Ultrasound findings in prenatal diagnosis of trisomy 18 associated with elevated levels of maternal serum alpha-fetoprotein: Case report : Medicine: Case Reports and Study Protocols

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Ultrasound findings in prenatal diagnosis of trisomy 18 associated with elevated levels of maternal serum alpha-fetoprotein

Case report

Chen, Yiming MBBSa,b; Ning, Wenwen MDb; Chen, Yijie MDb; Huai, Lei PhDc; Huang, Anqian MDd

Author Information
Medicine: Case Reports and Study Protocols 3(10):p e0238, October 2022. | DOI: 10.1097/MD9.0000000000000238


1. Introduction

Trisomy 18, also referred to as Edwards syndrome (ES), is the second most common autosomal trisomy syndrome.[1] The prevalence of live-born infants with trisomy 18 ranges from 1/6000 to 1/8000. Most fetuses with trisomy 18 are medically or surgically terminated during gestation; consequently, the incidence of trisomy 18 is far higher than current statistics and is estimated to range from 1/2500 to 1/2600.[1] Trisomy 18 is generally caused by the nondisjunction of chromosome 18 during the meiotic division of maternal germ cells, including full and mosaic trisomy 18.[2]

The clinical manifestations of trisomy 18 fetuses are complex and varied, including abnormalities in mental development along with multiple and severe structural abnormalities. Maternal age, pregnancy serological screening, and ultrasound screening have all been widely used for screening trisomy 18 and other chromosomal abnormalities.[3] Trisomy 18 can be identified during prenatal screening by the detection of abnormal maternal serum results and one or more structural abnormalities on ultrasound. Increased nuchal translucency thickness and nasal bones can be detected during the first and second trimesters of pregnancy. In the second and third trimesters, ultrasonography can often reveal congenital heart defects, choroid cysts, abnormal posturing of the hands, a “strawberry-shaped” cranium, omphalocele, and a single umbilical artery.[2–4] Previous studies confirmed that levels of pregnancy-related plasma protein A (PAPP-A), alpha-fetoprotein (AFP), and free β-subunit of human chorionic gonadotropin (free β-hCG) in the serum of pregnant women carrying fetuses with trisomy 18 were lower than those in women with normal pregnancies.[5] We encountered a case of trisomy 18 associated with elevated levels of maternal serum alpha-fetoprotein (MSAFP) and multiple abnormal features on ultrasonography in a fetus. Here, we present this case and provide a review of the relevant literature.

2. Case Report

The patient was a 29-year-old pregnant woman, G2A1, who was in normal health. There were no clinical signs of concern during pregnancy like vaginal bleeding. Her gynecologic history was normal. She did not receive folic acid supplements regularly and had a medical abortion 1 year prior to her current pregnancy. She had no history of viral infection, radiation exposure, tobacco, alcohol, or chemical exposure.

At 12 + 2 weeks of gestation, the results of maternal serum screening in the first trimester presented a PAPP-A of 1120 1220 mU/L (0.31 multiple of the median (MoM)), a free β-hCG of 4.21 ng/mL (0.07 MoM), a fetal nuchal translucency (NT) thicknessNT of 2.60 mm (1.95 MoM), a trisomy T21 risk value of 1/1016bn0, and a trisomy T18 risk value of 1/16. At 16 weeks of gestation, combined first and second trimester maternal serum screening results showed an AFP level of 125 U/mL (3.52 MoM), a free β-hCG of 2.39 ng/mL (0.11 MoM), a trisomy T18 risk value of 1/5, and a trisomy T21 risk value of 1/77121. At 21 weeks of gestation, the ultrasonic diagnosis was a “strawberry head,” multiple bilateral choroid plexus cysts, cleft lip and palate, and atrioventricular septal defect, as shown in Figures 1–3. After amniocentesis, we performed the BACs-on-Beads (Bobs) technique on amniotic fluid cells, and the results revealed a fetus with trisomy 18 (Fig. 4). The karyotype of the fetus was 47, XY, and + 18.

Figure 1.:
Ultrasound image showing a strawberry head.
Figure 2.:
Ultrasound image showing a choroid plexus cyst.
Figure 3.:
Ultrasound showing a cleft lip and palate.
Figure 4.:
Application of the BACs-on-Beads (Bobs) technique with amniotic fluid cells revealed a fetus with trisomy 18.

With the consent of the patient, the pregnancy was terminated at 21 + 2 weeks of gestation. A male stillbirth corresponding to the gestational age was delivered vaginally, weighing 292 g and measuring 23 cm. Upon examination, the proband exhibited a strawberry head along with cleft lip and palate, and the fetal membrane was completely developed.

3. Discussion

Chromosomal abnormalities are a major cause of death and disability in perinatal infants. Trisomy 18 is the second most common autosomal trisomy after Down syndrome.[6] The older the maternal woman, the higher the incidence of trisomy 18.[7] The prognosis for trisomy 18 after delivery is poor. Even if a fetus survives, the median survival is only 3–6 days, with less than a 50% chance of survival for a week and only a 5–10% chance of survival for 1 year.[8] Fetuses with complete trisomy 18 have multiple severe malformations, while mosaic trisomy 18 is associated with milder clinical manifestations and a longer survival time. A previous study described a girl with trisomy 18 who was more than 26 years old. She was in a stable condition but experienced repeated infections of the respiratory system.[9] Studies have found that the number of surviving female infants with trisomy 18 is far higher than the number of male infants, although this discrepancy disappears when the sex ratio of terminated fetuses is included.[10,11]

AFP is a glycoprotein that is often referred to as fetal albumin and is produced by the yolk sac of the embryo and the fetal liver. Levels of MSAFP increase during the first trimester, peak between 28 and 32 weeks of gestation, and then drop to lower levels in the third trimester.[12] MSAFP can be used as an efficient indicator of fetal growth and development. Elevated levels of MSAFP are usually associated with open neural tube defects (ONTD) and abdominal wall defects in fetuses. This is because AFP produced by the fetus is released into the amniotic fluid through the opening of the neural tube and then enters the mother’s body through the placenta. Therefore, a high level of MSAFP is commonly used to screen for neural tube defects (NTD); the detection rate for anencephaly exceeds 95%, whereas the detection rate for ONTD is 65–80%.[12,13]

The lower AFP levels seen in autosomal disorders are often caused by abnormal development of fetal liver and kidney function, along with impaired placental transport.[14] Consequently, the MSAFP can be used to screen for abnormal autosomal diseases. Many previous studies have shown that the levels of MSAFP in cases of trisomy 21 and trisomy 18 are lower than those in women with normal pregnancies.[15] Our patient had elevated MSAFP levels (3.52 MoM). A review of the literature has identified a wide range of MSAFP levels in trisomy 18 pregnancies. Some researchers believe that AFP levels are abnormally elevated when trisomy18 is combined with a malformation of the cerebral nervous system. For example, Lindenbaum et al[16] retrospectively studied the levels of MSAFP in 58 pregnant women with trisomy18; in pregnancies without fetal omphalocele or neural tube defects, MSAFP levels were significantly lower during the second trimester (0.6 MoM). However, in pregnancies with omphalocele and NTD, MSAFP levels were significantly elevated (4–5 MoM). This may be due to the constant release of AFP into the amniotic fluid from the opening of the neural tube. In the present case, we detected abnormally elevated AFP levels. This may have indicated a recessive neurological malformation in the fetus, although ultrasound did not identify such a structure. It is also possible that the case was affected by other diseases, such as placental inflammation, which could have affected placental permeability, thus leading to the elevation of AFP in the maternal serum. In addition, MSAFP levels are normally dependent on the gestational age. Fetuses with trisomy 18 usually experience intrauterine growth restriction; therefore, the estimation of gestational age based on the last menstruation may lead to a lower AFP level at the corresponding gestational age.

In this case, ultrasonography demonstrated multiple abnormalities, including a “strawberry head,” multiple bilateral choroid plexus cysts, cleft lip and palate, and atrioventricular septal defect. Fetuses with trisomy 18 usually have severe or mild deformities and growth restrictions. Screening using comprehensive ultrasonography is of significant clinical importance in the detection of fetuses with trisomy 18 and other chromosomal abnormalities. A previous study showed that 72% of fetuses with trisomy 18 (21/29) showed 1 or more abnormalities on ultrasound screening before 24 weeks of gestation.[17] Furthermore, approximately 80–100% of fetuses with trisomy 18 present with different forms of heart defects; the most frequently observed anomalies are atrioventricular septal defects, patent ductus arteriosus, and tetralogy of Fallot.[18,19] In 30 cases of trisomy 18 pregnancy, Brumfield et al[20] showed that ultrasound could detect 70% of abnormalities in fetuses with trisomy 18 (95% confidence interval (CI): 53–86), which was higher than the detection rate by maternal serum screening (43%). The older the gestational age, the more abnormal the results can be detected using ultrasound. Studies have shown that the detection rate of abnormal chromosomal diseases, based on maternal serum screening and ultrasonography, can be as high as 92.7%. This is far higher than that of maternal serum screening and ultrasonography screening when performed separately.[21]

In conclusion, fetuses with trisomy 18 can be identified by prenatal screening with abnormal maternal serum screening results and abnormal ultrasonography findings related to 1 or more structural abnormalities. The combination of serum screening and detailed ultrasound screening can significantly improve the efficiency of detecting fetuses with trisomy 18. If systemic ultrasonography suggests the existence of structural abnormalities, an invasive prenatal diagnosis is the best option.


The authors wish to acknowledge the assistance of a supportive colleague and our patient for motivating us during the clinical and genetic investigations. We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Author contributions

Yiming Chen designed the study, and Wenwen Ning wrote the paper. Yijie Chen, Lei Huai, and A. Huang collected data and reviewed the final manuscript. All the authors have read and approved the manuscript.


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alpha-fetoprotein; free β-subunit of human chorionic gonadotropin; prenatal diagnosis; maternal serum screen; trisomy 18

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