https://orcid.org/0000-0003-1806-3889
ABSTRACT
Background
To evaluate the correlation between elevated maternal serum alpha-fetoprotein (AFP) in the second trimester and ischemic placental disease (IPD).
Methods
A retrospective cohort study was conducted to analyze the data of 22,574 pregnant women who delivered in the Department of Obstetrics at Hangzhou Women’s Hospital from 2018 to 2020, and were screened for maternal serum AFP and free beta-human chorionic gonadotropin (free β-hCG) in the second trimester. The pregnant women were divided into two groups: elevated maternal serum AFP group (n = 334, 1.48%); and normal group (n = 22,240, 98.52%). Mann-Whitney U-test or Chi-square test was used for continuous or categorical data. Modified Poisson regression analysis was used to calculate the relative risk (RR) and 95% confidence interval (CI) of the two groups.
Results
The AFP MoM and free β-hCG MoM in the elevated maternal serum AFP group were higher than the normal group (2.25 vs. 0.98, 1.38 vs. 1.04) and the differences were all statistically significant (all P < .001). Placenta previa, hepatitis B virus carrying status of pregnant women, premature rupture of membranes (PROM), advanced maternal age (≥35 years), increased free β-hCG MoM, female infants, and low birth weight (RR: 2.722, 2.247, 1.769, 1.766, 1.272, 0.624, 2.554 respectively) were the risk factors for adverse maternal pregnancy outcomes in the elevated maternal serum AFP group.
Conclusions
Maternal serum AFP levels during the second trimester can monitor IPD, such as IUGR, PROM, and placenta previa. Maternal women with high serum AFP levels are more likely to deliver male fetuses and low birth weight infants. Finally, the maternal age (≥35 years) and hepatitis B carriers also increased maternal serum AFP significantly.
Introduction
Maternal serum alpha-fetoprotein (AFP) is a glycoprotein composed of 590 amino acids that is mainly produced by fetal liver cells and the soft yolk sac during pregnancy (Citation1). AFP synthesis by the proliferating fetal liver increases through 20 weeks gestation, after which synthesis remains fairly constant until 30–32 week gestation, then decreases until birth (Citation2). During pregnancy, AFP is excreted into fetal urine and diffuses into maternal serum through the placenta or fetal membranes. Adverse pregnancy reactions, such as fetal open neural tube defect (ONTD), congenital nephrotic syndrome, placental injury, serum, or cerebrospinal fluid leakage, and gastrointestinal tract damage, result in rapid protein filtration, placental channel changes, or obstruction, and maternal serum AFP levels increase (Citation3,Citation4).
In general, an elevated maternal serum AFP level suggests a high probability of fetal ONTD, and prenatal screening requires amniotic fluid AFP and acetylcholinesterase measurement, combined with fetal ultrasound and maternal tumor screening (Citation5). Indeed, pregnant women with elevated AFP levels are at higher risk for adverse pregnancy outcomes in the third trimester of pregnancy (Citation6–8). The clinical features of ischemic placental disease (IPD) mainly refer to one or more clinical manifestations of preeclampsia, fetal intrauterine growth restriction (IUGR), or placental abruption (Citation9,Citation10), whereas placenta-mediated IPD causes adverse pregnancy outcomes, usually with an increase in maternal serum AFP values (Citation11–14). In addition, maternal serum AFP may be affected by maternal characteristics, such as weight, height, and blood pressure, and fetal weight and length (Citation15).
Maternal serum AFP is a biochemical marker used for prenatal screening in the second trimester of pregnancy (Citation16), mainly used for screening of aneuploidy and open neural tube defects; however, there is no unified conclusion on the correlation between the maternal serum AFP level and IPD. Consequently, a large, retrospective cohort study was carried out to determine the relationship between the maternal serum APF level and IPD, including the screening efficiency of maternal serum AFP and adverse pregnancy outcomes, such as IPD, based on the clinical data of 22,574 women in the second trimester (15–20+6 weeks).
Methods
Participants
In the retrospective cohort design, we collected data from 24,001 pregnant women who hospitalized in the Department of Obstetrics at Hangzhou Women’s Hospital from January 2018 to December 2020, and participated in maternal serum AFP and free beta-human chorionic gonadotropin (free β-hCG) screening in the second trimester (15–20+6 weeks). After excluding cases that failed to satisfy the inclusion criteria, a total of 22574 cases were included, as shown in . Of these, 334 cases were in the elevated maternal serum AFP group [AFP ≥ 2.00 multiples of the median (MoM)] and 22,240 cases were in the normal maternal serum AFP group (0.50 MoM ≤ AFP < 2.00 MoM). This study was approved by the Medical Ethics Committee of the Hangzhou Women’s Hospital [2020 Medical Ethics Review A Citation10(11)]. Since this study is a retrospective study, the need to obtain informed consent was waived by the Human Research Ethics Committee of the Hangzhou Women’s Hospital.
Figure 1. Flow chart of participants selection in this study.
Diagnostic and exclusion criteria
Diagnostic criteria
All diagnoses were gotten from clinical records diagnosed by obstetricians in hospitals according to the corresponding Chinese guidelines (Citation17–20), which could be divided into pregnancy complications and pregnancy outcomes. Pregnancy complications included hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, thrombocytopenia, hyperlipidemia, and hypothyroidism/hyperthyroidism during pregnancy. The other included premature rupture of membranes (PROM), fetal distress, IUGR, placental abruption, oligohydramnios, nuchal umbilical cord. Maternal age was divided into 20 - 24 years, 25 - 29 years, 30 - 34 years, ≥35 years. Gestational ages were divided into 3 groups (<37 weeks, 37 - 41 weeks, > 41 weeks). Body Mass Index (BMI) was divided into four groups [Thin (<18.5 kg/m2), normal (18.5 - 24.9 kg/m2), overweight (25 - 30 kg/m2), obesity (>30 kg/m2)] according to the World Health Organization. HDP included preeclampsia and gestational hypertension, amniotic fluid volume includes polyhydramnios and oligohydramnios. Low birth weight referred to a neonatal weight < 2500 g, and a fetal macrosomia referred to a newborn weight ≥ 4000 g (Citation21).
Exclusion criteria
The exclusion criteria were as follows: twin or multiple gestations; maternal smoking; in vitro fertilization pregnancies; 21 and 18 trisomy, ONTD, and other congenital defects; history of immunotherapy or blood transfusion; history of special medication during pregnancy; chronic hypertension, heart disease, kidney disease, connective tissue disease, hematologic disease, and other chronic diseases; incomplete information; serum AFP < 0.5 MoM ().
AFP detection
Instruments and reagents
The following experimental equipment and reagents were used in this study: a 1235 Auto time-resolved fluorescence immunoassay (DELFIA®) analyzer (PerkinElmer, Shelton, USA); a dual labeling reagent kit (AFP/free β-hCG); enhancer, lotion, and quality standards (PerkinElmer).
Detection process
Fasting venous blood was drawn from mid-pregnant women, usually about 2 mL-3 mL, stored at 2–8°C after separation, and the AFP was detected within 1 week. Maternal serum AFP measurements were uniformly performed using the DELFIA® method in strict accordance with the instructions of the reagents and equipment. Internal and external quality assessments were used to ensure the test quality.
Expression of AFP level
We calibrated the multiple of the median (MoM) of the blood index, such as AFP or free β-hCG, and then instead of the maternal original concentration. The AFP MoM was based on characteristic parameters, such as gestational age and maternal weight. The following is the algorithm and definition of MoM, MoM = [Measured AFP (U/mL)]/[median AFP for gestational age (U/mL) × adjustments] (Citation22).
Statistical analysis
Statistical analysis was performed using IBM-SPSS (version 21.0; IBM-SPSS, Chicago, IL, USA). A one-sample Kolmogorov-Smirnov test was used to test the data normality. The skewed distribution was expressed as the median and percentile [M (P2.5 – P97.5)]. The Mann-Whitney U-test or Chi-square test was used for univariate analysis of continuous or categorical data. A P < .10 was selected as the screening criteria for modified Poisson regression analysis, which was used to determine the relative risk (RR) and the 95% confidence interval (CI) of variables relating to each relevant influencing factor. The first variables to be considered were maternal age, BMI, free β-hCG MoM, gravidity, mode of delivery, HDP, pregnancy with Mycoplasma infection, placenta previa, PROM, amniotic fluid volume, hepatitis B carriers, fetal IUGR, infant weight, infant length and infant gender, and the main effect method was used to establish the model. A P < .05 indicated that the results were statistically significant.
Results
Comparison of screening parameters among cohort participants
The AFP MoM and free β-hCG MoM in the elevated maternal serum AFP group were higher than the normal group (2.25 vs. 0.98, 1.38 vs. 1.04) and the differences were all statistically significant (Z = 31.421, Z = 8.521, all P < .001; ). In addition, maternal age, gestational age, and mode of delivery were also statistical differences between the two groups (x2 = 21.383, x2 = 38.528, x2 = 9.170, all P < .05; ). The fetal birth weight, length, and infant gender affected the maternal serum AFP level, and the results in the two groups were statistically significant, respectively (x2 = 135.545, Z = 10.193, x2 = 13.312, all P < .05; ). But maternal weight, height, BMI, systolic blood pressure, diastolic blood pressure, mean arterial pressure, gravidity and parity before delivery, and fetal score after birth between the AFP and normal groups were no statistically significant (all P ≥ .05; & ).
Table 1. Univariate demographic analysis of pregnant in the elevated maternal serum AFP group and normal group.
Table 2. Univariate demographic analysis of newborn in the elevated maternal serum AFP and normal groups.
Univariate analysis of influencing factors
Univariate analysis showed that hypertension during pregnancy, Mycoplasma infection, hepatitis B carrier, placenta previa, premature delivery, PROM, and fetal IUGR were significantly associated with an elevated maternal serum AFP level (all P < .10). The other variables were not statistically significant between the two groups (all P > .10; and ).
Table 3. Pregnancy complications of mothers in the elevated maternal serum AFP group and normal group n (%).
Table 4. Pregnancy outcomes of mothers in the elevated maternal serum AFP group and normal group n (%).
Modified Poisson regression analysis
As shown in , placenta previa (RR = 2.722; 95% CI = 1.335–5.550, P = .006), hepatitis B carrier (RR = 2.247; 95% CI = 1.571–3.212, P < .001), PROM (RR = 1.769; 95% CI = 1.377–2.271, P< .001), maternal age (≥35 years) (RR = 1.766; 95% CI = 1.038–3.004, P = .036), free β-hCG MoM (RR = 1.272; 95% CI = 1.212–1.334, P < .001) were significantly higher in women with elevated serum AFP. On the pregnancy outcome of the fetus, the correlation between infant gender (female) (RR = 0.624; 95% CI = 0.500–0.779, P < .001), low birth weight (RR = 2.554; 95% CI = 1.538–4.239, P < .001) and high maternal serum (AFP) was statistically significant. The other factors were not correlated with an increase in maternal serum AFP levels, and there was no significant difference between groups (P > .05).
Table 5. Modified Poisson regression analysis of maternal characteristics and pregnancy outcomes.
Discussion
We have reviewed the relevant of the maternal serum AFP level and pregnancy outcome in Hangzhou, and described how placental disease increases the maternal serum AFP level. In this cohort study, we found that the advanced maternal age (≥ 35 years) in the elevated maternal serum AFP group was significantly higher than in the normal group (RR = 1.766), the findings of Alexandra et al. (Citation23) also proved this, in which the maternal age of pregnant women with placental diseases was older, and the AFP MoM values were also higher. Souter et al. (Citation24) showed that there was no significant correlation between maternal age and the AFP value. Furthermore, we also showed that the BMI index of pregnant women in the high maternal serum AFP group was slightly lower, and Blumenfeld et al. (Citation25) are of the opinion that maternal serum AFP content is negatively correlated with the BMI index, which was similar to a current study, suggesting that maternal obesity is relevant to the protective effect of placental abruption, which is in contrast to other obstetric risks related to obesity.
showed that the probability of the increase of serum AFP levels in pregnant women with female fetuses was 0.624 times than that in male fetuses. It had been reported that the umbilical cord driven and venous AFP levels of male infants were significantly higher than those of female infants, so the maternal serum AFP levels were correspondingly increased (Citation26). Our results also showed that maternal women with high serum AFP levels were more likely to deliver low birth weight infants (RR = 2.554), Bartkute etal. (Citation27) found that newborn weight was significantly lower in the elevated maternal serum AFP group (P < .001), and newborns had a week lower gestational age at delivery (P < .05), which was consistent with the results of our study. However, the mechanism of maternal high AFP levels leading to low birth weight needs further study.
We also demonstrated a significant increase in maternal serum AFP in the second trimester of maternal carriers of hepatitis B virus (RR = 2.247). Pregnant women with hepatitis B had more bad pregnancy risks, such as intrahepatic cholestasis of pregnancy, postpartum anemia, PROM, and tubal cysts (Citation28,Citation29). AFP is the most commonly used diagnostic marker in primary liver cancer, and hepatocellular carcinoma is directly related to basic liver disease, especially caused by hepatitis B virus infection, so AFP is related to the size, differentiation, and transformation of hepatitis B, which can cause the increase of serum AFP concentration (Citation30).
From , AFP MoM and free β-hCG MoM were significantly different between the two groups, and the level of free β-hCG MoM in the elevated AFP group was 1.272 times higher than in the normal group. Zhang and his partner (Citation31) proposed that the screening marker of free β-hCG and AFP levels in the second trimester were related to adverse pregnancy outcomes, and free β-hCG (≥ 2.20 MoM) and AFP (≥1.88 MoM) were associated with placental-related complications (P < .01, 0.05, respectively).
A prospective study by Konachuk et al. (Citation32) showed that 35% of the pregnant women with unexplained elevated AFP levels had at least one adverse perinatal outcome, such as IUGR, PROM, placenta previa, preeclampsia, oligohydramnios, and placenta implantation (Citation13,Citation14). As is shown in , the risk of PROM (RR = 1.769) and placenta previa (RR = 2.722) in pregnant women with elevated serum AFP levels were much higher. Aboughalia et al. (Citation33) believed that the increase in serum AFP can be regarded as a doubling of the risk of PROM. Annular placenta is associated with a higher incidence of IUGR, premature delivery rate, and intrapartum hemorrhage. AFP may be a valuable predictor of IUGR in patients with an annular placenta (Citation12). Ischemic placenta and placenta implantation are also considered to be associated with IUGR, postpartum hemorrhage, preeclampsia (mainly premature delivery), and placental abruption (Citation22,Citation34). Placental interstitial dysplasia can also cause fetal and maternal complications (Citation35), and the specific symptoms are similar to the adverse pregnancy outcomes described herein.
Preeclampsia or IUGR caused the unexplained increase in maternal serum markers, which is related to placental dysfunction (Citation13). It has been reported that excessive maternal-fetal circulation due to placental surface damage results in an increased maternal serum AFP level (Citation36). In contrast, we found that the correlation between the elevated maternal serum AFP group and preeclampsia or IUGR was not significant, which was different from the above-mentioned studies, and thus, warrants further verification by enlarging the preeclampsia sample size.
However, there were some limitations that need to be considered. First, 22574 cases only represented the pregnancy outcome of singleton natural pregnant women in Hangzhou Women’s Hospital from 2018 to 2020. Second, the limitations of this study include the lack of more prenatal screening data related to IPD, and on this basis, modified Poisson regression analysis was conducted to preliminarily explore the relationship between pregnancy outcomes, such as IPD and maternal serum AFP. Third, this was a retrospective cohort study, not a targeted clinical study, which may lead to mixed bias and need to be verified by larger cohort or multicenter data.
Conclusion
This cohort study showed that the increase of AFP level was significantly related to IPD and other placenta-related adverse pregnancy outcomes, such as PROM, placenta previa, etc. Secondly, in fetuses, maternal women with high serum AFP levels are more likely to deliver male fetuses and low birth weight infants. Finally, advanced maternal age and hepatitis B carriers also increased serum AFP levels significantly. Therefore, the increase of maternal serum AFP level during the second trimester can dynamically monitoring the risk of adverse pregnancy outcomes. HDP is caused by high AFP levels, we need to further expand the sample size for prospective research.
Abbreviations
AFP: alpha-fetoprotein; free β-hCG: free beta human chorionic gonadotropin; IPD: ischemic placental disease; IUGR: intrauterine growth restriction; PROM: premature rupture of membranes; HBV: hepatitis B virus; HDP: hypertensive disorders of pregnancy; RR: relative risk; CI: 95% confidence intervals.
Ethics approval and consent to participate
The study has been conducted under the approval of the Human Research Ethics Committee of the Hangzhou Hospital [2020 Medical Ethics Review A (10)-11], and the procedures have been performed in accordance with the Declaration of Helsinki. Since this study is a retrospective study, the need to obtain informed consent was waived by the Human Research Ethics Committee of the Hangzhou Women’s Hospital.
Author contributions
X.Q. Dai and Y.M. Chen, design, and statistical analysis; Y.J. Chen and W.W. Ning wrote the first draft of the manuscript. H.M. Zang and B. Wu, provision of study material or patients; Y.M. Chen and X.Q. Dai, writing-review & editing. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Acknowledgments
The authors are grateful to all of the participants and contributors. We would like to thank Songhe Chen from Hangzhou Women’s Hospital for helping to collect the data. We would also like to thank Xiao Lu of the Data Analysis Department, Zhejiang Biosan Biochemical Technologies Co., Ltd., for their contribution to data matching. We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Additional information
Funding
References
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