Increased Cell-Free Fetal DNA Fraction in the First Trimester: A Sign of Abnormally Invasive Placenta?
05 November 2018 (eFirst)
Abnormally invasive placenta (AIP) is one of the most dangerous conditions associated with pregnancy, because it may cause severe peripartum hemorrhage resulting in acute maternal morbidity (i. e., due to the need for multiple blood transfusions, hysterectomy, uterine artery embolization, uterine balloon or uterine compression sutures or transfer to ICU) .
We report a case of a 35-year-old healthy, non-smoker pregnant woman, gravida 3, para 1, with a body mass index (BMI) of 21.7 presenting at 12 + 2 weeks of gestation for a first-trimester screening test. Her first pregnancy was complicated by late onset preeclampsia and she delivered vaginally at 36 + 6 weeks of gestation after induction of labor. After delivery, the retained placenta was removed with curettage. Six weeks later she underwent hysteroscopy and curettage due to retained placental tissue. In her second pregnancy she had an early missed miscarriage, treated with curettage.
The first-trimester screening test in her third pregnancy showed a low risk for trisomy 13, 18 and 21 as well as a low risk for preeclampsia. Nevertheless, she opted for non-invasive prenatal testing (NIPT) Harmony (Ariosa Diagnostics, San Jose, CA, USA) at 12 + 5 weeks of gestation, which showed a very low risk for all trisomies. The cell-free fetal (cff) DNA fraction of NIPT was highly elevated (35.3 %). During the next follow-up visit, an AIP was suspected on ultrasound studies conducted according to the recommendations from the European Working Group on Abnormally Invasive Placenta . On a 2 D grayscale image, a loss of clear zone with significant myometrium thinning and focal placental bulging as well as a large number of abnormal placental lacunae could be detected. Additional color Doppler ultrasound showed sub-placental hypervascularity and placental feeder vessels with high velocity blood flow, substantiating our suspicion for AIP.
We repeated NIPT at 26 + 6 weeks of gestation. At that time, the cff DNA fraction was still elevated (26.1 %). Due to high suspicion of AIP, cesarean hysterectomy was scheduled at 34 + 0 weeks of gestation. Intraoperatively the AIP was seen, but the urinary bladder was not invaded by placental tissue and could be separated from the placental surface and the cervix. Patho-histological examination eventually confirmed the diagnosis of AIP ([Fig. 1]).
Since AIP can lead to life-threatening bleeding with multisystem organ failure and significant maternal morbidity, it is important to know that accurate prenatal diagnosis and multidisciplinary management have improved outcomes.
Over the past years, noninvasive prenatal testing (NIPT) using cff DNA has been widely introduced into clinical practice for the detection of trisomies 21, 18, and 13 with pooled detection rates of about 99 % and low false-positive rates (less than 0.1 %) .
A reliable clinical result is related to the proportion of fetal-to-maternal cell-free DNA in the maternal plasma, where the requested ratio for analysis is minimally 4 %. Different factors can influence this varying value of fetal fraction (ff). Apart from technical aspects, different biological factors can alter the ff level: maternal weight or BMI seem to be the strongest influencing factors, but gestational age is another affecting component .
Wang et al. evaluated the relationship between maternal weight, gestational age and cff DNA in more than 22 000 samples from singleton pregnancies, starting at 10 weeks of gestation. They noted a median cff DNA of 10.2 % between 10 + 0 and 10 + 6 weeks of gestation. Between 10 and 21 weeks of gestation, the cff DNA increased at a rate of 0.1 % per week, but interestingly, this rise was significantly steeper (at a rate of about 1 % per week) after 21 weeks of gestation .
As the release of cff DNA is closely related to placental morphogenesis, increased levels have been reported in pregnancies complicated by preeclampsia, intrauterine growth restriction and preterm labor   .
In addition, Sekizawa et al. reported increased levels of cff DNA during the third trimester in cases of placenta previa and even higher levels in two cases of AIP .
However, Samuel et al. could not find a significant difference in the mean cff DNA fraction in 7 patients with AIP compared with 6 cases of placenta previa and 7 cases of normal placentation with prior cesarean delivery . It is important to note that cff DNA fractions were assessed at a relatively advanced gestational age, i. e., at 34.5, 33.5 and 34.3 weeks of gestation, respectively. As the authors have already discussed, the abnormality in placental invasion with possibly increased apoptosis and release of cff DNA may be a process that takes place much earlier in gestation. It is therefore reasonable to assume that differences in cff DNA could be more pronounced when analyzed earlier in pregnancy.
Our patient with AIP had a very elevated level of cff DNA fraction, i. e., 35.3 % at the end of the first trimester. According to published data by Wang et al., the median level of cff DNA fraction in normal pregnancies at this gestational age is only around 10.4 %. The cff DNA fraction then decreased to 26.1 % at 26 + 6 weeks of gestation (median level at this gestational age is around 18 % according to Wang et al.). Our case, therefore, supports the assumption proposed by Samuel et al. that cff DNA fraction may be a better biomarker for AIP in the first trimester than later in pregnancy. Our case report and previous data from Sekizawa et al. should, therefore, prompt further studies on the diagnostic value of cff DNA fraction in early pregnancy for detecting AIP. Cff DNA as a possible marker of subsequent AIP could help to improve the accuracy of the prenatal diagnosis of morbidly invasive placenta.
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