Introduction
Fetal growth restriction (FGR) is one of the major obstetric complications that has been associated with term consequences as poor postnatal outcomes, perinatal morbidity, and mortality. (1). Nowadays, early prediction of FGR is the primary goal in maternal-fetal medicine, followed by prevention strategies in the antenatal period. Many thriving screening models like combining biochemical markers with Doppler were studied, but further investigation was needed to contribute (2, 3).
Two groups were defined for classifying FGR as early and late-onset FGR. Pregnancies complicated with FGR before 32 weeks called as early-onset and more related to poorer neonatal outcomes, on the other hand, late FGR highly associated with placental insufficiency (4-6). The main underlying reasons for FGR are thought to be placental insufficiency along with chronic uteroplacental ischemia. Early-onset FGR seems to be more related to impaired placental perfusion and with chronic fetal hypoxia (7, 8). Whereas late-onset FGR also has placental insufficiency but milder and maybe not associated with the same type of placental disease as early (4, 5).
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Levels of placenta-derived markers as beta-globin DNA, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PIGF) were widely investigated in early diagnosis of placenta-associated diseases as FGR and preeclampsia (2, 3, 9, 10). Near for eight years, non-invasive prenatal tests (NIPT) are available for common aneuploidies, but clinical experience emerged that ‘cell-free DNA’ in maternal circulation means much more than aneuploidies. Circulating cell-free fetal DNA was highly associated with the placenta and even described as a marker for ‘placental health and disease’ (11). The fetal fraction is calculated by dividing cell-free fetal DNA to total circulating cell-free DNA, and various factors influence it. One of these factors was apoptosis plus necrosis of placental trophoblasts and placental cell turn-over (12, 13). Because an impaired placenta was suspected to be behind growth-restricted fetuses, fetal fraction emerged as a new marker for early prediction of FGR.
This study aimed to evaluate possible the variations of fetal fractions in NIPT in pregnancies that were previously assumed as low risk but later diagnosed with early or late-onset FGR compared to uncomplicated pregnancies.
Methods
We conducted a retrospective study between November 2016 and December 2019 with 247 women in Izmır Tepecik Training and Research Hospital, a referral center for maternal-fetal medicine on the west coast of the county. Pregnancies who have early or late fetal growth restriction and followed up and delivered by the maternal-fetal medicine unit of our hospital were collected. Pregnancies that have tested with cell-free DNA were retrospectively scanned. Three groups were set from as women pregnancies with early-onset fetal growth restriction, pregnancies with late-onset fetal growth restriction, and uncomplicated pregnancies as the control group. Ethical Board of Izmir Tepecik Training and Research Hospitals approved the study.
Indications for Non-Invasive Prenatal Tests and Sample Collection
National screening policy for aneuploidies is a combined test in the first trimester and a genetic sonogram in the second trimester in Turkey (14). We do not have a national screening policy for NIPT, but from November 2016, as a state hospital, we widely refer pregnancies with a suspect of aneuploidies to our Department of Genetics for non-invasive prenatal tests (NIPT). NIPT is not a primary screening our maternal-fetal medicine unit was defined its criteria for NIPT, as advanced maternal age ≥35 years, moderate risk in combined, triple and quadruple screening tests, a single minor sonographic finding in the genetic sonogram, and maternal anxiety (15-18). Cost effectivity was taken into consideration when setting up the criteria. The cell-free DNA testing was carried out by two different companies Clarigo® and NIFTY®. Our Department of Genetics collected all samples, and the test was performed carefully by considering the manufacturer’s sample processing guidelines. Risk groups were offered a non-invasive prenatal test (NIPT) that is fully covered by insurance. Body mass index (BMI) >35 and abnormal fetal karyotype in previous pregnancies and multiple pregnancies have not offered NIPT. Women with a positive NIPT test, a failed NIPT because of the low quality of analysis, and a failed NIPT because of low fetal fraction and multiple pregnancies were excluded. Cut off for low fetal fraction was accepted as 2.8 (13, 19). All women who had a NIPT test were informed about and consented the test.
Study Group
All participants' gestational age had been calculated with the last menstrual period and confirmed by the first-trimester crown-rump length (CRL) measurement. An experienced maternal-fetal specialist had been made all sonographic imaging with Samsung Ultrasound System HS70A (Samsung Medison Company, Republic of Korea). We classified pregnancies having an intrauterine fetal growth restriction before 32 weeks as early-onset and after 32 weeks as late-onset fetal growth restriction(1). Estimated fetal weight (EFW) 95 percentile, absent or reversed UA diastolic flow. Abnormal CPR was accepted as CPR< 5 percentile. Fetuses with 3-10 percentile in birth weight with normal UA Doppler were excluded in case of eliminating the fetuses with small for gestational age. Also, pregnancies with early or late-onset preeclampsia with growth-restricted fetuses were excluded. The control group was elected from uncomplicated pregnancies with fetal weight was between 10 to 90 percentiles for gestational age in delivery with UA PI Statistical Analysis
All statistical analyses were performed using the IBM SPSS Statistics 25.0 package program (IBM Corp., Armonk, New York, USA). Shapiro-Wilk’s test, a histogram, and Q-Q plot were examined to assess the data normality. After defining the normality, means and standard deviations or medians (25%-75% quartiles) were given for continuous variables. Frequencies and percentages were given for categorical variables. Levene’s test was applied to assess the variance homogeneity. A two-sided Mann-Whitney U test was applied to compare the differences between groups for continuous variables. Kruskal-Wallis test and Bonferroni-Dunn post hoc test were used for more than two-group comparisons. A two-sided Fisher’s Exact, Pearson Chi-Square and Continuity Correction test for (2 x 2) or (r x c) tables were applied to compare the differences between groups for categorical variables. Spearman's (rho) correlation coefficient was used to analyze the relationships between variables. A p value of < 0.05 was considered statistically significant.
Results
Among all pregnants tested with NIPT then delivered in our hospital, data of 122 women who had followed up for pregnancies complicated with fetal growth restriction was retrospectively collected. 6 of 20 pregnancies in the early-onset FGR group and 19 of 102 pregnancies in the late-onset FGR group were excluded because of accompanying hypertensive diseases of pregnancy as gestational hypertension or preeclampsia or HELLP syndrome to FGR. Also, data of 150 women tested with NIPT and delivered in our institution without antenatal and perinatal complications were collected as the control group.
The characteristics of pregnant women were listed in Table 1. There were two different kits for NIPT, 133 (53.8%) were tested with Clarigo®, and 114 (46.2%) were tested with NIFTY®. There was homogeneous distribution according to groups and no statistically significant difference between the three groups in terms of the NIPT companies (p=0.96).
When we studied the indications for NIPT, 45.3% of women had moderate risk in the combined test, and the second leading indication was a minor finding in genetic sonogram in 27.5% of women. Among groups, there was no statistical difference in terms of NIPT indications (p=0.338).
The relationship between the fetal fraction and gestational week was computed by A Spearman’s rho correlation coefficient. There was a week but a positive correlation between the two variables, r = 0.294, pNo statistical difference was found between pregnancies conceived spontaneously and pregnancies obtained by assisted reproductive techniques (p=0.779). The relation of fetal fraction and maternal BMI was also evaluated, and no statistically significant correlation was found between them (p=0.571).
We mentioned that we excluded hypertensive diseases of pregnancy from the FGR group, but concomitant complications of FGR were not only hypertensive diseases. Our early-onset FGR group had 5 women (35.8.%) had complications as 1 gestational diabetes, 2 had placental abruption, 2 had premature rupture of membranes with preterm delivery. In the late-onset FGR group, 6 women (7.2%) had complications as 1 gestational diabetes, 1 placenta previa, 1 premature rupture of membranes, and 3 threatened preterm labor. Eary onset FGR group had statistically significantly had more concurrent t pregnancy complications than late-onset FGR (p=.001).
A necessity for a C- section because of fetal distress was present in %78.5 of early-onset, 44.9% of late-onset FGR, but only 13.9% of the control group. The difference was statistically significant in the early and late-onset FGR group compared to controls (p=0.002).
Discussion
cf-DNA is known to be derived from the turnover of villous trophoblast and cycle of placental apoptosis (11). Regarding this knowledge, cf-DNA can be considered as a promising marker for placenta related diseases such as preeclampsia (PE), placenta accreta spectrum, and fetal growth restriction (11, 20-23). This data had oriented us to investigate the possible relation between fetal fractions in maternal serum and FGR. Consequently, we have found that lower fetal fractions in NIPT could be associated with early-onset FGR. Nevertheless, fetal fractions of late-onset FGR had no difference from the low-risk population.
Recent studies broadly discussed that pathophysiology of early-onset FGR is far different from the late-onset one REF (24). Spinillo et al. declared that early FGR related to ‘more placental infarcts, distal villous hypoplasia, atherosis, persistent endovascular trophoblast, and a low fetal/placental weight’ than late-onset FGR. Unfortunately, in investigating the fetal fractions and cf-DNA, previous studies were not taken into account the ‘onset of FGR’ that was proven to be quite significant(7, 8, 10). For the first time, Morano et al. grouped pregnancies with FGR as early-onset and late-onset FGR. They stated that low fetal fraction is associated with early-onset FGR, but not with late-onset FGR (13). Even so, this study had two women with preeclampsia (PE) in the early-onset FGR group. Some studies showed that women with hypertensive diseases of pregnancy had lower fetal fractions (22, 23), while some studies associated higher cf-DNA with PE (25, 26). Eventually, Rafaeli-Yehudai et al. separated PE with FGR from isolated FGR and stated that women with PE had higher maternal serum cf-DNA’s, but women with FGR had similar cf-DNA levels as uncomplicated pregnancies (7). With the help of this study, it was evident that PE can be interpreted as a disruptive factor in levels of fetal fractions in maternal serum. As a result, we strongly believed that PE could be a confounding factor for fetal fractions, and we excluded 25 pregnancies with FGR and PE in our study.
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