Obstetrics & Gynecology:
Circulating Angiogenic Factors in Early Pregnancy and the Risk of Preeclampsia, Intrauterine Growth Restriction, Spontaneous Preterm Birth, and Stillbirth
Smith, Gordon C. S. MD, PhD1; Crossley, Jennifer A. PhD2; Aitken, David A. PhD2; Jenkins, Nicola2; Lyall, Fiona PhD2; Cameron, Alan D. MD3; Connor, J Michael MD, DSc2; Dobbie, Richard BSc4
From the 1Department of Obstetrics and Gynaecology, Cambridge University, Cambridge, United Kingdom; 2Institute of Medical Genetics, Yorkhill NHS Trust, Glasgow, United Kingdom; 3Department of Fetal Medicine, the Queen Mother's Hospital, Glasgow, United Kingdom; and 4Information and Statistics Division, Common Services Agency, Edinburgh, United Kingdom.
Funded by a project grant (CBZ/4/81) from the Chief Scientists Office of the Scottish Executive Health Department. The record linkage was funded by a project grant from the Foundation for the Study of Infant Deaths, United Kingdom (245). The Combined Ultrasound and Biochemical Screening study was funded by the Chief Scientists Office (K/MRS/50/C2593) and the Fetal Medicine Foundation.
Corresponding author: Gordon C. S. Smith, MD, PhD, Professor of Obstetrics and Gynaecology, Cambridge University, Rosie Maternity Hospital, Cambridge, CB2 2SW, United Kingdom; e-mail: firstname.lastname@example.org.
OBJECTIVE: To estimate the relationship between maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) in early pregnancy with the risk of subsequent adverse outcome.
METHODS: A nested, case–control study was performed within a prospective cohort study of Down syndrome screening. Maternal serum levels of sFlt-1 and PlGF at 10–14 weeks of gestation were compared between 939 women with complicated pregnancies and 937 controls. Associations were quantified as the odds ratio for a one decile increase in the corrected level of the analyte.
RESULTS: Higher levels of sFlt-1 were not associated with the risk of preeclampsia but were associated with a reduced risk of delivery of a small for gestational age infant (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.88–0.96), extreme (24–32 weeks) spontaneous preterm birth (OR 0.90, 95% CI 0.83–0.99), moderate (33–36 weeks) spontaneous preterm birth (OR 0.93, 95% CI 0.88–0.98), and stillbirth associated with abruption or growth restriction (OR 0.77, 95% CI 0.61–0.95). Higher levels of PlGF were associated with a reduced risk of preeclampsia (OR 0.95, 95% CI 0.90–0.99) and delivery of a small for gestational age infant (OR 0.95, 95% CI 0.91–0.99). Associations were minimally affected by adjustment for maternal characteristics.
CONCLUSION: Higher early pregnancy levels of sFlt-1 and PlGF were associated with a decreased risk of adverse perinatal outcome.
LEVEL OF EVIDENCE: II
Preeclampsia, intrauterine growth restriction, and preterm birth account for a large proportion of perinatal mortality. There are currently very few interventions in routine clinical practice that have been clearly shown to reduce perinatal deaths due to these complications. The lack of available interventions reflects continuing uncertainty regarding the underlying biologic processes that lead to these outcomes. Recently, a novel approach to preeclampsia has been proposed. Human and animal studies have suggested that a protein released from the placenta, soluble fms-like tyrosine kinase-1 (sFlt-1), may cause the maternal endothelial dysfunction which is characteristic of preeclampsia.1–3 Recent animal studies have suggested that administration of vascular endothelial growth factor A121 (VEGF-A121) to bind and inactivate sFlt-1 may attenuate the preeclamptic phenotype in the animal model.4 This approach may have promise as a means of treating preeclampsia or preventing its onset in high-risk women. However, there are minimal data on the association between circulating angiogenic factors and other complications of pregnancy. Here we report the association between maternal serum levels of sFlt-1 and placental growth factor (PlGF) at 10–14 weeks of gestation and the risk of preeclampsia, delivery of a small for gestational age (SGA) infant, spontaneous preterm birth, or stillbirth
MATERIALS AND METHODS
We performed a nested case–control study using serum samples that were stored as part of the Combined Ultrasound and Biochemical Screening study, a prospective, noninterventional, multicenter study of screening for Down syndrome.5 The Combined Ultrasound and Biochemical Screening study evaluated the use of ultrasound measurement of fetal nuchal translucency in combination with analysis of maternal serum pregnancy-associated plasma protein A and the free subunit of hCG as a first trimester screening test for Down syndrome in a routine prenatal clinic setting. Information leaflets about the study were sent to women with the notification of their first appointment for prenatal care. Those women with a singleton pregnancy whose first visit was at 14 weeks of gestation or less were invited to participate, and those who agreed signed a consent form. Participation in the study involved measurement of nuchal translucency at the time of the first ultrasonography and obtaining additional blood at the time of phlebotomy for routine prenatal investigations. Serum was analyzed for pregnancy-associated plasma protein A and free β-hCG, and the remainder of the sample was frozen and stored. No results were reported to either the obstetrician or patient, and prenatal care was not modified in any way by participation in the study.
Ethical approval for the cohort study and the subsequent nested case–control study was obtained from the Scottish Multicenter Research Ethics Committee. Fifteen Scottish maternity units participated,5 recruiting women over a 2-year period between 1997 and 1999. A total of 96.6% of records came from births in 11 hospitals (see Appendix). Ninety-eight percent of the births occurred between May 1998 and July 2000. Births to women recruited to the study constituted 28.6% of all births in these 11 hospitals over that period of time.
The outcome of the pregnancy was ascertained in two ways. First, case notes were manually retrieved from approximately 75% of the cohort, and they were used to identify women diagnosed with preeclampsia.6 Preeclampsia was defined as women for whom the diagnosis was documented in the clinical record, and this was performed by trained midwives. To obtain outcome data on birth weight percentile, spontaneous preterm birth, and stillbirth for the entire cohort, records were linked to the Scottish Morbidity Record, a national register of pregnancy outcome data,7 and the Scottish Stillbirth and Infant Death Enquiry, a national register that routinely classifies all perinatal deaths in Scotland.8 Both registries are close to 100% complete and are described in detail elsewhere.7,8
Maternal height, smoking status, marital status, ethnicity, and body mass index (weight in kg divided by the height in meters squared) were ascertained at the time of the first prenatal visit. Maternal age was defined as the age at delivery. Socioeconomic status was estimated based on the post code of residence, using Carstairs socioeconomic deprivation categories9 (based on 1991 Census data on car ownership, unemployment, overcrowding, and social class within post code sectors of residence, which contain, on average, around 1,600 residents), and women were categorized into quintiles of socioeconomic deprivation. The gestational age at birth was defined as completed weeks of gestation and was based on ultrasound dating performed between 10 weeks and 14 weeks of gestation. Cases were defined as women who had one or more of the following: a diagnosis of preeclampsia; an SGA infant (a liveborn infant with a birth weight less than the 3rd percentile for sex and gestational age); and spontaneous preterm delivery, which was divided into extreme (between 24 weeks and 32 weeks of gestational age) and moderate (between 33 weeks and 36 weeks of gestational age), or stillbirth. Spontaneous preterm deliveries were defined as those where 1) the birth was vaginal or there was a documented duration of labor and 2) labor was not documented as having been induced. All other preterm births were regarded as indicated. Indicated preterm birth was not analyzed as a separate outcome, but was used in the subclassification of preeclampsia: complicated preeclampsia was defined as cases where the mother was had a medically indicated preterm birth or where the fetus was SGA.
Stillbirths excluded those due to congenital abnormality or rhesus disease. The cause of perinatal death was classified by a modified version of the Wigglesworth system.8 Explained stillbirths were defined as those where there was an apparent direct cause, such as placental abruption. All other stillbirths were classified as unexplained. Unexplained stillbirths were subdivided into those that were SGA and those appropriate for gestational age. Unexplained SGA stillbirths were assumed to reflect chronic placental insufficiency. Therefore, stillbirths due to placental abruption and SGA unexplained stillbirths were also considered collectively as stillbirths due to placental causes, as previously described.10 Controls were selected at random from among cohort members who delivered a liveborn infant of birth weight between the 10th and 90th percentile at or after 37 weeks of gestation.
Assays were performed by enzyme-linked immunosorbent assay for human sFlt-1 and free PlGF using commercial kits (product numbers DVR100 and DPG 00, respectively; R&D Systems, Abingdon, United Kingdom). All analyses were performed within the West of Scotland Regional Genetics Service of the Institute of Medical Genetics, Glasgow, which performs all prenatal biochemical screening assays for the West of Scotland.11 The minimal detectable concentrations in the assays for sFlt-1 and PlGF were 5 and 7 pg/mL. The interassay and intra-assay coefficients of variation were 14.9% and 10.4%, respectively, for sFlt-1 and 13.7% and 11.3%, respectively, for PlGF.
Maternal serum levels of sFlt-1 and PlGF were expressed as multiples of the median (MoM) for gestational age, as is conventional for biochemical indices in pregnancy which vary with week of gestation. The gestational age–specific medians were calculated from the control group. Multiples of the median values were corrected for maternal weight using reciprocal-linear regression. This is widely employed in standardizing biochemical tests for Down syndrome screening and is described in detail elsewhere.12 Where levels of an analyte varied in relation to maternal smoking, MoMs were adjusted for smoking status using the data from controls. Cut points for deciles were estimated from the controls and used to classify the levels of the analytes for both cases and controls into deciles. Univariable comparison of continuous variables was performed using the Mann-Whitney U test and categorical data using the χ2 and the χ2 for trend.13 All P values were two-tailed. Statistical significance was assumed at P<.05. Comparison of cases and controls was by odds ratios and 95% confidence intervals (CIs). Multivariable analysis was by logistic regression. Interactions were assessed using the likelihood ratio test14 and statistical significance of interactions was assumed at P<.05, after correcting for the number of comparisons using the Bonferroni method. Due to the rarity of the event, exact logistic regression was used for the analysis of stillbirth data.15 All statistical analyses were performed using the Stata 8.2 software package (StataCorp LP, College Station, TX), LogExact 5 (Cytel Corporation, Cambridge, MA) or SPSS 12.0 (SPSS Inc., Chicago, IL).
The study group consisted of 939 cases and 937 controls. Among the cases, 309 had a diagnosis of preeclampsia, 65 were spontaneous preterm births between 24 and 32 weeks of gestation, 227 were spontaneous preterm births between 33 and 36 weeks of gestation, 333 had a birth weight less than the 3rd percentile, and 26 were stillbirths, 14 of which had a placental cause. Twenty-one women had two of the preceding diagnoses. Among the 309 women with preeclampsia, 3 (1.0%) had a spontaneous preterm birth, 58 (18.8%) had an indicated preterm birth, and of the 248 births at term, 16 (6.4%) had a birth weight less than the 3rd percentile.
Blood was obtained between 70 and 104 days of gestation in 1,876 (99.5%) of the study group. The median gestational age at sampling was 87 days of gestation (interquartile range 82–92 days). Median sFlt-1 concentration declined from 996 pg/mL at 10 weeks to 834 pg/mL at 14 weeks gestational age. Median PlGF concentrations rose from 38.5 pg/mL at 10 weeks to 76.4 pg/mL at 14 weeks gestational age. There were weak inverse relationships between maternal weight and levels of both sFlt-1 and PlGF. The median MoM for PlGF was 36% higher among smokers whereas there was no significant difference in sFlt-1 between smokers and nonsmokers. Calculation of MoMs and the cutoff points for deciles and quintiles are described in the Appendix.
The characteristics of the cohort are tabulated by status as case or control (Table 1). Cases were younger, were less likely to be married, were more likely to live in an area of high socioeconomic deprivation, were less likely to be white, were more likely to smoke, were more likely to be primigravid, had more previous early pregnancy losses, and were shorter than controls. There were negative linear associations between decile of sFlt-1 and the risk of all adverse outcomes, delivery of an SGA infant, both extreme and moderate spontaneous preterm birth, and stillbirths due to a placental cause (Fig. 1 and Table 2). There was no association between sFlt-1 levels and the risk of preeclampsia. There were negative linear associations between decile of PlGF and the risk of preeclampsia and delivery of an SGA infant (Fig. 2 and Table 2). There was no relationship between levels of either analyte and nonplacental causes of stillbirth (data not shown). We repeated the analyses removing the top and bottom deciles of the given analyte to determine whether the odds ratios were strongly influenced by extreme values. In all but one case, the point estimate of the odds ratio fell within the 95% confidence intervals in Table 2, indicating that the results were consistent with those including the whole cohort. The exception was the association between sFlt-1 and extreme preterm birth. When the top and bottom deciles were excluded, the odds ratio for a 1-decile increase in sFlt-1 was 1.08 (95% confidence interval 0.94–1.24, P=.3).
Adjusting for the level of the other analyte and for maternal characteristics had a minimal effect on the nature and strength of associations (Table 2). There were no statistically significant interactions between decile of either analyte and maternal characteristics (all P>.05, adjusted for number of comparisons). There was a statistically significant interaction between decile of sFlt-1 and decile of PlGF in relation to all adverse outcome (odds ratio for the interaction 1.015, 95% CI 1.004–1.026, P=.007). The interaction was weaker for preeclampsia but stronger for all other outcomes. The interaction between sFlt-1 and PlGF was then assessed for a composite adverse outcome, namely all cases where there was no diagnosis of preeclampsia. This analysis demonstrated a highly statistically significant interaction between the two analytes (odds ratio for the interaction 1.018, 95% CI 1.006–1.031, P=.003). When the analysis of the relationship between sFlt-1 and this composite outcome was stratified by the level of PlGF, it was apparent that the association was stronger when PlGF was lower (Fig. 3).
The association between PlGF and preeclampsia was more marked among women with complicated preeclampsia (defined as being associated with preterm delivery or with an SGA infant; odds ratio 0.88, 95% CI 0.81 to 0.96) than among women with preeclampsia who delivered an infant with birth weight appropriate for gestational age at term (odds ratio 0.99, 95% CI 0.95 to 1.04). There was no significant association between sFlt-1 and either complicated (odds ratio 0.96, 95% CI 0.89–1.04) or uncomplicated preeclampsia (odds ratio 1.01, 95% CI 0.96–1.06). When the analyses were confined to women whose blood was obtained before 13 weeks of gestation, the pattern of associations was very similar to the findings for the whole population (Fig. 4).
We found no association between circulating levels of sFlt-1 at 10–14 weeks of gestation and the risk of preeclampsia, but a decreased risk of the disease among women with higher levels of PlGF. These findings are in complete agreement with a previous large-scale nested case–control study that found no association between maternal serum levels of sFlt-1 and the risk of preeclampsia in early pregnancy but a reduced risk of the disease among women with high levels of PlGF from 13 weeks onward.3 However, we demonstrate that women with higher circulating levels of sFlt-1 at 10–14 weeks of gestation were at lower risk of other complications of pregnancy, specifically delivery of an SGA infant, spontaneous preterm birth, and stillbirth. Higher levels of PlGF at 10–14 weeks of gestation were associated with a decreased risk of delivery of an SGA infant but were not associated with the other outcomes.
The finding of improved outcome in association with higher levels of sFlt-1 is of particular interest. It could be that high circulating levels of sFlt-1 have some physiologic role in early pregnancy. Alternatively, it could be that high levels of sFlt-1 reflect some other aspect of placental function that is in turn associated with better outcome. It is unlikely that sFlt-1 is acting simply as a marker of placental mass, because we have previously related maternal serum levels of the free β-hCG at the same gestational age to the risk of later adverse outcome and failed to demonstrate any association.6
Previous studies have related maternal serum levels of sFlt-1 in pregnancy to the risk of adverse outcome for the offspring. Two demonstrated no association between maternal levels of sFlt-1 and the risk of delivering an SGA infant.16,17 A further study demonstrated elevated levels of sFlt-1 at 23–25 weeks gestational age among women with high-resistance patterns of uterine artery flow velocimetry and established early onset growth restriction.18 None of these studies corrected sFlt-1 levels for the gestational age at the time of sampling or for maternal weight, and none included more than 30 cases. Previous studies had demonstrated inconsistent relationships between levels of PlGF and the risk of delivering an SGA infant, with both higher19 and lower20,21 levels of PlGF reported.
We observed a statistically significant interaction between sFlt-1 and PlGF. There was no prior hypothesis that these factors would interact. We found that among women with low PlGF, elevated levels of sFlt-1 were significantly protective against adverse perinatal outcome, whereas there was no association between levels of sFlt-1 among women with PlGF levels in the upper two quintiles (Fig. 3). The assay employed in this study measured free PlGF. Soluble Flt-1 binds PlGF, and high levels of sFlt-1 would be anticipated to lead to low levels of free PlGF. The interaction could indicate that low circulating PlGF due to high levels of sFlt-1 is associated with better outcome than low circulating PlGF due to other causes, such as reduced placental production. Alternatively, it could indicate that a protective effect of sFlt-1 is antagonized by high circulating levels of PlGF.
Higher levels of sFlt-1 in late pregnancy are associated with an increased risk of preeclampsia. In contrast, we show that higher levels of sFlt-1 in very early pregnancy are associated with a decreased risk of other pregnancy complications. This finding is potentially clinically relevant. It has been hypothesized that there is a causal association between elevated maternal levels of sFlt-1 and preeclampsia.3 It is proposed that sFlt-1 is released by the placenta into the maternal circulation and binds maternal PlGF and VEGF-A, leading to maternal endothelial dysfunction,3 and animal studies are consistent with this model.1,4 These data suggest that administration of VEGF-A121, or alternative approaches to reducing maternal circulating levels of sFlt-1, may be therapeutically useful among women with established preeclampsia or among women who are at increased risk of the disease. The current data indicate that this has the potential to be harmful in early pregnancy. It may be prudent to conduct further observational studies of the associations in late pregnancy before evaluation of such treatments.
Haig22 has advanced the hypothesis that “preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.” Given that high levels of sFlt-1 are associated with an increased risk of preeclampsia but a decreased risk of growth restriction, preterm birth, and stillbirth, it is possible that high levels of sFlt-1 in the maternal circulation represent a physiologic signal from the placenta to optimize uterine perfusion. Longitudinal assessment of sFlt-1 in pregnancy in combination with maternal blood pressure and assessment of uteroplacental blood flow would help determine whether sFlt-1 may have such a role.
The biologic basis for the association between sFlt-1 and preterm birth warrants further study. There are some data that indicate an association is biologically plausible. Studies of pregnant human uterus have demonstrated expression of VEGF-A in the myometrium.23 Studies in the pregnant rat demonstrated expression of VEGF-A and its main functional receptor in the cervix. Moreover, VEGF-A expression peaks in association with ripening of the cervix.24 If VEGF-A also had a role in human cervical ripening, low levels of sFlt-1 could result in increased free VEGF-A and hence promote preterm birth. There are no data on the possible effects of PlGF on the myometrium and cervix, and this should also be addressed.
In conclusion, higher levels of sFlt-1 in early pregnancy were associated with a decreased risk of intrauterine growth restriction, spontaneous preterm labor, and stillbirth. Strategies aimed at reducing the risk of preeclampsia by inactivating sFlt-1 in the maternal circulation may adversely affect perinatal outcome.
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Regressed median of soluble fms-like tyrosine kinase-1 (sFlt-1) in relation to gestational age:
sFlt-1 (in pg/mL)=e(6.389+33.366/x), where x is the gestational age in days.
Regressed multiple of the median of sFlt-1 in relation to maternal weight:
Multiple of the median of sFlt-1=0.6944+18.2822/x, where x is the maternal weight in kilograms.
Regressed median of placental growth factor (PlGF) in relation to gestational age:
PlGF (in pg/mL)=e(2.071+0.02288/x), where x is the gestational age in days.
Regressed multiple of the median of PlGF in relation to maternal weight:
Multiple of the median of PlGF=0.8609+9.8629/x, where x is the maternal weight in kilograms.
Correction of multiple of the median of PlGF for maternal smoking:
Smokers: Multiples of the median (MoM) value divided by 1.29. Nonsmokers: MoM value divided by 0.95
Cut points for deciles of sFlt-1 (expressed as MoM):
0.572, 0.702, 0.814, 0.909, 1.016, 1.117, 1.219, 1.366, and 1.611.
Cut points for deciles of PlGF (expressed as MoM):
0.610, 0.720, 0.824, 0.907, 1.003, 1.092, 1.197, 1.332, and 1.575
Cut point for quintiles of PlGF (expressed as MoM):
0.720, 0.907, 1.092, and 1.332.
Eleven hospitals recruiting 98.6% of patients:
The Queen Mother's Hospital, Glasgow; Simpson Maternity, Edinburgh; Southern General Hospital, Glasgow; Royal Maternity Hospital, Glasgow; Royal Alexandria Hospital, Paisley; Ninewells, Dundee; Ayrshire Central Hospital, Irvine; Forth Park, Kikcaldy; Stirling Royal Infirmary, Stirling; Falkirk and District Royal Infirmary, Falkirk, and Inverclyde Royal Hospital, Greenock. Cited Here...
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