Changes in maternal placental growth factor levels during term labour

Placenta 61 (2018) 11e16

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Changes in maternal placental growth factor levels during term labour Liam Dunn a, Christopher Flatley a, Sailesh Kumar a, b, * a b

Mater Research Institute e University of Queensland, Level 3 Aubigny Place, Raymond Terrace, South Brisbane, Queensland 4101, Australia School of Medicine, The University of Queensland, 288 Herston Road, Herston, Queensland 4006, Australia

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 September 2017 Received in revised form 1 November 2017 Accepted 6 November 2017

Placental growth factor (PlGF) has important angiogenic function that is critical to placental development. Lower levels of PlGF are associated with fetal growth restriction, pre-eclampsia and intrapartum fetal compromise. The aim of this study was to investigate the effect of labour on maternal PlGF levels. Method: This was a prospective observational cohort study. Normotensive women with a singleton, normally grown, non-anomalous, fetus between 37 þ 0 and 42 þ 0 weeks gestation were eligible for inclusion. PlGF was assayed at two time-points in labour. Women undergoing elective caesarean section served as controls. The primary outcome was the intrapartum change in maternal PlGF levels. Results: Fifty-nine labouring and 43 non-labouring participants were included. Median PlGF decreased from 105.5 pg/mL to 80.9 pg/mL during labour (-23.9%, p < 0.001). PlGF levels were significantly lower in the second stage of labour irrespective of onset of labour, parity, mode of birth or gestation 40 weeks. Compared to multiparous women, nulliparous women had significantly lower PlGF levels at both timepoints but had similar overall decline in PlGF. Women who required operative vaginal delivery or emergency caesarean section had lower median PlGF levels at both PlGF time-points and greater drop in PlGF during labour compared to spontaneous vaginal deliveries but these were not statistically significant. No correlation was observed between duration of labour and decline in PlGF levels. Conclusion: Overall, median PlGF levels fall by nearly one quarter during labour. This decline may reflect deteriorating placental function during labour. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Placental growth factor Placental function Labour Placental biomarker

1. Introduction For the majority of pregnancies, placental function is usually adequate to support fetal growth. During labour however, the fetoplacental relationship is tested to the highest degree when considerable haemodynamic changes occur in the uteroplacental circulation [1,2]. Intra-uterine pressures of just 35 mmHg during labour result in absent end-diastolic flow and a 60% reduction in perfusion in the uterine arteries [1,3]. Consequently, repetitive and sustained uterine contractions and uteroplacental vessel occlusions during parturition can lead to hypoxic-reperfusion injury [4] and oxidative stress in the placenta resulting in release of inflammatory cytokines and anti-angiogenic mediators [5e7]. Placental oxidative stress has been implicated in the aetiology of both early and late pregnancy complications including miscarriage [8], fetal growth

* Corresponding author. Mater Research Institute e University of Queensland, Level 3, Aubigny Place, Raymond Terrace, South Brisbane, Queensland 4101, Australia. E-mail address: [email protected] (S. Kumar). https://doi.org/10.1016/j.placenta.2017.11.003 0143-4004/© 2017 Elsevier Ltd. All rights reserved.

disorders [9,10] and pre-eclampsia [11]. During labour however, with the exception of rare catastrophic interruptions to the fetoplacental circulation from unpredictable events such as cord prolapse, placental abruption or uterine rupture, it is generally the gradual decline in placental function [5] and the eventual exhaustion of fetal physiological reserves that precipitates fetal compromise. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family and is highly expressed in trophoblasts [12]. It binds specifically to the receptor VEGFR-1 (Flt1) and it has a pivotal role in placental angiogenesis and vasodilatation [13]. PlGF levels are lower in pregnancies complicated by gestational hypertension [14,15], pre-eclampsia [16,17] and fetal growth restriction (FGR) [9,10,18] e conditions that share a common placental aetiology (i.e. defective trophoblast invasion) that leads to altered expression and aberrant release of proinflammatory and anti-angiogenic factors [10,19]. There is evidence to suggest that women with non-growth restricted, term fetuses that develop intrapartum fetal compromise (IFC) have lower median PLGF levels compared to those that have

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uncomplicated vaginal births [20]. Collectively these data suggest that low maternal PlGF levels are not only related to overt manifestations of abnormal placentation such as FGR and pre-eclampsia but also complications that occur when placental function is compromised more acutely during parturition. Given that labour has a substantial influence on placental perfusion, the aim of this study was to investigate the impact of labour at term on maternal PlGF levels. We hypothesised that maternal PlGF levels would decrease during labour reflecting the gradual deterioration in placental function.

2. Methods This was a prospective observational study conducted at Mater Mothers' Hospital, Brisbane, Australia between September 2015 and February 2017. Inclusion criteria were women 16 years of age with a singleton pregnancy at term (37þ0 to 42þ0 weeks) and an appropriately grown fetus (birthweight >10th centile for gestation [21]) with no known structural, chromosomal or genetic abnormality. Exclusion criteria were pre-eclampsia or gestational hypertension. As the aim of this study was to assess the impact of labour on maternal PlGF levels, women undergoing induction of labour (IOL) and those that spontaneously laboured were considered eligible. Participants satisfying the same inclusion criteria undergoing elective lower segment caesarean (ELCS) provided the control group. This study was assessed and approved by the Mater Health Services Human Research and Ethics Committee (HREC Ref: EC00332, Study Approval Ref: HREC/15/MHS/33). Gestational age was calculated based on a first trimester ultrasound scan. Two maternal venous blood samples were collected the first sample (1st PLGF) was collected prior to a diagnosis of established labour (<4 cm cervical dilatation) or at the commencement of induction of labour (artificial rupture of membranes and/or syntocinon infusion). The second sample (2nd PLGF) was collected once the second stage of labour was diagnosed or just prior to delivery of the baby if an emergency caesarean section (EMCS) was required. Women undergoing ELCS had a blood sample collected in the operating theatre when venous cannulation was performed by the anaesthetist. Each blood sample required one 8.5 mL serum separator tube (SST) and one 3.0 mL ethylene diamine tetra-acetic acid (EDTA) tube which were then batch processed by Mater Pathology, Brisbane, Australia using the DELFIA Xpress immunoassay (PerkinElmer, Turku, Finland). The DELFIA

platform requires a 40 mL SST plasma sample and reports a concentration in the range 7 - 4000 pg/mL with an overall coefficient of variation of 10.1e5.1% at 27.6 pg/mL and 74.2 pg/mL, respectively [22]. Assay quality control was performed routinely as specified by the manufacturers. Labour was managed according to institutional clinical guidelines. Clinicians and participants were blinded to all PlGF results. The primary outcome measure was change in PlGF levels over the course of labour. Maternal characteristics (age, parity, ethnicity, Body Mass Index (BMI), gestational diabetes, onset of labour, indication for IOL), intrapartum outcomes (mode of birth, duration of labour, and use of regional anaesthesia) and neonatal outcomes (gestational age at delivery, gender, birthweight, meconium stained liquor (MSL), Apgar score <7 at 5 min, cord arterial pH < 7.2, need for resuscitation [interventions other than stimulation and facial oxygen] and nursery admission) were recorded. 3. Statistical analysis Normally distributed variables are reported as mean with standard deviation and non-normally distributed variables are reported as median with interquartile range (IQR). Associations between categorical variables were assessed using Fisher's exact test or chi-squared test, as appropriate. A student's t-test or Wilcoxon rank-sum test was used to compare continuous variables between groups, as appropriate. When more than two groups existed, continuous variables were compared by Dunn tests with Bonferroni correction. Correlation between continuous variables was assessed using Spearman's correlation. All analyses were undertaken using Stata 14.0 (StataCorp, College Station, Texas, USA). Comparisons were deemed statistically significant at the P < 0.05 level. 4. Results Over the study period 43 participants delivered by ELCS and 59 participants had paired PlGF samples collected in labour (Fig. 1). Participant characteristics and neonatal outcomes are presented in Table 1. The ELCS group were more likely to be older, multiparous and have a higher BMI. Other than more neonatal nursery admissions in women that laboured there were no significant differences in neonatal outcomes between the ELCS and the labour cohorts (Table 1). Of women that laboured, 42 (71.2%) underwent IOL and 17 (28.8%) had spontaneous labour (Table 2). Women undergoing

Fig. 1. Participant flow diagram.

L. Dunn et al. / Placenta 61 (2018) 11e16

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Table 1 Participant characteristics and neonatal outcomes. Outcome

No labour (ELCS), n ¼ 43

Labour, n ¼ 59

P value

Maternal age Nulliparous Ethnicity Caucasian ATSI Indian Asian Other Body Mass Index Gestational diabetes mellitus Gestational age at labour, weeks Male neonate Birthweight, g Meconium stained liquor Apgar <7 at 5 mins Cord pH < 7.2 Resuscitation Nursery admission

32.8 ± 5.6 8 (18.6)

30.1 ± 5.1 39 (66.1)

0.012 <0.001

28 (65.1) 2 (4.7) 2 (4.7) 4 (9.3) 7 (16.3) 28.7 [22.0e34.8] 3 (7.0) 39.0 [38.6e39.2] 21 (48.4) 3569 ± 418 4 (7.3) 0 2 (4.7) 7 (16.3) 0

35 (59.3) 1 (1.7) 5 (8.5) 10 (17.0) 8 (13.6) 23.0 [21.5e27.9] 10 (17.0) 39.3 [38.3e40.3] 28 (47.5) 3509 ± 403 11 (18.6) 1 (1.7) 6 (10.2) 12 (20.3) 7 (11.9)

0.672

0.010 0.116 0.098 0.890 0.464 0.146 1.0 0.462 0.603 0.020

ELCS elective caesarean section. ATSI Aboriginal and Torres Strait Islander.

IOL were less likely to deliver by spontaneous vaginal delivery (SVD) (although this difference was not statistically significant), more likely to use regional anaesthesia and less likely to have meconium stained liquor (Table 2). The median PlGF level in the ELCS cohort was greater than that in both the 1st and 2nd PlGF samples in the labouring group (Table 3). Overall, median change between the 1st and 2nd PlGF samples during labour was -23.9% [-47.4 - -5.0] (105.5 pg/ml [78.6e203.4] to 80.9 pg/ml [53.6e137.1], p < 0.001) (Table 4). This change however was not correlated with duration of labour (r ¼ 0.150, p ¼ 0.259). Fig. 2 shows the trend of paired PlGF samples during labour. The median change in PlGF over the course of labour remained significant in subgroup analyses of all labouring groups when analysed by onset of labour, parity, mode of birth and gestation (<40 weeks vs. 40 weeks) (Table 4). Although both 1st PlGF (102.8 pg/ml [67.2e148.8] vs. 147.8 pg/ml [102.9e215.4], p ¼ 0.048) and 2nd PlGF (78.4 pg/ml [43.9e99.3] vs. 112.5 pg/ml [78.9e180.2], p ¼ 0.01) levels were significantly lower in the IOL group compared to the spontaneous labour group the overall change did not reach significance (-29.9% [-48.5 - -5.0] vs. -15.2% [-23.9 - -5.0], p ¼ 0.209) (Table 4). Nulliparous women also had significantly lower 1st PlGF

(102.1 [67.2e130.6] vs. 164.0 [103.2e339.1], p ¼ 0.011) and 2nd PlGF (77.7 [43.9e105.9] vs. 99.5 [79.2e193.1], p ¼ 0.008) compared to multiparous women, although both cohorts had similar decreases in PlGF over the duration of labour (-22.9 [-47.3 - -5.0] vs. -27.2 [-50.4 - 2.2], p ¼ 0.885). The largest decline in PlGF levels was seen in the instrumental delivery and emergency caesarean section (EMCS) cohorts (SVD: -17.9% [-51.2 - 0.6] vs. instrumental vaginal birth: -33.0% [-52.6 - 0.2] vs. EMCS: -29.6% [-48.0 - -13.7]). 5. Discussion The results of this study clearly demonstrate that median maternal PlGF levels decrease significantly over the course of labour at term, irrespective of onset of labour, parity, mode of birth or gestation (<40 weeks vs  40 weeks). We also found that the rate of intrapartum PlGF decline did not correlate with duration of labour. In our study, overall PlGF levels fell by nearly 25% during labour, and were lower in the labouring group than those delivering by ELCS. Our results are consistent with a previous study [23] showing that both maternal and cord blood PlGF levels were significantly lower in pregnancies with vaginal births compared to ELCS, although that study included both preterm and term pregnancies.

Table 2 Intrapartum outcomes. Outcome Mode of Birth SVD Instrumental vaginal deliveryz EMCS Labour duration (mins) Labour duration (mins) by birth mode SVD Instrumental vaginal deliveryz EMCS Epidural Gestational age at labour, weeks Male neonate Birthweight, g Meconium stained liquor Apgar <7 at 5 min s Cord pH < 7.2 Resuscitation Nursery admission

Spontaneous labour, n ¼ 17

IOL, n ¼ 42

P value

13 (76.5) 2 (11.8) 2 (11.8) 340 [258.0e513]

20 (47.6) 8 (19.1) 14 (33.3) 417.5 [245.0e676.0]

0.081 0.708 0.115 0.688

340.0 [258.0e465.0] 516.5 [324.0e709.0] 724.0 [315.0e1133.0] 7 (41.2) 39.5 [39e40.4] 10 (58.8) 3557 ± 438 7 (41.2) 1 (5.9) 2 (11.8) 5 (29.4) 2 (11.8)

273.5 [231.5e394.0] 417.5 [278.0e725.0] 682.0 [591.0e806.0] 32 (76.2) 39.1 [38.2e40.2] 18 (42.9) 3490 ± 391 4 (9.5) 0 4 (9.5) 7 (16.7) 5 (11.9)

0.269 1.0 0.874 0.010 0.162 0.266 0.561 0.009 0.288 1.0 0.271 1.0

IOL induction of labour. SVD spontaneous vaginal delivery. Instrumental vaginal deliveryz includes vacuum and forceps deliveries. EMCS emergency caesarean section.

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Table 3 PlGF in elective caesarean compared to labouring cohorts. ELCS, n ¼ 43

117.7 [79.2e184.9]

Labour, n ¼ 59 1st PlGF

2nd PlGF

105.5 [78.6e203.4]

e 80.9 [53.6e137.1]

e

P value

% change in median PlGF

0.513 0.003

10.4 31.3

PlGF placental growth factor. ELCS elective caesarean section. Data in median pg/mL and [inter-quartile range].

Additionally, other investigators have shown that PlGF levels isolated from placentae from women that laboured at term were lower compared to placentae from women undergoing elective caesarean section [5]. Placental growth factor is predominantly synthesised by trophoblasts [12] and secreted both in an autocrine and paracrine manner [24]. In normal pregnancy, maternal PlGF levels peak at around 30 weeks gestation before gradually decreasing towards term [25]. Aberrant placental development causes a proinflammatory and relative hypoxic placental environment with high resistance and turbulent placental perfusion, as seen in early onset pre-eclampsia and FGR [26,27]. In response to hypoxia, trophoblasts undergo apoptosis [28] and subsequent downregulation of PlGF expression and production [29,30], with ex vivo data demonstrating significantly less PlGF mRNA in pre-eclamptic placentae compared to normal controls [31]. Our findings suggest that a similar phenomenon may be occurring in labour. The sustained albeit episodic hypoxic nature of labour and increased trophoblast apoptosis [5], may in part explain our findings of a decrease in PlGF levels over the course of labour. Placental hypoxia has been shown to induce substantial morphological changes to cultured trophoblasts and reduce differentiation of cytotrophoblasts [23,32]. Other in vitro studies suggest that oxidative stress downregulates trophoblast expression and production of PlGF by augmenting endoplasmic reticulum stress and negatively impacting PlGF transcription in a severity-dependent manner [33,34]. Mizuuchi et al. using an in vitro ischaemia-reperfusion injury model of human placental cell cultures showed that repeated episodes of hypoxia followed by oxygenation reduced PlGF mRNA by approximately 50% [34]. Oxidative stress has been purported to promote release of the soluble PlGF receptor (sFlt-1) to a similar or greater extent as hypoxia [35] e the net effect of which further decreases circulating PlGF levels. Furthermore, a hallmark of ischaemiareperfusion injury is the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO) which is enhanced in placentae

Fig. 2. Paired 1st and 2nd PlGF spaghetti plot. PlGF placental growth factor. 1st PlGF collected prior to onset of active labour (<4 cm cervical dilatation) or at commencement of induction of labour (artificial rupture of membranes and/or syntocinon infusion. 2nd PlGF collected at diagnosis of second stage or prior to active pushing.

from women that laboured and had vaginal births [36] whereas biochemical evidence of oxidative stress is absent in placentae from women who delivered by ELCS [5]. Cumulatively both our results and in vitro data suggest that the intermittent placental hypoxia and subsequent ischaemia-reperfusion injury that occurs during labour leads to significant alterations in trophoblastic function and subsequent downturn in PlGF expression and secretion. Despite the association between the hypoxic nature of labour and altered PlGF levels, the duration of labour did not appear to influence either the rate or quantum of decline in PlGF levels. Our findings are consistent with a previous study that showed maternal PlGF levels did not correlate with the overall duration or the length

Table 4 Median percentage difference between paired 1st PlGF and 2nd PlGF samples.

Overall, n ¼ 59 Spontaneous, n ¼ 17 IOL, n ¼ 42 Nulliparous, n ¼ 39 Multiparous, n ¼ 20 SVD, n ¼ 33 Instrumental vaginal deliveryz, n ¼ 10 EMCS, n ¼ 16 40 þ 0 weeks, n ¼ 20 <40 þ 0 weeks, n ¼ 39

1st PlGF

2nd PlGF

P value

% change between 1st and 2nd samples

105.5 [78.6e203.4] 147.8 [102.9e215.4] 102.8 [67.2e148.8] p ¼ 0.048* 102.1 [67.2e130.6] 164.0 [103.2e339.1] p¼0.011y 124.3 [97.8e202] 103.1 [78.6e128.0] 89.8 [60.8e210.4] p¼0.565∞ 107.8 [73.0e204.4] 105.5 [82.3e202] p ¼ 0.532Ƶ

80.9 [53.6e137.1] 112.5 [78.9e180.2] 78.4 [43.9e99.3] p ¼ 0.01* 77.7 [43.9e105.9] 99.5 [79.2e193.1] p ¼ 0.008y 88.9 [70e147.8] 74.4 [40.4e105.9] 76.4 [44.5e90.4] p ¼ 0.320∞ 73.3 [41.1e124.8] 86.5 [60.2e147.8] p ¼ 0.206Ƶ

<0.001 0.028 <0.001

23.9 [-47.4 - -5.0] 15.2 [-23.9 - -5.0] 29.9 [-48.5 - -5.0] p ¼ 0.209* 22.9 [-47.3 - -5.0] 27.2 [-50.4 - -2.2] p ¼ 0.885y 17.9 [-51.2 - 0.6] 33.0 [-52.6e0.2] 29.6 [-48.0 - -13.7] p ¼ 0.445∞ 19.1 [-58.6 - 2.9] 23.9 [-45.3 - -7.6] p ¼ 0.911Ƶ

<0.001 0.006 0.002 0.047 0.002 0.014 <0.001

ELCS elective caesarean section. IOL induction of labour. SVD spontaneous vaginal delivery. Instrumental vaginal deliveryz includes vacuum and forceps deliveries. EMCS emergency caesarean section. Data in median pg/mL [inter-quartile range] or percentage (%) [inter-quartile range]. * spontaneous v IOL. y nulliparous v multiparous. ∞ SVD v instrumental v EMCS. Ƶ 40 þ 0 weeks v < 40 þ 0 weeks.

L. Dunn et al. / Placenta 61 (2018) 11e16

of either the first or second stage of labour [23]. Another study comparing short (<5 h), long (>15 h) and no labour (ELCS) groups reported that there was a difference in placental PlGF levels only between the long labour and ELCS cohorts but not between the long and short labour groups [5]. These data corroborate our findings suggesting that the intrapartum decline in PlGF levels may be independent of the duration of labour. Our results also suggest that regardless of parity, PlGF declines significantly over the course of labour. However, nulliparous women had significantly lower PlGF at both time-points. There are limited data on PlGF and its relationship with parity - Bdolah et al. [37] collected serum PlGF levels from 251 singleton, uncomplicated pregnancies at term (>37 þ 0) and established that parity did not influence maternal PlGF levels. However, these investigators did observe significantly higher sFlt-1 levels and thus a higher sFlt-1/ PlGF ratio in nulliparous women compared to multiparous women. In a study of pregnancies between 11 þ 0 and 13 þ 0 weeks gestation, Nucci et al. [38] reported that PlGF levels were lower in nulliparous women. Overall, these data suggest that nulliparity appears to be associated with an angiogenic imbalance similar to that observed in women who develop complications related to placental dysfunction [18,24,39e43]. The onset of labour may also have influenced the change in PlGF levels. When comparing 1st and 2nd PlGF levels, our data show both PlGF samples in the IOL cohort were up to 30% lower than the equivalent PlGF samples in the spontaneous labour cohort. One possible explanation for this may be the influence of uterine contractions in the latent phase of labour. There was however no difference in the overall duration of labour between the IOL and spontaneous labour cohorts. Importantly, birthweights between the spontaneous labour and IOL cohorts were not significantly different and no women with hypertension or pre-eclampsia or small for gestational age were included in this study, raising the possibility that there may be other factors responsible for the lower PlGF levels observed in the IOL cohort. Limitations of our study include the relatively small sample size and the difficulty in standardising time-points for sample collection. Furthermore, it is known that trophoblast secrete soluble receptors for PlGF into the maternal circulation possibly influencing its bioavailability and assay characteristics [44]. In addition, there is also evidence that up to 30% of circulating PlGF is attributable to circulating peripheral cell secretion/release thus accounting for significant individual variation in measured levels [45] which may have influenced our findings. Nevertheless, our results demonstrate the profound impact the process of labour has on PlGF levels and potentially its impact on perinatal outcomes. Further work is needed to elucidate aberrations in the synthesis and secretion of PlGF in labour. References [1] A. Fleischer, A. Anyaegbunam, H. Schulman, G. Farmakides, G. Randolph, Uterine and umbilical artery velocimetry during normal labor, Am. J. Obstet. Gynecol. 157 (1) (1987) 40e43. [2] H.S. Brar, L.D. Platt, G.R. DeVore, J. Horenstein, A.L. Medearis, Qualitative assessment of maternal uterine and fetal umbilical artery blood flow and resistance in laboring patients by Doppler velocimetry, Am. J. Obstet. Gynecol. 158 (4) (1988) 952e956. [3] T. Janbu, B.-T. Neshetm, Uterine artery blood velocities during contractions in pregnancy and labour related to intrauterine pressure, BJOG 94 (12) (1987) 1150e1155. [4] P.C.A.M. Bakker, P.H.J. Kurver, D.J. Kuik, H.P. Van Geijn, Elevated uterine activity increases the risk of fetal acidosis at birth, Am. J. Obstet. Gynecol. 196 (4) (2007), 313.e1-.e6. [5] T. Cindrova-Davies, H.-W. Yung, J. Johns, O. Spasic-Boskovic, S. Korolchuk, E. Jauniaux, G.J. Burton, D.S. Charnock-Jones, Oxidative stress, gene expression, and protein changes induced in the human placenta during labor, Am. J. Pathol. 171 (4) (2007) 1168e1179. [6] K.J. Lee, S.H. Shim, K.M. Kang, J.H. Kang, D.Y. Park, S.H. Kim, A. Farina, S.S. Shim,

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