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Identifying placental dysfunction in women with reduced fetal movements can be used to predict patients at increased risk of pregnancy complications
Medical Hypotheses 76 (2011) 17–20
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Identifying placental dysfunction in women with reduced fetal movements can be used to predict patients at increased risk of pregnancy complications Lynne K. Warrander, Alexander E.P. Heazell ⇑ Maternal and Fetal Health Research Centre, University of Manchester, St. Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK
a r t i c l e
i n f o
Article history: Received 25 May 2010 Accepted 13 August 2010
s u m m a r y Maternal perception of fetal movements has historically been used to indicate fetal wellbeing, and has been used with varying success in recent years to identify those pregnancies at increased risk of stillbirth, and other placental pathologies. We present a hypothesis that links reduced fetal movements (RFM) to fetal growth restriction (FGR) and stillbirth through placental dysfunction, and suggests the possibility that this can allow development of a reliable method to identify those women experiencing RFM who are at increased risk of adverse outcome. Reduced fetal movement is thought to represent fetal compensation in a chronic hypoxic environment due to inadequacies in the placental supply of oxygen and nutrients. Placental analysis in FGR and in stillbirth has revealed a number of structural abnormalities and an imbalance in cell turnover, and in terms of function, FGR is also associated with reduced nutrient transport. Both FGR and stillbirth are linked to changes in maternal levels of placental hormones. However, no such studies have been performed in samples from pregnancies affected by RFM. Currently, there are no formal guidelines to direct the management of such women, although it is recommended they undergo measurement of symphysis-fundal height and cardiotocography, and possibly Doppler ultrasound and biophysical profiling. Novel tests could involve the measurement of placental-derived hormones in maternal serum. To address this hypothesis, macroscopic and microscopic analysis of placental samples from both normal pregnancies and those affected by RFM is needed to detect any changes in structure. Placental function could be evaluated by levels of placental hormones in maternal blood. If placental dysfunction can be linked to RFM, and a robust method of identifying those women with placental insufficiency can be developed; screening patients with RFM could lead to a reduction in perinatal morbidity and mortality. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Stillbirth remains a significant problem in both the developed and developing world. In the UK, stillbirth affects approximately 1 in 200 pregnancies after 24 weeks gestation [1]. The most common single cause of stillbirth is fetal growth restriction (FGR), which describes a failure of fetal growth in utero [2]. Despite significant advances in obstetric care, including widespread use of ultrasound imaging, the incidence of stillbirth has not declined significantly in the UK in the last two decades [3]. This is in part due to the lack of sufficiently sensitive and specific tests to identify pregnancies at risk of stillbirth to promote timely intervention. One screening tool to identify pregnancies at risk of stillbirth that has shown varying popularity throughout the last 40 years is maternal awareness of reduced fetal movements (RFM). Maternal perception of fetal movements has been used as an indicator of fetal wellbeing for at least 500 years, being described in ‘‘The Byrth of Mankynde” by Thomas Raynalde in 1545. In con⇑ Corresponding author. Tel.: +44 0161 701 6968. E-mail address: [email protected] (A.E.P. Heazell). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.08.020
trast, a reduction in these perceived movements is associated with both pathological and non-pathological conditions [4]. Some of the most frequent and important adverse outcomes preceded by a period of RFM include fetal growth restriction (FGR) and stillbirth [5,6]. Studies from 1973–2006 described the incidence of small for gestational age infants or FGR in 1.5–45% of women presenting with RFM [5–15]. The risk of stillbirth in these studies is reported to be 2.4–50% of those presenting with RFM [5–15]. A more recent study in 2009 using customised birthweight centiles corrected for gestational age, ethnicity and parity found that 24% of infants were small for gestational age, defined as a birthweight <10th centile, and the risk of stillbirth was 1.5%; all of the stillbirths in this cohort study had severe FGR (birthweight <0.4th centile) [16]. Importantly, 72% of the cases of FGR were not identified before presentation for RFM. Therefore, RFM may be a clinical sign that can alert clinicians to pregnancy at increased risk of complications. Given the increased risk of stillbirth and FGR, women presenting with RFM require further assessment to identify any potential risk to their pregnancy. In a detailed investigation of antepartum stillbirths, the UK Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) found that 1 in 6 stillbirths were associated with
18
L.K. Warrander, A.E.P. Heazell / Medical Hypotheses 76 (2011) 17–20
a period of RFM [17], proposing that correct identification of RFM may provide a window of opportunity in which intervention could prevent stillbirth. However, a lack of guidelines in the UK to instruct the identification and management of women presenting with RFM has led to a wide variation in practice [18]. This study also found that clinicians’ knowledge of associations with RFM was variable, with over 30% of clinicians being unaware of the link between RFM, FGR, fetal hypoxia and stillbirth [18]. Currently, there is a lack of an accepted and coherent hypothesis to link maternal perception of RFM to increased FGR and stillbirth. The absence of such a premise leads to inappropriate investigations which have insufficient sensitivity and specificity to predict and prevent stillbirth in this high risk group [19]. Here we present a hypothesis that links RFM to FGR and stillbirth through placental dysfunction. This understanding may also lead to the development of a reliable method of identifying women who are at an increased risk of adverse outcome, potentially in the form of ultrasound scanning or novel blood tests for placentallyderived factors.
Fig. 1). Initially, the fetus adapts to nutrient and oxygen deprivation by reducing growth rate, conserving cerebral development at the expense of subcutaneous fat deposition, the so-called brainsparing effect. Following prolonged chronic hypoxia or a profound acute insult, e.g. feto-maternal haemorrhage, the fetus reduces its activity, allowing it to conserve energy and lessen oxygen consumption [21]. This proposal is supported by data indicating that fetuses with RFM prior to planned Caesarean section were hypoxaemic and acidaemic compared to women feeling normal fetal movements [22] and fetuses with FGR have fewer movements detected by ultrasound than normal fetuses [6]. The underlying cause for such nutrient and oxygen restriction in FGR is placental insufficiency – an inability of the placenta to meet the metabolic demands of the fetus. Whether similar placental insufficiency occurs with RFM in infants of any birthweight has not yet been investigated, but would account for the association between RFM and stillbirth.
Hypothesis
Investigation of the placenta in pregnancies complicated by FGR has revealed changes in structure and function compared to normal pregnancies. Although there have been fewer studies of placental changes in stillbirth, a number of histological changes have been identified.
It is hypothesised that RFM is a sign of underlying placental insufficiency and that pregnancies at greatest risk of complications may be detected by investigation of altered placental structure or function. Proposed pathophysiology of RFM Fetal movements are generally noted from around 20 weeks gestation, although they diminish in magnitude but not frequency during the third trimester as the fetus increases in size [20]. A pathological reduction in the frequency of movement is thought to be a late reaction of the fetus to chronic hypoxia (described in
Fig. 1. The proposed fetal response to stress which results in RFM (shown in capitals) (adapted from Maulik, D (Ed.), Doppler ultrasound in obstetrics and gynaecology, 1997;349, New York: Springer-Verlag).
Placental abnormalities in FGR and stillbirth
Changes in placental structure in FGR and stillbirth The human placenta is comprised of a villous tree, centred around fetal blood vessels. The terminal villi are regarded as the functional exchange units, in a similar manner to the terminal alveoli in the lung. In FGR, it has been found that the terminal villi have a different structure to those seen in normal pregnancies. They are smaller in diameter and display reduced vascularisation and branching, with increased collagen deposition in the stroma and a thicker basal lamina [23]. Similarly, placental examination following stillbirth has revealed reduced vascularity of the terminal villi, and increased fibrin deposition [24]. The terminal villi are covered in a multinucleate cell layer, termed syncytiotrophoblast which is responsible for nutrient transport, immune modulation and hormone synthesis throughout pregnancy. The syncytiotrophoblast is maintained by continual proliferation, differentiation and fusion of underlying cytotrophoblast cells [25]. In FGR, placental samples show an increased rate of apoptosis, a form of programmed cell death [26,27] and increased formation of syncytial knots, aggregates of syncytial nuclei, believed to represent the end point of nuclear degeneration [28]. This is accompanied by a reduction in proliferation, impairing renewal of the syncytiotrophoblast [29]. This imbalance in placental cell turnover contributes to a reduction in the surface area available for nutrient exchange and a reduction in placental function which hence leads to FGR, and if prolonged and severe, to stillbirth. In stillbirth, placental lesions include infarction, decreased villous vascularity, perivillous fibrin deposition and leukocyte infiltration, with infarction most closely associated with FGR [24,30]. Fetal vascular thrombosis is associated with abnormalities of the umbilical cord. From these studies there is clear evidence for the interruption of maternal-fetal exchange in the aetiology of stillbirth. Interestingly, Parast et al. found that non-acute cord compression has a role in over half of currently unexplained fetal deaths, suggesting that chronic placental insufficiency has an important role in stillbirth [31]. It is in these pregnancies that mothers may notice RFM. Altered placental function in FGR Birthweight reflects the ability of the placenta to transfer nutrients from mother to fetus during gestation [32]. There is reduced
L.K. Warrander, A.E.P. Heazell / Medical Hypotheses 76 (2011) 17–20
placental amino acid transport in FGR, particularly, system A amino acid transporter activity [33]. The placental syncytiotrophoblast secretes many hormones necessary for the maintenance of pregnancy. In FGR, placental hormone release is altered. Expression of human placental lactogen (hPL) is increased in FGR placental samples at term, compared to normal [34], whereas human placental growth hormone (hPGH) is downregulated in small for gestational age pregnancies [35,36]. To summarise, in this hypothesis, abnormalities of placental structure, nutrient transport and hormonal function lead to placental insufficiency, where the placenta cannot transfer sufficient oxygen and nutrients to the developing fetus. The fetus adapts to cope with oxygen and nutrient restriction initially by restricting its growth, then by directing blood away from non-essential organs, then restricting its activity, and finally when the fetus decompensates there are abnormalities of the fetal heart rate, and ultimately death.
RFM, placental insufficiency and stillbirth Stillbirth can be attributed to a range of causes, including congenital abnormality to maternal infection [37] and feto-maternal haemorrhage [38]. However, the single largest cause relates to abnormal placental function, particularly in currently ‘‘unexplained” stillbirths, where over half have been shown to have FGR or have chronic fetal vascular insufficiency [39]. This suggests that FGR and placental insufficiency are key risk factors for stillbirth. Therefore, stillbirth is likely to share similar placental abnormalities to those that are seen in FGR or chronic vascular insufficiency. This is consistent with our hypothesis that RFM is associated with FGR and stillbirth through placental pathology. If placental abnormalities are a common feature linking RFM with FGR and stillbirth, identifying women with abnormal placental structure or function should highlight their high risk status, which could be delivered to reduce perinatal morbidity and mortality. However, this poses a challenge in terms of finding a sufficiently specific and sensitive method of identifying placental dysfunction antenatally. Currently, structural placental abnormalities in the circumstances described here have been found on close examination of the placenta in RFM [40]. Potential methods to identify placental dysfunction include conventional tests such as ultrasound measurement of fetal growth and liquor volume (to assess nutrient transfer to the fetus), and measurement of umbilical artery Doppler (to measure blood flow through the cord). Novel tests include measurement of placental shape and size or, placental hormones or metabolites in the maternal circulation.
Current tests after RFM International guidelines recommend that women experiencing RFM are assessed by measurement of symphysiofundal height and assessment of the fetal heart rate by cardiotocography (CTG). Further investigations are usually based on the results of these tests, but can include ultrasound biophysical profile (incorporating assessment of fetal movements, breathing and tone, heart rate reactivity and amniotic fluid volume) or umbilical artery Doppler [6,18,21]. These investigations aim to exclude immediate fetal compromise and FGR. Oligohydraminos (a reduction of fluid around the baby), a recognised indicator of placental insufficiency [41]. However, none of these investigations has sufficient sensitivity or specificity to detect pregnancies most at risk of complications, with sensitivity varying from 4–33.3% and specificity from 91.3–98% [6,13]. This lack of efficacy may be attributed to the indirect measurement of placental insufficiency. To date there have
19
been no studies which assess placental appearance to detect placental insufficiency in utero after RFM.
Novel tests for placental dysfunction after RFM Direct tests for placental dysfunction could involve the measurement of placenta-derived factors in maternal blood. As placental dysfunction originates in early pregnancy, investigators have measured placental factors such as pregnancy-associated plasma protein A (PAPP-A) and placental protein-13 (PP-13) to identify women who are at increased risk of adverse pregnancy outcome [42–45]. Low levels of pregnancy-associated plasma protein A (PAPP-A) during the first trimester are associated with an increased risk of FGR and stillbirth [42]. This association was strongest for stillbirth due to placental dysfunction (placental abruption or unexplained stillbirth associated with growth restriction), and a level in the lowest 5th centile corresponded to a 46fold increase in the risk of stillbirth due to placental dysfunction [43]. Combining PAPP-A measurements with a-fetoprotein (AFP) was shown to be a potential method for identifying those women at increased risk of adverse perinatal outcome [46]. Reduced first trimester levels of PP-13 were significantly associated with FGR and pre-term delivery [45]. The use of placenta-derived factors to detect placental dysfunction is supported by in vitro studies that demonstrate altered release of lactate dehydrogenase (LDH), human chorionic gonadotrophin (hCG) and PP-13 in low hypoxic environments [47].
Testing this hypothesis To address this hypothesis placental insufficiency needs to be proven in RFM, and similar pathology to that seen in FGR and stillbirth identified. Placental dysfunction could also be detected by measuring placentally-derived hormones and metabolites in maternal blood. To correlate changes in hormones and metabolites in maternal serum to changes occurring in the placenta, the transcription and translation of placental hormones should be analysed in the same patients as those giving serum samples. The levels of these placental factors could then be correlated with perinatal outcome to determine if any of these hormonal markers are capable of identifying those women with placental insufficiency.
Conclusion Awareness of RFM could be used to decrease perinatal mortality, particularly in cases of stillbirth secondary to placental dysfunction. This hypothesis merits further investigation for a number of reasons. Firstly, it will determine whether RFM is associated with placental abnormalities and this would indicate if women experiencing RFM should be identified as high risk. Secondly, it may reveal a placental marker that could be used in the subsequent management of these women to ascertain who is at a higher risk of adverse outcome, and therefore who should receive closer monitoring or be delivered. Finally, by using RFM as a screening test to identify those women at increased risk of adverse outcome due to placental dysfunction, and subsequently closely monitoring them throughout pregnancy, a reduction in perinatal mortality could be achieved.
Conflicts of interest statement None declared.
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Acknowledgements Dr. Alexander Heazell holds a grant from the Manchester Wellcome Trust Clinical Research Facility to recruit patients to a cohort study investigating tests to predict poor pregnancy outcome in women presenting with reduced fetal movements. The sponsors of the research had no input in the production of this manuscript. LW is supported by a studentship from Wolfson foundation. References [1] Confidential Enquiry into Maternal and Child Health, Perinatal Mortality 2007: England, Wales and Northern Ireland. 2009, Confidential Enquiry into Maternal and Child Health: London. [2] Gardosi J et al. Classification of stillbirth by relevant condition at death (ReCoDe): population based cohort study. BMJ 2005;331(7525):1113–7. [3] CEMACH. Confidential Enquiry into Maternal and Child Health (CEMACH) Perinatal Mortality 2007. London: CEMACH; 2009. [4] Heazell AE, Froen JF. Methods of fetal movement counting and the detection of fetal compromise. J Obstet Gynaecol 2008;28(2):147–54. [5] Sadovsky E, Yaffe H. Daily fetal movement recording and fetal prognosis. Obstet Gynecol 1973;41(6):845–50. [6] Heazell AE, Sumathi GM, Bhatti NR. What investigation is appropriate following maternal perception of reduced fetal movements? J Obstet Gynaecol 2005;25(7):648–50. [7] Pearson JF, Weaver JB. Fetal activity and fetal wellbeing: an evaluation. Br Med J 1976;1(6021):1305–7. [8] Ehrstrom C. Fetal movement monitoring in normal and high-risk pregnancy. Acta Obstet Gynecol Scand Suppl 1979;80:1–32. [9] Fischer S, Fullerton JT, Trezise L. Fetal movement and fetal outcome in a lowrisk population. J Nurse Midwifery 1981;26(1):24–30. [10] Rayburn WF. Clinical implications from monitoring fetal activity. Am J Obstet Gynecol 1982;144(8):967–80. [11] Valentin L, Marsal K. Fetal movement in the third trimester of normal pregnancy. Early Hum Dev 1986;14(3–4):295–306. [12] Whitty JE, Garfinkel DA, Divon MY. Maternal perception of decreased fetal movement as an indication for antepartum testing in a low-risk population. Am J Obstet Gynecol 1991;165(4 Pt 1):1084–8. [13] Dubiel M et al. Doppler velocimetry and nonstress test for predicting outcome of pregnancies with decreased fetal movements. Am J Perinatol 1997;14(3):139–44. [14] Sergent F et al. Decreased fetal movements in the third trimester: what to do? Gynecol Obstet Fertil 2005;33(11):861–9. [15] Tveit JV et al. Reduction of late stillbirth with the introduction of fetal movement information and guidelines – a clinical quality improvement. BMC Pregnancy Childbirth 2009;9:32. [16] O’Sullivan O et al. Predicting poor perinatal outcome in women who present with decreased fetal movements. J Obstet Gynaecol 2009;29(8):705–10. [17] Confidential, et al. Eighth Annual Report. London: Maternal and Child Health Research Consortium; 2001. [18] Heazell AE et al. Midwives’ and obstetricians’ knowledge and management of women presenting with decreased fetal movements. Acta Obstet Gynecol Scand 2008;87(3):331–9. [19] Froen JF et al. Management of decreased fetal movements. Semin Perinatol 2008;32(4):307–11. [20] Mangesi L, Hofmeyr GJ. Fetal movement counting for assessment of fetal wellbeing. Cochrane Database Syst Rev 2007(1):CD004909. [21] Unterscheider J et al. Reduced fetal movements. Obstetrician Gynaecol 2009;11(4):245–51. [22] Vintzileos AM et al. Relationship between fetal biophysical activities and umbilical cord blood gas values. Am J Obstet Gynecol 1991;165(3):707–13.
[23] Macara L et al. Structural analysis of placental terminal villi from growthrestricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 1996;17(1):37–48. [24] Heazell AE, Martindale EA. Can post-mortem examination of the placenta help determine the cause of stillbirth? J Obstet Gynaecol 2009;29(3):225–8. [25] Huppertz B. The anatomy of the normal placenta. J Clin Pathol 2008;61(12):1296–302. [26] Smith SC, Baker PN, Symonds EM. Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 1997;177(6):1395–401. [27] Levy R et al. Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol 2002;186(5):1056–61. [28] Scifres CM, Nelson DM. Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol 2009;587(Pt 14):3453–8. [29] Chen C-P, Bajoria R, Aplin JD. Decreased vascularization and cell proliferation in placentas of intrauterine growth-restricted fetuses with abnormal umbilical artery flow velocity waveforms. Am J Obstet Gynecol 2002;187(3):764–9. [30] Kidron D, Bernheim J, Aviram R. Placental findings contributing to fetal death, a study of 120 stillbirths between 23 and 40 weeks gestation. Placenta 2009;30(8):700–4. [31] Parast MM, Crum CP, Boyd TK. Placental histologic criteria for umbilical blood flow restriction in unexplained stillbirth. Hum Pathol 2008;39(6):948–53. [32] Sibley CP. Understanding placental nutrient transfer – why bother? New biomarkers of fetal growth. J Physiol 2009;587(Pt 14):3431–40. [33] Dicke JM, Henderson GI. Placental amino acid uptake in normal and complicated pregnancies. Am J Med Sci 1988;295(3):223–7. [34] Sheikh S, Satoskar P, Bhartiya D. Expression of insulin-like growth factor-I and placental growth hormone mRNA in placentae: a comparison between normal and intrauterine growth retardation pregnancies. Mol Hum Reprod 2001;7(3):287–92. [35] Barrio E et al. Study of apoptosis and related proteins, CRH and hpGH in placentas of newborns small for gestational age (SGA). Pediatr Endocrinol Rev 2009;6(Suppl 3):337–42. [36] Shokry M et al. Maternal serum placental growth factor and soluble FMS-like tyrosine kinase 1 as early predictors of preeclampsia. Acta Obstet Gynecol Scand 2010;89(1):143–6. [37] Smith GC, Fretts RC. Stillbirth. Lancet 2007;370(9600):1715–25. [38] Giacoia GP. Severe fetomaternal hemorrhage: a review. Obstet Gynecol Surv 1997;52(6):372–80. [39] Froen JF. A kick from within-fetal movement counting and the cancelled progress in antenatal care. J Perinat Med 2004;32(1):13–24. [40] Heazell AE, et al. Placental size is reduced and placental infarction and syncytial knots are increased in pregnancies complicated by decreased fetal movements. Placenta 2010; 31(suppl.), in press. [41] Chamberlain PF et al. Ultrasound evaluation of amniotic fluid volume. I. The relationship of marginal and decreased amniotic fluid volumes to perinatal outcome. Am J Obstet Gynecol 1984;150(3):245–9. [42] Smith GC et al. Early pregnancy levels of pregnancy-associated plasma protein a and the risk of intrauterine growth restriction, premature birth, preeclampsia, and stillbirth. J Clin Endocrinol Metab 2002;87(4):1762–7. [43] Smith GC et al. First-trimester placentation and the risk of antepartum stillbirth. JAMA 2004;292(18):2249–54. [44] Smith GC et al. Pregnancy-associated plasma protein A and alpha-fetoprotein and prediction of adverse perinatal outcome. Obstet Gynecol 2006;107(1):161–6. [45] Chafetz I et al. First-trimester placental protein 13 screening for preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol 2007;197(1):35. e17. [46] Smith GC. Predicting antepartum stillbirth. Curr Opin Obstet Gynecol 2006;18(6):625–30. [47] Heazell AE et al. Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. Placenta 2008;29(2):175–86.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Identifying placental dysfunction in women with reduced fetal movements can be used to predict patients at increased risk of pregnancy complications Lynne K. Warrander, Alexander E.P. Heazell ⇑ Maternal and Fetal Health Research Centre, University of Manchester, St. Mary’s Hospital, Oxford Road, Manchester, M13 9WL, UK
a r t i c l e
i n f o
Article history: Received 25 May 2010 Accepted 13 August 2010
s u m m a r y Maternal perception of fetal movements has historically been used to indicate fetal wellbeing, and has been used with varying success in recent years to identify those pregnancies at increased risk of stillbirth, and other placental pathologies. We present a hypothesis that links reduced fetal movements (RFM) to fetal growth restriction (FGR) and stillbirth through placental dysfunction, and suggests the possibility that this can allow development of a reliable method to identify those women experiencing RFM who are at increased risk of adverse outcome. Reduced fetal movement is thought to represent fetal compensation in a chronic hypoxic environment due to inadequacies in the placental supply of oxygen and nutrients. Placental analysis in FGR and in stillbirth has revealed a number of structural abnormalities and an imbalance in cell turnover, and in terms of function, FGR is also associated with reduced nutrient transport. Both FGR and stillbirth are linked to changes in maternal levels of placental hormones. However, no such studies have been performed in samples from pregnancies affected by RFM. Currently, there are no formal guidelines to direct the management of such women, although it is recommended they undergo measurement of symphysis-fundal height and cardiotocography, and possibly Doppler ultrasound and biophysical profiling. Novel tests could involve the measurement of placental-derived hormones in maternal serum. To address this hypothesis, macroscopic and microscopic analysis of placental samples from both normal pregnancies and those affected by RFM is needed to detect any changes in structure. Placental function could be evaluated by levels of placental hormones in maternal blood. If placental dysfunction can be linked to RFM, and a robust method of identifying those women with placental insufficiency can be developed; screening patients with RFM could lead to a reduction in perinatal morbidity and mortality. Ó 2010 Elsevier Ltd. All rights reserved.
Introduction Stillbirth remains a significant problem in both the developed and developing world. In the UK, stillbirth affects approximately 1 in 200 pregnancies after 24 weeks gestation [1]. The most common single cause of stillbirth is fetal growth restriction (FGR), which describes a failure of fetal growth in utero [2]. Despite significant advances in obstetric care, including widespread use of ultrasound imaging, the incidence of stillbirth has not declined significantly in the UK in the last two decades [3]. This is in part due to the lack of sufficiently sensitive and specific tests to identify pregnancies at risk of stillbirth to promote timely intervention. One screening tool to identify pregnancies at risk of stillbirth that has shown varying popularity throughout the last 40 years is maternal awareness of reduced fetal movements (RFM). Maternal perception of fetal movements has been used as an indicator of fetal wellbeing for at least 500 years, being described in ‘‘The Byrth of Mankynde” by Thomas Raynalde in 1545. In con⇑ Corresponding author. Tel.: +44 0161 701 6968. E-mail address: [email protected] (A.E.P. Heazell). 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.08.020
trast, a reduction in these perceived movements is associated with both pathological and non-pathological conditions [4]. Some of the most frequent and important adverse outcomes preceded by a period of RFM include fetal growth restriction (FGR) and stillbirth [5,6]. Studies from 1973–2006 described the incidence of small for gestational age infants or FGR in 1.5–45% of women presenting with RFM [5–15]. The risk of stillbirth in these studies is reported to be 2.4–50% of those presenting with RFM [5–15]. A more recent study in 2009 using customised birthweight centiles corrected for gestational age, ethnicity and parity found that 24% of infants were small for gestational age, defined as a birthweight <10th centile, and the risk of stillbirth was 1.5%; all of the stillbirths in this cohort study had severe FGR (birthweight <0.4th centile) [16]. Importantly, 72% of the cases of FGR were not identified before presentation for RFM. Therefore, RFM may be a clinical sign that can alert clinicians to pregnancy at increased risk of complications. Given the increased risk of stillbirth and FGR, women presenting with RFM require further assessment to identify any potential risk to their pregnancy. In a detailed investigation of antepartum stillbirths, the UK Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) found that 1 in 6 stillbirths were associated with
18
L.K. Warrander, A.E.P. Heazell / Medical Hypotheses 76 (2011) 17–20
a period of RFM [17], proposing that correct identification of RFM may provide a window of opportunity in which intervention could prevent stillbirth. However, a lack of guidelines in the UK to instruct the identification and management of women presenting with RFM has led to a wide variation in practice [18]. This study also found that clinicians’ knowledge of associations with RFM was variable, with over 30% of clinicians being unaware of the link between RFM, FGR, fetal hypoxia and stillbirth [18]. Currently, there is a lack of an accepted and coherent hypothesis to link maternal perception of RFM to increased FGR and stillbirth. The absence of such a premise leads to inappropriate investigations which have insufficient sensitivity and specificity to predict and prevent stillbirth in this high risk group [19]. Here we present a hypothesis that links RFM to FGR and stillbirth through placental dysfunction. This understanding may also lead to the development of a reliable method of identifying women who are at an increased risk of adverse outcome, potentially in the form of ultrasound scanning or novel blood tests for placentallyderived factors.
Fig. 1). Initially, the fetus adapts to nutrient and oxygen deprivation by reducing growth rate, conserving cerebral development at the expense of subcutaneous fat deposition, the so-called brainsparing effect. Following prolonged chronic hypoxia or a profound acute insult, e.g. feto-maternal haemorrhage, the fetus reduces its activity, allowing it to conserve energy and lessen oxygen consumption [21]. This proposal is supported by data indicating that fetuses with RFM prior to planned Caesarean section were hypoxaemic and acidaemic compared to women feeling normal fetal movements [22] and fetuses with FGR have fewer movements detected by ultrasound than normal fetuses [6]. The underlying cause for such nutrient and oxygen restriction in FGR is placental insufficiency – an inability of the placenta to meet the metabolic demands of the fetus. Whether similar placental insufficiency occurs with RFM in infants of any birthweight has not yet been investigated, but would account for the association between RFM and stillbirth.
Hypothesis
Investigation of the placenta in pregnancies complicated by FGR has revealed changes in structure and function compared to normal pregnancies. Although there have been fewer studies of placental changes in stillbirth, a number of histological changes have been identified.
It is hypothesised that RFM is a sign of underlying placental insufficiency and that pregnancies at greatest risk of complications may be detected by investigation of altered placental structure or function. Proposed pathophysiology of RFM Fetal movements are generally noted from around 20 weeks gestation, although they diminish in magnitude but not frequency during the third trimester as the fetus increases in size [20]. A pathological reduction in the frequency of movement is thought to be a late reaction of the fetus to chronic hypoxia (described in
Fig. 1. The proposed fetal response to stress which results in RFM (shown in capitals) (adapted from Maulik, D (Ed.), Doppler ultrasound in obstetrics and gynaecology, 1997;349, New York: Springer-Verlag).
Placental abnormalities in FGR and stillbirth
Changes in placental structure in FGR and stillbirth The human placenta is comprised of a villous tree, centred around fetal blood vessels. The terminal villi are regarded as the functional exchange units, in a similar manner to the terminal alveoli in the lung. In FGR, it has been found that the terminal villi have a different structure to those seen in normal pregnancies. They are smaller in diameter and display reduced vascularisation and branching, with increased collagen deposition in the stroma and a thicker basal lamina [23]. Similarly, placental examination following stillbirth has revealed reduced vascularity of the terminal villi, and increased fibrin deposition [24]. The terminal villi are covered in a multinucleate cell layer, termed syncytiotrophoblast which is responsible for nutrient transport, immune modulation and hormone synthesis throughout pregnancy. The syncytiotrophoblast is maintained by continual proliferation, differentiation and fusion of underlying cytotrophoblast cells [25]. In FGR, placental samples show an increased rate of apoptosis, a form of programmed cell death [26,27] and increased formation of syncytial knots, aggregates of syncytial nuclei, believed to represent the end point of nuclear degeneration [28]. This is accompanied by a reduction in proliferation, impairing renewal of the syncytiotrophoblast [29]. This imbalance in placental cell turnover contributes to a reduction in the surface area available for nutrient exchange and a reduction in placental function which hence leads to FGR, and if prolonged and severe, to stillbirth. In stillbirth, placental lesions include infarction, decreased villous vascularity, perivillous fibrin deposition and leukocyte infiltration, with infarction most closely associated with FGR [24,30]. Fetal vascular thrombosis is associated with abnormalities of the umbilical cord. From these studies there is clear evidence for the interruption of maternal-fetal exchange in the aetiology of stillbirth. Interestingly, Parast et al. found that non-acute cord compression has a role in over half of currently unexplained fetal deaths, suggesting that chronic placental insufficiency has an important role in stillbirth [31]. It is in these pregnancies that mothers may notice RFM. Altered placental function in FGR Birthweight reflects the ability of the placenta to transfer nutrients from mother to fetus during gestation [32]. There is reduced
L.K. Warrander, A.E.P. Heazell / Medical Hypotheses 76 (2011) 17–20
placental amino acid transport in FGR, particularly, system A amino acid transporter activity [33]. The placental syncytiotrophoblast secretes many hormones necessary for the maintenance of pregnancy. In FGR, placental hormone release is altered. Expression of human placental lactogen (hPL) is increased in FGR placental samples at term, compared to normal [34], whereas human placental growth hormone (hPGH) is downregulated in small for gestational age pregnancies [35,36]. To summarise, in this hypothesis, abnormalities of placental structure, nutrient transport and hormonal function lead to placental insufficiency, where the placenta cannot transfer sufficient oxygen and nutrients to the developing fetus. The fetus adapts to cope with oxygen and nutrient restriction initially by restricting its growth, then by directing blood away from non-essential organs, then restricting its activity, and finally when the fetus decompensates there are abnormalities of the fetal heart rate, and ultimately death.
RFM, placental insufficiency and stillbirth Stillbirth can be attributed to a range of causes, including congenital abnormality to maternal infection [37] and feto-maternal haemorrhage [38]. However, the single largest cause relates to abnormal placental function, particularly in currently ‘‘unexplained” stillbirths, where over half have been shown to have FGR or have chronic fetal vascular insufficiency [39]. This suggests that FGR and placental insufficiency are key risk factors for stillbirth. Therefore, stillbirth is likely to share similar placental abnormalities to those that are seen in FGR or chronic vascular insufficiency. This is consistent with our hypothesis that RFM is associated with FGR and stillbirth through placental pathology. If placental abnormalities are a common feature linking RFM with FGR and stillbirth, identifying women with abnormal placental structure or function should highlight their high risk status, which could be delivered to reduce perinatal morbidity and mortality. However, this poses a challenge in terms of finding a sufficiently specific and sensitive method of identifying placental dysfunction antenatally. Currently, structural placental abnormalities in the circumstances described here have been found on close examination of the placenta in RFM [40]. Potential methods to identify placental dysfunction include conventional tests such as ultrasound measurement of fetal growth and liquor volume (to assess nutrient transfer to the fetus), and measurement of umbilical artery Doppler (to measure blood flow through the cord). Novel tests include measurement of placental shape and size or, placental hormones or metabolites in the maternal circulation.
Current tests after RFM International guidelines recommend that women experiencing RFM are assessed by measurement of symphysiofundal height and assessment of the fetal heart rate by cardiotocography (CTG). Further investigations are usually based on the results of these tests, but can include ultrasound biophysical profile (incorporating assessment of fetal movements, breathing and tone, heart rate reactivity and amniotic fluid volume) or umbilical artery Doppler [6,18,21]. These investigations aim to exclude immediate fetal compromise and FGR. Oligohydraminos (a reduction of fluid around the baby), a recognised indicator of placental insufficiency [41]. However, none of these investigations has sufficient sensitivity or specificity to detect pregnancies most at risk of complications, with sensitivity varying from 4–33.3% and specificity from 91.3–98% [6,13]. This lack of efficacy may be attributed to the indirect measurement of placental insufficiency. To date there have
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been no studies which assess placental appearance to detect placental insufficiency in utero after RFM.
Novel tests for placental dysfunction after RFM Direct tests for placental dysfunction could involve the measurement of placenta-derived factors in maternal blood. As placental dysfunction originates in early pregnancy, investigators have measured placental factors such as pregnancy-associated plasma protein A (PAPP-A) and placental protein-13 (PP-13) to identify women who are at increased risk of adverse pregnancy outcome [42–45]. Low levels of pregnancy-associated plasma protein A (PAPP-A) during the first trimester are associated with an increased risk of FGR and stillbirth [42]. This association was strongest for stillbirth due to placental dysfunction (placental abruption or unexplained stillbirth associated with growth restriction), and a level in the lowest 5th centile corresponded to a 46fold increase in the risk of stillbirth due to placental dysfunction [43]. Combining PAPP-A measurements with a-fetoprotein (AFP) was shown to be a potential method for identifying those women at increased risk of adverse perinatal outcome [46]. Reduced first trimester levels of PP-13 were significantly associated with FGR and pre-term delivery [45]. The use of placenta-derived factors to detect placental dysfunction is supported by in vitro studies that demonstrate altered release of lactate dehydrogenase (LDH), human chorionic gonadotrophin (hCG) and PP-13 in low hypoxic environments [47].
Testing this hypothesis To address this hypothesis placental insufficiency needs to be proven in RFM, and similar pathology to that seen in FGR and stillbirth identified. Placental dysfunction could also be detected by measuring placentally-derived hormones and metabolites in maternal blood. To correlate changes in hormones and metabolites in maternal serum to changes occurring in the placenta, the transcription and translation of placental hormones should be analysed in the same patients as those giving serum samples. The levels of these placental factors could then be correlated with perinatal outcome to determine if any of these hormonal markers are capable of identifying those women with placental insufficiency.
Conclusion Awareness of RFM could be used to decrease perinatal mortality, particularly in cases of stillbirth secondary to placental dysfunction. This hypothesis merits further investigation for a number of reasons. Firstly, it will determine whether RFM is associated with placental abnormalities and this would indicate if women experiencing RFM should be identified as high risk. Secondly, it may reveal a placental marker that could be used in the subsequent management of these women to ascertain who is at a higher risk of adverse outcome, and therefore who should receive closer monitoring or be delivered. Finally, by using RFM as a screening test to identify those women at increased risk of adverse outcome due to placental dysfunction, and subsequently closely monitoring them throughout pregnancy, a reduction in perinatal mortality could be achieved.
Conflicts of interest statement None declared.
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