The 11-14 weeks scan - KH Nicolaides, NJ Sebire, RJM Snijders, AP Souka

Chapter 1

CALCULATION OF PATIENT-SPECIFIC RISK FOR CHROMOSOMAL DEFECTS

Every woman has a risk that her fetus/baby has a chromosomal defect. In order to calculate the individual risk, it is necessary to take into account the background or a priori risk, which depends on maternal age and gestation, and multiply this by a series of factors or likelihood ratios, which depend on the results of a series of screening tests carried out during the course of the pregnancy to determine the patient-specific risk. The likelihood ratio for a given sonographic or biochemical measurement is calculated by dividing the percentage of chromosomally abnormal fetuses by the percentage of normal fetuses with that measurement. Every time a test is carried out the a priori risk is multiplied by the likelihood ratio of the test to calculate a new risk, which then becomes the a priori risk for the next test (Snijders and Nicolaides 1996). This process of sequential screening necessitates that the different tests are independent of each other. If the tests are not independent of each other then more sophisticated techniques, involving multivariate statistics, can be used to calculate the combined likelihood ratio. With the introduction of OSCAR, the process of sequential screening can all be achieved in one session at about 12 weeks of pregnancy (Figure 3).

Sequential screening

• Every woman has a risk that her fetus/baby has a chromosomal defect.
• The background or a priori risk depends on maternal age and gestation
• The individual patient-specific risk is calculated by multiplying the a priori risk with a series of likelihood ratios, which depend on the results of a series of screening tests carried out during the course of the pregnancy.
• Every time a test is carried out the a priori risk is multiplied by the likelihood ratio of the test to calculate a new risk, which then becomes the a priori risk for the next test.

Maternal age and gestation

The risk for many of the chromosomal defects increases with maternal age (Figure 4). Additionally, because fetuses with chromosomal defects are more likely to die in utero than normal fetuses, the risk decreases with gestational age (Figure 5).

Estimates of the maternal age-related risk for trisomy 21 at birth are based on surveys with almost complete ascertainment of the affected patients (Hecht and Hook 1994). In the last 15 years, with the introduction of maternal serum biochemical testing and ultrasound screening for chromosomal defects at different stages of pregnancy, it has become necessary to establish maternal age and gestational age-specific risks for chromosomal defects (Snijders et al 1995, 1999). Such estimates were derived by comparing the birth prevalence of trisomy 21 to the prevalence in women undergoing second-trimester amniocentesis or first-trimester chorionic villus sampling. Rates of spontaneous fetal death between different gestations and delivery at 40 weeks were estimated on the basis of both the observed prevalence in pregnancies that had antenatal fetal karyotyping and the reported prevalence in live births.

The rates of fetal death in trisomy 21 between 12 weeks (when NT screening is carried out) and 40 weeks is about 30% and between 16 weeks (when second trimester maternal serum biochemical testing is carried out) and 40 weeks is about 20%. Similar methods were used to produce estimates of risks for other chromosomal abnormalities. The risk for trisomies 18 and 13 increases with maternal age and decreases with gestation; the rate of intrauterine lethality between 12 weeks and 40 weeks is about 80% (Table 2). Turner syndrome is usually due to loss of the paternal X chromosome and, consequently, the frequency of conception of 45,X embryos, unlike that of trisomies, is unrelated to maternal age. The prevalence is about 1 per 1500 at 12 weeks, 1 per 3000 at 20 weeks and 1 per 4000 at 40 weeks. For the other sex chromosome abnormalities (47,XXX, 47,XXY and 47,XYY), there is no significant change with maternal age and since the rate of intrauterine lethality is not higher than in chromosomally normal fetuses the overall prevalence (about 1 per 500) does not decrease with gestation. Polyploidy affects about 2% of recognized concep- tions but it is highly lethal and thus very rarely observed in live births; the prevalences at 12 and 20 weeks are about 1 per 2000 and 1 per 250 000, respectively.

Table 2 Estimated risk for trisomies 21, 18 and 13 (1/number given in the table) in relation to maternal age and gestation.

Effect of maternal age and gestation on risk

• The risk for trisomies increases with maternal age
• The risk for Turner syndrome and triploidy does not change with maternal age
• The earlier the gestation, the higher the risk for chromosomal defects.
• The rates of fetal death in trisomy 21 between 12 weeks (when NT screening is carried out) and 40 weeks is about 30% and between 16 weeks (when second trimester maternal serum biochemical testing is carried out) and 40 weeks is about 20%.
• In trisomies 18 and 13 and Turner syndrome, the rate of fetal death between 12 and 40 weeks is about 85%.

Previous affected pregnancy

The risk for trisomies in women who have had a previous fetus or child with a trisomy is higher than the one expected on the basis of their age alone. In women who had a previous pregnancy with trisomy 21, the risk of recurrence in the subsequent pregnancy was 0.75% higher than the maternal and gestational age-related risk for trisomy 21 at the time of testing. Thus, for a woman aged 35 years who has had a previous baby with trisomy 21, the risk at 12 weeks of gestation increases from 1 in 249 (0.40%) to 1 in 87 (1.15%), and, for a woman aged 25 years, it increases from 1 in 946 (0.106%) to 1 in 117 (0.856%).

The possible mechanism for this increased risk is that a small proportion (less than 5%) of couples with a previously affected pregnancy have parental mosaicism or a genetic defect that interferes with the normal process of dysjunction, so in this group the risk of recurrence is increased substantially. In the majority of couples (more than 95%), the risk of recurrence is not actually increased. Currently available evidence suggests that recurrence is chromosome-specific and, therefore, in the majority of cases, the likely mechanism is parental mosaicism.

Recurrence of chromosomal defects

• If a woman has had a previous fetus or baby with a trisomy, the risk in the current pregnancy is 0.75% higher than her a priori risk
• Recurrence is chromosome-specific

Fetal nuchal translucency

Fetal NT normally increases with gestation (crown–rump length). In a fetus with a given crown–rump length, every NT measurement represents a likelihood ratio which is multiplied by the a priori maternal and gestational age-related risk to calculate a new risk. The larger the NT, the higher the likelihood ratio becomes and therefore the higher the new risk. In contrast, the smaller the NT measurement, the smaller the likelihood ratio becomes and therefore the lower the new risk (Figure 6).

Figure 6 Maternal age-related risk for trisomy 21 at 12 weeks of gestation and the effect of fetal nuchal translucency thickness (NT)

Nasal bone and other first-trimester sonographic markers

At 11-13+6 weeks the nasal bone is not visible by ultrasonography in about 70% of fetuses with trisomy 21 and in about 2% of chromosomally normal fetuses. Abnormalities in the flow velocity waveform from the ductus venosus are observed in about 80% of fetuses with trisomy 21 and in 5% of chromosomally normal fetuses. Similarly, the incidences of other sonographic markers, such as exomphalos, megacystis and single umbilical artery, are higher in certain chromosomal abnormalities than in chromosomally normal fetuses. Each of these sonographic markers is associated with a likelihood ratio, which can be multiplied by the a priori risk to calculate a new risk.

Maternal serum biochemistry in the first-trimester

The level of free β-hCG in maternal blood normally decreases with gestation. In trisomy 21 pregnancies free β-hCG is increased. The level of PAPP-A in maternal blood normally increases with gestation and in trisomy 21 pregnancies the level is decreased. For a given gestation, each β-hCG and PAPP-A level represents a likelihood ratio that is multiplied by the a priori risk to calculate the new risk. The higher the level of β-hCG and the lower the level of PAPP-A the higher the risk for trisomy 21 (Figure 7).

Figure 7 Maternal age-related risk for trisomy 21 at 12 weeks of gestation and the effect of maternal serum free β-hCG (left) and PAPP-A (right)