European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 4852

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European Journal of Obstetrics & Gynecology and Reproductive Biology

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Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption
Jenni K. Ranta a, Kaisa Raatikainen b, Jarkko Romppanen c, Kari Pulkki d, Seppo Heinonen e,*
a Department of Clinical Chemistry, School of Medicine, Faculty of Health Sciences, University of Eastern Finland and Eastern Finland Laboratory Centre, P.O. Box 1700, 70211 Kuopio, Finland b Department of Obstetrics and Gynaecology and Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1777, Kuopio University Hospital, 70211 Kuopio, Finland c Eastern Finland Laboratory Centre and University of Eastern Finland, P.O. Box 1700, 70211 Kuopio, Finland d Department of Clinical Chemistry, School of Medicine, Faculty of Health Sciences, University of Eastern Finland and Eastern Finland Laboratory Centre, P.O. Box 1700, 70211 Kuopio, Finland e Department of Obstetrics and Gynaecology and Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1777, Kuopio University Hospital, 70211 Kuopio, Finland

A R T I C L E I N F O

A B S T R A C T

Article history: Received 2 September 2010 Received in revised form 9 February 2011 Accepted 5 March 2011 Keywords: First trimester Screening Adverse outcomes Pre-eclampsia Placental abruption

Objective: To investigate links between rst trimester Downs syndrome screening markers and adverse pregnancy outcomes; preeclampsia (PE), small for gestational age (SGA), preterm delivery (PD) and placental abruption (PA) in spontaneous, chromosomally normal pregnancies. Study design: Cohort study in a university hospital. Data during pregnancy were routinely collected from a total study population of 2844 pregnant women between 2005 and 2007. Four study groups were pregnancies with PE (N = 175), PA (N = 17), PD (N = 213) and SGA (N = 275) plus a reference group with normal outcome (N = 2164). The median MOMs of maternal serum concentrations of pregnancy associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fb-hCG) were compared using two-tailed pooled t-tests, continuous variables were compared using Students two-way t-tests, and Chi-square tests were used to analyse dichotomous variables. Fishers exact test was used when there were fewer than ve units in any of the classes. Results: The median MOM of maternal serum PAPP-A was signicantly lower in women with PE, PD and SGA (0.79, 0.80 and 0.79 MOM, respectively) than in the reference group (0.99 MOM) (p < 0.01). The median MOM of maternal serum fb-hCG was also signicantly lower in the SGA group (0.90 MOM) and in the PE and PD groups (0.86 and 0.92 MOM) than in the reference group (0.99 MOM, p = 0.02). There was no detectable difference between the biochemical markers in the PA group and the reference group. No statistical difference was found between NT MOMs in the reference and study groups. Conclusion: The concentrations of rst trimester screening (FTS) serum markers were lower in pregnancies where PE, PD and SGA occurred. In the latter two cases, there was an inverse association between incidence and PAPP-A and fb-hCG values. However, the development of PA during pregnancy could not be predicted from biochemical marker concentrations. The mechanism behind PA is probably less dependent on the placenta than on the decidua. 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Adverse pregnancy outcomes such as pre-eclampsia (PE), small for gestational age (SGA) infants, preterm delivery (PD) and placental abruption (PA) are associated with higher mortality and subsequent need for intensive care, in addition to affecting the child adversely for many years [13]. Whilst it is known that chronic maternal diseases, such as hypertension, lead to an

Abbreviations: fb-hCG, human chorionic gonadotropin, free beta subunit; FTS, rst trimester screening; MOM, multiples of medians; NT, nuchal translucency; PA, placental abruption; PAPP-A, pregnancy associated plasma protein A; PE, preeclampsia; PD, preterm delivery; SGA, small for gestational age. * Corresponding author. Tel.: +358 17 172325; fax: +358 17 172685. E-mail address: seppo.heinonen@kuh. (S. Heinonen). 0301-2115/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2011.03.004

increased risk of adverse pregnancy outcomes [4,5], the vast majority of such outcomes happen to healthy pregnant women with no known chronic diseases [6]. PE has been shown to be associated strongly with alterations in angiogenetic and antiangiogenetic factors in the rst and second trimesters [79]. Levels of serum markers during rst trimester screening (FTS) for Downs syndrome have been consistently reported abnormal in chromosomally normal pregnancies affected by PE, PD and SGA [10 15], whereas in pregnancies affected by PA the ndings are more controversial [16,17]. Some degree of familial clustering is shown with PA. Additionally, the risk of recurrence of PA is known to be relatively high; of the order of 12% [18], whereas PE usually occurs in only one pregnancy. The mechanisms underlying these adverse outcomes are likely to be initiated early in pregnancy, although the clinical endpoint

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usually does not manifest itself until the second half of pregnancy. So far, clinically effective predictive and preventive strategies have been unavailable [19], but recently evidence has been found for antithrombotic medication in prevention of PE [20]. The objective of this study was to evaluate the relationship between FTS markers and pregnancy outcomes in a cohort of 2844 pregnant women. In particular, the performance of PAPP-A in screening for specic pregnancy complications was explored, as it is known to play a role in placentation and early fetal growth. Outcomes investigated included PA, a disease of the decidua rather than the placenta. The hypothesis was that alterations in maternal serum PAPP-A concentrations would be associated with PE and fetal growth restriction but not with PA. 2. Materials and methods The study was a retrospective cohort study. The data were collected from the Department of Gynaecology and Obstetrics of Kuopio University Hospital and the Eastern Finland Laboratory Centre. The study setting was a university hospital. The women included in the study had spontaneously conceived and had structurally normal singleton pregnancies. They all underwent FTS, lived in the Kuopio catchment area, and gave birth at Kuopio University Hospital between January 2005 and December 2007. Information was collected in maternity care units of the Kuopio University Hospital district and at the maternity clinic of Kuopio University Hospital. Patient-reported information included the weight and height of the mother, chronic diseases (hypertension and diabetes), smoking habits before the pregnancy (yes/no), possible prior pregnancy complications and infertility treatment. Systematically gathered information included the results of the FTS (the age of the mother, maternal serum fbhCG and PAPP-A concentrations and the nuchal translucency (NT) of the fetus), maternal body mass index (BMI) before and at the end of the index pregnancy, pregnancy duration, possible pregnancy complications, pregnancy outcome, gender of the fetus and birth weight. The following criteria were used to assess the pregnancy outcomes: PE (repeated blood pressure measurements >140/ 90 mm Hg with proteinuria >0.5 g/day), PD (birth before 37 completed pregnancy weeks), SGA (sex- and age-adjusted birth weight below the normal 10th percentile according to our records) and abruption of the placenta. Reference pregnancies were taken to have a normal outcome when the mother and newborn did not require any prenatal, perinatal or postnatal follow-up, care or interventions over and above what was considered to be routine. The exclusion criteria for the study population were pregnancies with more than one fetus and those which showed major fetal structural anomalies, since such pregnancies carry a higher risk of adverse outcomes. The register of births included only pregnancies extending to at least the 22nd gestational week, therefore miscarriages and induced abortions were excluded, as were cases with information missing (N = 259). Of the total study population, individuals were assigned to study groups as follows: pregnancies with PE (N = 175), pregnancies with PD (N = 213), pregnancies with SGA (N = 275), and pregnancies with PA (N = 17). The reference group included 2164 women. The numbers of cases with missing information in one or more information classes (maternal age, BMI, weight gain, primigravida, smoking before the pregnancy, chronic and gestational illnesses, placenta praevia, birth weight, placental weight, caesarean section, vacuum delivery, asphyxia, Apgar scores, intensive care, stillbirth, neonatal death, low birth weight, fetal gender, and FTS information) in each of the groups were: 11 in the PE group (6.29%), 20 in PD group (9.39%), 23 in the SGA group (8.36%), 0 in PA group, and 156 in the reference group (7.21%). The FTS was performed according to the recommendations of the Finnish Ministry of Social Affairs and Health. The maternal

serum samples were collected in maternity care units during weeks 9 + 0 to 13 + 0. The NT and crown-rump length measurements were performed at healthcare centres and the Kuopio University Hospital maternity clinic by ultrasound-trained midwives and gynaecologists between weeks 11 + 0 and 13 + 6. Serum samples were analysed in the Eastern Finland Laboratory Centre in Kuopio. Concentrations of maternal serum fb-hCG and PAPP-A were measured by time-resolved uoroimmunoassay using an Auto-DELFIA kit (PerkinElmer Wallac, Turku, Finland). The risk gures for biochemical markers and the NT scan were calculated using LifeCycle software version 2.0 (PerkinElmer LifeSciences, Wallac, Turku, Finland). The risk gure program compares a patients results with a population model described by a set of multivariate Gaussian distributions. The results were given as multiples of medians (MOMs) relative to values recorded for normal pregnancies at specic weeks. We used a cut-off limit of 1:250, for a xed false-positive rate of 5%. Both the fb-hCG and PAPP-A results were corrected for maternal weight and diabetes, but only fb-hCG measurements were corrected for smoking. To determine the effects of smoking on screening with PAPP-A, a separate analysis was run to compare median PAPP-A MOMs among the smoking and non-smoking women. Within- and between-assay variations were both <3.4% in the detection range of 4157 ng/mL for fb-hCG and <2.4% and <4.0%, respectively, and in the detection range of 447300 mUI/L for PAPP-A. The limit of detection for fb-hCG and PAPP-A was 0.2 ng/mL and 5 mUI/L, respectively. Quality assurance was supervised by an international quality assurance company (UK NEQAS, Edinburgh, Great Britain). Parameters of variables were tabulated and the differences between the subject and reference groups were tested for statistical signicance. The median MOMs of maternal serum concentrations of PAPP-A and fb-hCG were compared using twotailed pooled t-tests, since the MOMs tted Gaussian distributions. Continuous variables such as mean maternal age, birth weight and the pregnancy duration were compared using Students two-way ttests, and Chi-square tests were used to analyse dichotomous variables. Fishers exact test was used when there were fewer than ve units in any of the classes. When p values were less than 0.05 differences were considered statistically signicant. The odds ratios for adverse outcomes at different MOM levels were also calculated. Data were analysed using SAS software (SAS Institute Inc., Cary, NC, USA). This study was approved by the Ethnical Research Committee of Kuopio University Hospital and the Institutional Review Board. The Committee has given permission for the results to be published. 3. Results Table 1 shows the characteristics of the mothers and pregnancies. The proportion of overweight women was highest in the PE group (48.0%, p < 0.001). As expected, the highest proportions of primigravidas were in the PE and SGA groups (52.0% and 58.2%, respectively), and the differences were signicant in all study groups as compared to the reference group (36.3%, p < 0.001). The proportion of mothers with hypertension was signicantly higher in all study groups as compared to the reference group (p < 0.001). Diabetes was most common amongst mothers with PE and PD, and signicantly higher as compared to the reference group (p < 0.001), whereas gestational diabetes was most common in the PE group (p < 0.01). There was no statistical difference between the groups in occurrence of anaemia or gestational hepatosis. The highest occurrence of placenta praevia was in the PD group (p < 0.001). The mean maternal age in the whole study population was 29.9 years. The proportion of mothers aged 36 years was lowest in the reference group and highest in the PA group, but differences between the reference and study groups were not statistically

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J.K. Ranta et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 4852

Table 1 Maternal and pregnancy characteristics in the study groups (N = 2844). Characteristic Reference group (N = 2164) 29.8 609a (28.1%) 24.3 29.7 14.3 784 (36.3%) 582a (26.9%) 353 1 18 390 26 23 (16.3%) (0.1%) (0.8%) (18.0%) (1.2%) (1.1%) Preeclampsia (N = 175) 30.0 84a (48.0%) 27.1 32.6 13.8 91 (52.0%) 42a (24.0%) 49 68 11 47 6 1 (28.0%) (38.9%) (6.3%) (26.9%) (3.4%) (0.6%) p Premature delivery (N = 213) 30.3 63a (29.6%) 24.5 28.3 11.0 89 (41.8%) 60a (28.2%) 52 28 20 25 7 8 (24.4%) (13.1%) (9.4%) (11.7%) (3.3%) (3.8%) p Small for gestational age infants (N = 275) 29.7 66a (24.0%) 23.5 28.1 12.0 160 (58.2%) 79a (28.7%) 45 13 3 39 3 1 (16.4%) (4.7%) (1.1%) (14.2%) (1.1%) (0.4%) p Placental abruption (N = 17) 31.6 6 (35.3%) 23.8 28.4 12.0 7 (41.2%) 5 (29.4%) 5 (29.4%) 2 (11.8%) 0 0 0 1 (5.9%) p

Mean maternal age (years) BMI  25 before pregnancy Mean BMI prior to pregnancy (kg/m2) Mean BMI at the end of pregnancy (kg/m2) Mean weight gain during pregnancy (kg) Primigravida Smoking before pregnancy (yes/no) Chronic illness Hypertonia arterialis Diabetes Gestational diabetes Gestational hepatosis Placenta praevia
a *

0.66 <0.001 <0.001 <0.001 0.49 <0.001 0.27 <0.001 <0.001 <0.001 <0.01 0.01 1.0*

0.24 0.92 0.62 0.01 <0.001 0.11 0.54 0.003 <0.001 <0.001 0.02 0.01 <0.001

0.76 0.15 0.01 <0.001 <0.001 <0.001 0.44 0.98 <0.001 0.72* 0.12 1.00* 0.51*

0.24 0.65 0.65 0.41 0.21 0.67 1.00 0.15 <0.001* 1.00* 0.76* 1.00* 0.17*

Data missing in less than 10% of cases. When a class included less than 5 variables, Fishers exact test was used.

signicant. When previous infertility treatment, miscarriages, induced abortions, intrauterine deaths, or surgically scarred uteri were compared, no signicant differences were found between the study groups. Across all groups approximately 28% of the pregnant women were smokers before the pregnancy, and 15% during the current pregnancy. Mean birth weights were 16.343.1% lower in all the study groups as compared to the reference group (p < 0.001), being lowest in the PA group. In addition, the mean placental weight/ birth weight ratio expressed as a percentage was higher in all the study groups as compared to the reference group (p < 0.001). The mean pregnancy duration was shorter in all study groups as compared to the reference group (p < 0.001) and was shortest in the PD group (17.8% shorter than in the reference group). As anticipated, caesarean sections, abnormal Apgar scores, the need for intensive care and low birth weight infants were more common in all the study groups and their occurrence in these groups was signicantly greater as compared to the reference group (p < 0.01). The outcomes of the pregnancies are presented in Table 2.

The results of FTS screening are presented in Table 3. The most signicant nding was the lower PAPP-A median MOMs in the PE, PD and SGA groups as compared to the reference group (p < 0.001). The fb-hCG median MOM was also lower in these groups (p = 0.02 in the PE and PD groups, and p < 0.01 in the SGA group) as compared to the reference group. However, the median MOMs of PAPP-A and fb-hCG of the PA and the reference group appeared to be statistically similar. The median MOM of NT was similar in reference, PE, PD and SGA pregnancies, whereas in the PA group it was higher, but the difference was statistically insignicant. The proportion of screening positives was lowest in the reference group (2.6%) and PA group (0%), whilst the highest rate of positive screening results was in the PD group (6.6%), and the difference was statistically signicant (p = 0.001). Excluding women (approximately 15% in each group) who continued smoking during pregnancy (>5 cigarettes/day) did not change the results (data not shown). It was estimated that the odds ratio of fb-hCG MOM <1.0 for an adverse pregnancy outcome was 1.32 for PE, 1.16 for PD, 1.22 for

Table 2 Pregnancy outcomes in the study groups (N = 2844). Characteristic Reference group (N = 2164) 3660.2 g 17.2 280.3 days Preeclampsia (N = 175) p Premature delivery (N = 213) 2082.3 g (56.9%) 23.8 230.4 days (82.2%) 106 (49.8%) 7a (3.3%) 4 (1.9%) 68 (31.9%) 48 (22.5%) 136 (63.8%) 9a (4.2%) 16 (7.5%) 141 (66.2%) 123a (57.7%) p Small for gestational age infants (N = 275) 2714.5 g (74.2%) 18.1 275.8 days (98.4%) 65 (23.6%) 25a (9.1%) 4 (1.5%) 27 (9.8%) 18 (6.5%) 37 (13.5%) 1 (0.4%) 1 (0.4%) 48 (17.5%) 144 (52.4%) p Placental abruption (N = 17) 2605.0 g (71.2%) 21.8 253.8 days (90.5%) 8 (47.1%) 1a (5.9%) 2 (11.8%) 7 (41.2%) 4 (23.5%) 8 (47.1%) 1 (5.9%) 1 (5.9%) 7 (41.2%) 8 (47.1%) p

Mean birth weight (study group percentage of the reference group) Mean placental weight/birth weight ratio (%) Mean duration of pregnancy (study group percentage of the reference group) Caesarean section Vacuum delivery Asphyxia Abnormal Apgar (<7) at 1 min Abnormal Apgar (<7) at 5 min Intensive care Stillbirth Neonatal death Low birth weight Fetal gender male
a *

3064.2 g (83.7%) 19.0 265.2 days (94.6%) 68 (38.9%) 11a (6.3%) 4 (2.2%) 32 (18.3%) 13 (7.4%) 43 (24.6%) 0 0 39 (22.3%) 95 (54. 3%)

<0.001 <0.001 <0.001

<0.001 <0.001 <0.001

<0.001 <0.001 <0.001

<0.001 <0.001 <0.001

346 (16.0%) 154a (7.1%) 26 (1.2%) 98 (4.5%) 36 (1.7%) 99 (4.6%) 0 0 0 1156 (53. 4%)

<0.001 0.46 0.22* <0.001 <0.001 <0.001 1 1 <0.001 0.83

<0.001 0.01 0.34* <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.01

<0.01 0.47 0.77* <0.001 <0.001 <0.001 0.11* 0.11* <0.001 0.74

<0.001 1.00* 0.02* <0.001 <0.001* <0.001 <0.001* <0.001* <0.001* 0.63*

Data missing in less than 10% of cases. When a class included less than 5 variables, Fishers exact test was used.

J.K. Ranta et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 157 (2011) 4852 Table 3 First trimester Downs syndrome screening in the study groups (N = 2844). Characteristic Study groups Reference group (N = 2164) fb-hCG median MOM PAPP-A median MOM NT median MOM Screening positive
*

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Preeclampsia (N = 175) 0.86 0.79 1.06 9 (5.1%)

Premature delivery (N = 213) 0.92 0.80 1.06 14 (6.6%)

Small for gestational age infants (N = 275) 0.90 0.79 1.05 13 (4.7%)

Placental abruption (N = 17) 0.92 1.00 1.22 0

0.99 0.99 1.05 57 (2.6%)

0.02 <0.001 0.63 0.06

0.02 <0.001 0.52 0.001

<0.01 <0.001 0.75 0.05

0.62 0.76 0.59 1.00*

When a class included less than 5 variables, Fishers exact test was used.

Table 4 Odds ratios (95% condence interval) for adverse pregnancy outcomes relative to MOM values in the study groups (N = 2844). Biochemical marker Reference group (N = 2164) Preeclampsia (N = 175) OR (CI) Premature delivery (N = 213) OR (CI) Small for gestational age infants (N = 275) 177 (64.4%) 140 (50.9%) 99 (36.0%) 54 (19.6%) OR (CI) Placental abruption (N = 17) OR (CI)

PAPP-A MOM <1.0 <0.8 <0.6 <0.4 fb-hCG MOM <1.0 <0.8 <0.6 <0.4

1097 (50.7%) 768 (35.5%) 445 (20.6%) 154 (7.1%)

121 (69.1%) 92 (52.6%) 61 (34.9%) 27 (15.4%)

2.06 (1.512.81) 1.91 (1.432.53) 1.94 (1.442.60) 2.18 (1.493.18) 1.32 (0.991.76) 1.45 (1.091.93) 1.51 (1.112.07) 1.12 (0.651.93)

138 (64.8%) 107 (50.2%) 71 (33.3%) 29 (13.6%)

1.70 (1.302.23) 1.73 (1.342.24) 1.80 (1.382.36) 1.89 (1.322.71) 1.16 (0.901.50) 1.16 (0.891.51) 1.42 (1.071.89) 1.41 (0.912.17)

1.65 (1.312.09) 1.75 (1.402.18) 1.96 (1.562.46 2.62 (2.023.40) 1.22 (0.971.52) 1.36 (1.091.70) 1.42 (1.111.82) 1.70 (1.222.38)

9 (52.9%) 5 (29.4%) 2 (11.8%) 2 (11.8%)

1.09 (0.422.82) 0.76 (0.272.15) 0.52 (0.122.25) 1.73 (0.407.50) 1.76 (0.654.75) 1.24 (0.473.24) 1.24 (0.413.79) 2.97 (0.8710.28)

1101 (50.9%) 780 (36.0%) 429 (19.8%) 143 (6.6%)

102 (58.3%) 80 (45.7%) 49 (28.0%) 13 (7.4%)

117 (54.9%) 85 (39.9%) 57 (26.8%) 20 (9.4%)

155 (56.6%) 122 (44.4%) 74 (26.9%) 32 (11.6%)

11 (64.7%) 7 (41.2%) 4 (23.5%) 3 (17.7%)

SGA, and 1.76 for PA. The odds ratio of PAPP-A MOM <1.0 was 2.06 for PE, 1.70 for PD, 1.65 for SGA, and 1.09 for PA. In pregnancies with PD and SGA, the odds ratio with decreasing PAPP-A MOM increased linearly, whereas in pregnancies with PE the odds ratios were variably higher with low PAPP-A MOMs. In PA pregnancies, the odds ratios were most variable; 0.76 for PAPP-A MOM <0.8, 0.52 for PAPP-A MOM <0.6, and 1.73 for PAPP-A MOM <0.4. The odds ratios of developing an adverse outcome at different MOM levels are presented in Table 4, including the sizes of the subgroups with different MOM levels.

4. Comment Many previous studies have examined the usefulness of rst trimester maternal biochemistry in predicting adverse pregnancy outcomes and have shown that, in particular, low PAPP-A is associated with preterm birth, PE and impaired fetal growth. Our data are consistent with previously reported results [10,12,21]. Low levels of fb-hCG and PAPP-A probably reect impaired placentation, and in addition, pregnancy-associated plasma protein A (PAPP-A) is known to be an insulin-like growth factor binding protein (IGFBP) protease and to increase the bioavailability of IGF. In turn, IGF is believed to play a role in fetal growth [22] by mediating trophoblast invasion to the decidua, and to regulate steroidogenesis and glucose and amino acid transport in the chorionic villi [23]. The mechanism involved with most adverse outcomes such as PD, PE, and SGA may be related to the protease activity of PAPP-A affecting free IGF concentrations in early pregnancy. In our study, the more the PAPP-A and fb-hCG

concentrations were below the normal median value, the more likely was the occurrence of PD, PE and SGA. Our main interest, however, was in pregnancies with PA, since prediction of this outcome has clear clinical relevance, due to familial clustering and a substantial risk of recurrence. It was signicant that no changes were seen in rst trimester maternal serum PAPP-A and fb-hCG concentrations in patients who subsequently developed PA. It is also interesting that during the second trimester, no difference between normal pregnancies and PA pregnancies has been found in fb-hCG levels, whereas alpha fetoprotein (AFP) has been found normal [24] or signicantly higher in PA pregnancies [25]. Alpha fetoprotein is a glycoprotein secreted by fetal tissues alone. PA has been considered to be a disease of the decidua rather the placenta. Furthermore, it has been established that in pregnancies with PA fetal growth is usually not compromised [6] and, therefore, the lack of signs of early placental dysfunction was to be expected. One multi-centre study into the association between low PAPP-A and PA, where diagnosis of the condition was based on bleeding in late pregnancy, found a signicant association in cases with a very low rst trimester PAPP- A (<5th percentile, 0.42 MoM); but using this cut-off less than 10% of all PAs were recognized [16]. The association between serum markers and adverse outcomes was relatively weak in the present study, which, therefore, limits the clinical usefulness of the screening data. On the other hand, clinical risk factors such as smoking during pregnancy, which increase the risk of preterm birth [26], are considered signicant at a much lower risk level. Our ndings, as well as earlier reports, imply that pregnancies with moderate or high risk for developing PD, PE or SGA can be recognised during the rst trimester, and

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guided for further testing. Since the number of pregnancies with PA is very low at population level, our estimation of odds ratios on low PAPP-A is only directional. Unfortunately, cases of PA, even where patient and familial history may both identify patients at risk, appeared to be unpredictable on the basis of the biochemical screening used here. Furthermore, there is no treatment for PA, whereas for PE evidence has been found that antithrombotic medication is efcient in prevention [20]. In PD, PE, and SGA, placental dysfunction may be the primary disturbance underlying the mechanisms that give rise to these outcomes. Assessment of placentation and placental function in the rst trimester may offer new insights into the etiological aspects of adverse outcomes of pregnancy. The overall number of complicated pregnancies was low in the present study, and it is obvious that further studies are needed to fully evaluate the potential of rst trimester screening markers to predict adverse outcomes. References
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