is viable and after completion of steroids. Even when the venous Doppler waveforms are normal, delivery is recommended by 32 weeks' gestation in the presence of reversed or absent end diastolic flow in the umbilical artery, and should be considered from 30 weeks. If fetal growth restriction is detected after 32 weeks' gestation with an
8.1. Consequences of preterm growth restriction Preterm growth restricted neonates face an increased risk of multiple complications: intracranial haemorrhage, sepsis, necrotising enterocolitis and respiratory distress syndrome, hypoglycaemia and polycythaemia compared with appropriately grown preterm neonates [37]. A meta-analysis assessed short-term neonatal outcomes associated with fetal growth restriction, reporting that for all perinatal outcomes the risk of adverse events decreased as gestation increased. Table 2 shows the increased risk compared with appropriately grown fetuses at comparable gestations [37]. Neonatal thrombocytopaenia has an also been reported to have an increased incidence in babies of women with pre-eclampsia, and is usually identified within the first three days of delivery with resolution by day 10 [38], but the exact pathogenesis for this finding is uncertain. 8.2. Long term health consequences Although the association between pre-eclampsia and long-term maternal cardiovascular and metabolic disease in later life is well documented, associated aberrant placentation can also have a significant impact on the long-term health of the child. Many studies evaluating long-term child health outcomes have focussed on the outcomes of pre-eclampsia associated with fetal growth restriction. Children of women with pre-eclampsia are at increased risk of high blood pressure, stroke, cognitive delay and depression [3]. This may be related to the malnourished fetus being programmed to exhibit a thrifty phenotype with increased fat deposition and possibly decreased energy 29
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Table 2 Predicted risk of outcomes with 95% confidence intervals for complications associated with fetal growth restriction (FGR) in comparison with appropriately grown neonates (AGA), stratified for gestation. All comparisons were statistically significant: p < 0.01 in all cases. Table adapted from Damodaram et al. [37]. Complication
Neonatal death Intracranial haemorrhage Necrotising enterocolitis Respiratory complications
24–28 weeks
28–32 weeks
32–37 weeks
FGR
AGA
FGR
AGA
FGR
AGA
21.8% (19.7–24) 32% (29.5–34.6) 20.5% (18.1–23.1) 75.6% (71.7–79.2)
6.1% (5.8–6.3) 19.6% (19.1–20.2) 8.1% (7.7–8.5) 41.3% (40.6–42)
15.5% (13.6–17.4) 14.8% (12.9–16.7) 11.6% (9.7–13.7) 53.4% (49.0–57.7)
2.8% (2.7–2.9) 6.2% (6.1–6.4) 2.8% (2.7–2.9) 20.0% (19.7–20.2)
9.5% (8.0–11.1) 2.1% (1.4–3.0) 4.1% (3.0–5.5) 26.7% (23.0–30.6)
0.6% (0.5–0.7) 0% (0.0–0.0) 0.1% (0.0–0.1) 3.5% (3.3–3.6)
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