In this study, we found that elevated first-trimester MS-AFP is associated with increased risks of preterm birth, preeclampsia and SGA. However, the predictive efficiencies were low and it is not a good predictor for these APOs.
In our previous studies on second-trimester MS-AFP and APOs, the AUROC was 0.686, 0.717 and 0.611 for preterm birth, preeclampsia and SGA, respectively; women with second-trimester MS-AFP ≥ 2.5 MoM had increased risks (OR, 95% CI) of preterm birth (4.10, 2.44~6.88), preeclampsia (3.95, 2.23~6.99) and SGA (3.45, 1.91~6.21) . The results were in general agreement with other studies on second-trimester MS-AFP and APOs [6,9-12]. A case-control study on MS-AFP and preeclampsia also revealed that MS-AFP was elevated in both the first and the second trimesters in pregnancies that developed preeclampsia, but the performance of second-trimester MS-AFP combined with maternal factors for preeclampsia screening was better than that of first-trimester MS-AFP . Taking others’ and our findings together, we can conclude that first-trimester MS-AFP is less predictive of APOs than second-trimester MS-AFP.
The lower efficiencies of first-trimester MS-AFP than second-trimester MS-AFP for the predictions of APOs may be interpreted by the mechanism of MS-AFP elevation. Unlike other maternal serum markers produced by the placenta, AFP is fetal-derived during pregnancy. Elevated MS-AFP is thought to reflect excessive placental permeability that leads to the escape of AFP from the fetus to the mother [24,25]. This was verified in the animal studies that lipopolysaccharide-induced intrauterine inflammation gave rise to increased placental permeability and lipopolysaccharide-treated pregnant rats had elevated MS-AFP [26,27]. It has been known that the placenta plays important roles in the pathophysiology of a number of APOs. Preterm birth, preeclampsia and SGA are currently considered as “placenta-mediated” disorders [28-30]. A series of evidences indicated that increased placental permeability might occur in these disorders [31-33]. Therefore, we may infer that, starting from the end of the first trimester when the primitive placenta undergoes remodeling to form the definitive organ, the increase in placental permeability is a gradually developed process under certain pathological conditions. In the process, placental permeability to AFP is also increasing from the first to the second trimester. As a typical placenta-mediated disease, the pathogenesis of preeclampsia may support our inference by its “two-stage” model: maternal vascular malperfusion caused by poor trophoblast uterine invasion and impaired transformation of the spiral arteries in the first trimester leads to placental inflammation and vascular endothelial injury that cause placental dysfunction and precipitate the onset of the maternal syndrome in the later gestation .
In the recent years, much concern has been raised about the first-trimester screenings for APOs which are considered as a window of opportunity to predict and prevent these disorders . In addition to preeclampsia, it has been reported that low-dose aspirin use during pregnancy is also effective in the prevention of other APOs [36-38]. ACOG Committee opinion recommends that low-dose aspirin prophylaxis commenced optimally before 16 gestational weeks . Given this, the need for early predictions of APOs is important. Although our findings indicated that first-trimester MS-AFP is not efficient enough for the predictions of APOs, it showed significant associations with these disorders and may play a role in the combined multi-marker screenings. In addition to preeclampsia screening which has achieved much progress, the first-trimester combined multi-marker screenings for other APOs have also been explored in the recent years. Beta et al described a model based on the factors identifiable in the first trimester which detected 18.4 and 38.2% of preterm birth for nulliparous or primiparous women at a 10% false-positive rate . Greco et al described a screening method combining cervical echography with maternal characteristics and obstetric history which detected 54.8% of preterm birth at a 10% false-positive rate . Poon et al published a predictive algorithm involving demographic, biophysical and biochemical parameters which had a detection rate of 55.5% for preterm SGA and 44.3% for term SGA with a 10.9% false-positive rate . Akolekar et al reported a screening model base on maternal factors, PlGF, fetal ductus venosus and uterine artery pulsatility index which predicted 42% of all stillbirths and 61% of those due to impaired placentation at a false-positive rate of 10% . These models for APOs screenings are in the developing stage. Incorporation of further variables may help to improve the screening efficacies, and first-trimester MS-AFP may be a promising biochemical marker.
It was reported that singleton pregnancies following assisted reproductive technology had increased risk of APOs; MS-AFP levels in women who were conceived using assisted reproductive technology was different from that of natural conceptions [43-45]. These might be the reason why elevated MS-AFP group had higher proportion of assisted reproductive technology in our study. Besides, elevated MS-AFP group had lower maternal serum PAPP-A. The possible reason is that PAPP-A is also a marker for APOs, and decreased PAPP-A is associated with increased risk of APOs . In our data analysis, it was indeed that MS-AFP was negatively correlated to PAPP-A (Pearson correlation P = 0.010). In China, the caesarean section rate increased from 29% in 2008 to 35% in 2014. After the relaxation of the one-child policy in November 2013, considering the safety of delivery, hospitals in China were generally reluctant to try vaginal birth after cesarean (VBAC). In 2016, the caesarean section rate was 41.1% in China . That was the reason why we had a high caesarean section percentage in this study.
Altogether, this study provides evidence that elevated first-trimester MS-AFP is associated with increased risk of preterm birth, preeclampsia and SGA, but the predictive efficiencies were low for these APOs, even if the subdivisions of APOs were applied for analysis. However, as the importance of first-trimester combined multi-marker screenings for APOs are increasingly emphasized in the recent years, first-trimester MS-AFP may also be a useful marker in the future studies on this subject.