Charas Y. T. Ong

First trimester maternal serum free β human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications

Objective To examine the value of first trimester maternal serum free β human chorionic gonadotrophin (β hCG) and pregnancy associated plasma protein A (PAPP‐A) as predictors of pregnancy complications.

Screening for trisomy 18 by fetal nuchal translucency and maternal serum free β ‐hCG and PAPP‐A at 10–14 weeks of gestation

In a study of 50 cases of trisomy 18 compared with 947 controls we have found the median multiple of the median (MoM) of maternal serum free beta human chorionic gonadotrophin to be significantly decreased (0.281 MoM) in samples collected between the 10th and 14th week of gestation. Similarly, maternal serum pregnancy associated plasma protein A (PAPP-A) levels are also decreased (0.177 MoM), whilst the median nuchal translucency is significantly higher (3.272 MoM). Free beta-hCG MoM was less than the 5th centile of normal in 64 per cent of cases of trisomy 18 and for PAPP-A was less than the 5th centile in 78 per cent of cases. Also, in 78 per cent of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, we predict that 89 per cent of cases of trisomy 18 could be detected at a 1 per cent false-positive rate. We conclude that specific trisomy 18 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21.

The influence of ethnic origin on first trimester biochemical markers of chromosomal abnormalities

In a first trimester study of 5422 Caucasian women, 752 Afro‐Caribbean women and 170 Asian women we have shown that the median maternal serum marker MoMs for free β‐hCG and PAPP‐A were 19% and 48% higher in Afro‐Caribbean women and 19% higher and 35% higher in Asian women, compared to Caucasian women. Correcting for maternal weight made very little difference to the effect in Afro‐Caribbeans (21% and 57% higher after weight correction) but reduced the effect in Asians (4% and 17% higher after weight correction ). It is estimated that correcting for maternal weight and ethnicity overall would increase the detection rate by a modest 1.4%. However, the effect on an individuals risk could result in as much as a two‐fold increase in the patient specific risk for trisomy 21. The impact of ethnic origin seems to be greater than that observed with second trimester biochemical markers and larger studies are required in order to develop robust algorithms for correcting for ethnic origin in the first trimester. Copyright

First-trimester maternal serum levels of placenta growth factor as predictor of preeclampsia and fetal growth restriction☆

OBJECTIVE To determine whether the reported decrease in maternal serum placenta growth factor concentration in preeclampsia is evident from the first trimester and before clinical onset of the disease. We also examined levels in pregnancies that subsequently resulted in fetal growth restriction (FGR). METHODS Placenta growth factor concentration was measured in stored maternal serum samples obtained at 11–14 weeks of gestation from 131 women who subsequently developed preeclampsia, 137 women who subsequently developed FGR, and 400 randomly selected controls who did not develop preeclampsia or FGR. Preeclampsia was defined as diastolic blood pressure of 90 mmHg or more on two occasions 4 hours apart, accompanied by proteinuria (more than 300 mg of total protein in a 24‐hour urine collection or a positive test for albumin on reagent strip) in women with no pre‐existing hypertensive or renal disease. Fetal growth restriction was considered present if a woman subsequently delivered a live infant with a birth weight below the fifth centile for gestation. RESULTS In the control group, maternal serum placenta growth factor concentration increased with gestation. Compared with the controls (median multiple of the median 0.98, standard deviation [SD] 0.51), levels in the pre‐eclampsia group (median multiple of the median 1.09, SD 0.52) were not significantly different (t = 1.83, P = .07), but in the FGR group (median multiple of the median 1.57, SD 0.74), levels were significantly increased (t = 10.85, P < .001). CONCLUSION The previously reported decrease in serum placenta growth factor levels in women with preeclampsia might not precede clinical onset of the disease and is not apparent in the first trimester of pregnancy. Levels are significantly increased in pregnancies resulting in FGR.

The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free β‐hCG and PAPP‐A at 10–14 weeks of gestation

In a study of 2923 normal pregnancies and 203 pregnancies affected by trisomy 21 we have shown a significant difference in the median MoM of the markers: fetal nuchal translucency, maternal serum free β‐hCG and PAPP‐A in the presence of a female fetus compared with a male fetus. For maternal serum free β‐hCG levels are higher by 15% if the fetus is chromosomally normal and by 11% if the fetus has trisomy 21. For maternal serum PAPP‐A the levels in chromosomally normal fetuses are 10% higher in the presence of a female fetus and 13% higher if the fetus has trisomy 21. In contrast, fetal nuchal translucency is 3–4% lower in both chromosomally normal and trisomy 21 female fetuses. The consequence of such changes when screening for trisomy 21 will be a reduction in the detection rate in female fetuses by a factor of 1–2%. Correction of risk algorithms for fetal sex, however, is probably not feasible, since ultrasound detection of fetal sex is only 70–90% accurate in the 10–14 week period. Copyright

Serum CA125 at 11-14 weeks of gestation in women with morphologically normal ovaries.

In a number of pregnant women ovarian cysts are found incidentally during the routine first trimester scan. These cysts may pose diagnostic difficulties, and the measurement of serum CA125 levels can be used to aid management. In this study we measured maternal serum CA125 levels in 188 women with uncomplicated pregnancies between 11–14 weeks of gestation. All women had morphologically normal ovaries observed on ultrasound examination. The median serum CA125 levels were 23.4 U/mL (range 2.2–166.3 U/mL, 95% reference interval 5.28–70.15) and did not change significantly with gestation. We conclude that CA125 levels are increased at 11–14 weeks of gestation and cut off values which are used to assess the nature of ovarian cysts in nonpregnant women cannot be applied to pregnant women at this gestation.

The influence of parity and gravidity on first trimester markers of chromosomal abnormality

We have studied changes in first trimester fetal nuchal translucency (NT) and maternal serum free β‐hCG and PAPP‐A with gravidity and parity in 3252 singleton pregnancies unaffected by chromosomal abnormality or major pregnancy complications. We have shown that gravidity and parity is associated with a small but progressive decrease in fetal NT and a small but progressive increase in free β‐hCG and PAPP‐A. None of these small changes with increasing gravidity or parity are statistically significant and hence correction for these variables is not necessary when considering first trimester screening for chromosomal abnormalities. Copyright

First-trimester maternal serum activin A in pre-eclampsia and fetal growth restriction.

Objective: To investigate whether the reported increase in maternal serum activin A concentration in pre-eclampsia is evident from the first trimester.Design: This was a case-control study carried out in antenatal clinics among singleton pregnancies at 10–14 weeks of gestation.Methods: Activin A concentration was measured in stored maternal serum samples obtained at 11–14 weeks of gestation from 131 women who subsequently developed pre-eclampsia, 77 who developed non-proteinuric pregnancy-induced hypertension, 141 with fetal growth restriction in the absence of hypertensive complications and from 494 normotensive controls.Results:  Compared to the median activin A level in the control group (1.00 MoM), the median MoM in the patients who subsequently developed pre-eclampsia and pregnancy-induced hypertension (1.49 MoM and 1.32 MoM, respectively) was significantly increased (p<0.001), and in patients with fetal growth restriction (1.02 MoM) it was not significantly different (p=0.57). In the pre-eclampsia group (n=131) the disease was considered to be sufficiently severe to necessitate iatrogenic delivery before 35 weeks in 25 patients, and in this group the median MoM was 1.92.Conclusion:  Maternal serum activin A concentration at 12 weeks of gestation in pregnancies which subsequently develop hypertensive disease is increased, whereas in those complicated by fetal growth restriction it is normal.

First trimester markers of trisomy 21 and the influence of maternal cigarette smoking status

Maternal cigarette smoking is associated with alterations in maternal serum analytes used in screening for trisomy 21 during the second trimester of pregnancy. Thus, serum free b-hCG levels in women who smoke are reduced by 11±14% in unaffected pregnancies (Spencer, 1998; Ferriman et al., 1999) and by 16% in pregnancies affected by trisomy 21 (Spencer, 1998). The consequence of this reduction in serum free bhCG levels is that in cigarette smokers there is a 10% decrease in sensitivity for trisomy 21 and a 50% reduction in the false positive rate. Although correcting for smoking status improves the detection rate by only 1±2%, the increase in accuracy of the estimated risk for an individual patient is considerable. There is now interest in moving screening for chromosomal abnormalities to the ®rst trimester of pregnancy (Grudzinskas and Ward, 1997). Combining maternal serum pregnancy associated plasma protein ± A (PAPP-A) and free b-hCG with fetal nuchal translucency thickness (NT) can identify about 90% of pregnancies affected by trisomies 21, 18 and 13, triploidy and sex chromosome aneuploidies for a false positive rate of about 5% (Spencer et al., 1999, 2000a,b,c; Tul et al., 1999). In an earlier study of 2887 unaffected pregnancies (Spencer, 1999) we observed that levels of maternal serum free b-hCG were not altered in the ®rst trimester of pregnancy, whilst PAPP-A levels were reduced by 15%. We have now had the opportunity to examine the effect of self-reported maternal cigarette smoking status on ®rst trimester maternal serum levels of free b-hCG and PAPP-A and fetal NT in normal and trisomy 21 pregnancies. For NT in the unaffected group we used NT data from the 2887 previously reported (Spencer, 1999) unaffected pregnancies screened in our OSCAR clinic (Spencer et al., in press). For pregnancies affected by trisomy 21 we used available information from our previous study of NT and maternal serum biochemical marker levels from 204 of the 210 cases (Spencer et al., 1999), supplemented with a further series of 20 cases identi®ed during prospective screening in our OSCAR clinics. All biochemical measurements were performed using the CIS Kryptor system and all markers were expressed a MoMs corrected for maternal weight when appropriate (Spencer et al., 1999). The median maternal age, weight and gestation in the trisomy 21 and unaffected pregnancies according to cigarette smoking status are shown in Table 1. In the unaffected population the median NT MoM in smokers was identical to that in non-smokersÐ0.996 (95% con®dence interval 0.975±1.017) versus 1.000 (0.990±1.010)Ðwith a log10 MoM SD of 0.1086 in smokers and 0.1155 in non-smokers. The log10 MoM distributions in the two groups were compared by t-tests assuming equal variance and no signi®cant difference ( p=0.244) was observed. In trisomy 21 pregnancies the median MoM NT in the smokers was again similar to that in non-smokersÐ2.539 (CI 2.07±3.17) versus 2.607 (CI 2.44±2.80)Ðwith a log10 MoM SD of 0.2025 in smokers and 0.1918 in nonsmokers. The log10 MoM distributions in the two groups were compared by t-tests assuming equal variance and no signi®cant difference ( p=0.334) was observed. In trisomy 21 pregnancies the median weight corrected MoM free b-hCG in the smokers was 13% lower than in non-smokersÐ1.787 (CI 1.09±2.24) versus 2.048 (CI 1.88±2.26)Ðwith a log10 MoM SD of 0.2648 in smokers and 0.2784 in non-smokers. The log10 MoM distributions in the two groups were compared by t-tests assuming equal variance but this difference did not reach statistical signi®cance ( p=0.198). The median weight corrected MoM PAPPA in the smokers was 6% higher in the smokers than in non-smokersÐ0.556 (CI 0.36±0.72) versus 0.526 (CI 0.45±0.56)Ðwith a log10 MoM SD of 0.2720 in smokers and 0.2821 in non-smokers. The log10 MoM distributions in the two groups were compared by ttests assuming equal variance but no signi®cant difference ( p=0.279) was observed. The ®ndings of this study in the ®rst trimester suggest that maternal cigarette smoking does not affect fetal NT in either trisomy 21 or unaffected pregnancies. Furthermore, the data suggest that in trisomy 21 pregnancies cigarette smoking is associated with a 13% decrease in maternal serum free b-hCG concentration, which is similar to the previously reported 16% decrease in affected pregnancies in the second trimester (Spencer, 1998). In unaffected pregnancies cigarette smokers have an 11±14% reduction in free b-hCG levels during the second trimester (Spencer, 1998; Ferriman et al., 1999), but the levels are not altered in the ®rst trimester of pregnancy (Spencer, 1999). The consequence of these ®ndings would be a decrease in the detection of trisomy 21 in cigarette smokers. In trisomy 21 pregnancies cigarette smoking is

First trimester maternal serum AFP and total hCG in aneuploidies other than trisomy 21

Total human chorionic gonadotropin (hCG) and alpha‐fetoprotein (AFP) were measured in maternal serum at 10–14 weeks of gestation from 53 pregnancies affected by trisomy 18, 42 cases with trisomy 13, 46 with Turners syndrome and 13 with other sex aneuploides. The only significant association was the finding of reduced levels of total hCG in cases of trisomy 18 and 13. The association of increased levels of AFP in cases of trisomy 18 with ventral wall defects and the slight increase in AFP in cases of sex chromosomal anomalies other than Turners syndrome was found. AFP and total hCG are not likely to replace the markers free β‐hCG and PAPP‐A in first trimester screening for chromosomal anomalies. Copyright