Ralph L. Kramer

Second-trimester maternal serum marker screening: Maternal serum α-fetoprotein, β-human chorionic gonadotropin, estriol, and their various combinations as predictors of pregnancy outcome ☆ ☆☆

OBJECTIVE We evaluated the value of all 3 common biochemical serum markers, maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome. STUDY DESIGN A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum alpha-fetoprotein measurements; beta-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points. RESULTS In confirmation of previous observations, increased maternal serum alpha-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased beta-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (<0.5 MoM) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, intrauterine growth restriction, and intrauterine fetal death. As with increased second-trimester maternal serum alpha-fetoprotein levels, increased serum beta-human chorionic gonadotropin and low unconjugated estriol levels are significantly associated with adverse pregnancy outcomes. These are most likely attributed to placental dysfunction. CONCLUSION Multiple-marker screening can be used not only for the detection of fetal anomalies and aneu-ploidy but also for detection of high-risk pregnancies.

Determinants of parental decisions after the prenatal diagnosis of Down syndrome

We evaluated demographic factors and factors specific to the current pregnancy, and their relationship to the decision to continue or terminate a pregnancy after prenatal diagnosis of Down syndrome. All cases of Down syndrome (DS) managed at a tertiary care center from 1989-1997 were retrospectively analyzed with respect to maternal age, parity, gestational age, sonographic findings, insurance status, and race. Of 145 cases of trisomy 21, 19 (13.1%) of women chose continuation of pregnancy, while 126 (86.9%) chose termination. There were no differences between groups in parity, sonographic findings, insurance status, or race at the time of diagnosis. However, patients who chose termination were significantly older and earlier in gestation than those electing to continue their pregnancy. When Down syndrome is diagnosed prenatally, the choice of termination is related to maternal age and gestational age, but only gestational age is a significant independent predictor of pregnancy termination.

Fetal gender impact on multiple‐marker screening results

Maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), and unconjugated estriol (uE3) are used in combination with maternal age to calculate the risk for Down syndrome (DS) in pregnancy. Increased levels of hCG and decreased levels of MSAFP and uE3 are consistent with an increased risk for DS. We retrospectively evaluated second-trimester maternal serum marker levels in a large cohort of patients with known normal outcomes and documented fetal gender. These included 15,428 patients who had MSAFP measurements, 11,428 patients with both MSAFP and hCG, and 6,090 patients with all three markers including uE3. MSAFP levels in patients with female fetuses were consistently lower than those with males. Conversely, hCG was higher in pregnancies with females as compared to males. No gender-related difference was noted for uE3. These results would suggest that the computed DS risk for female fetuses is higher than for males, despite the fact that the incidence of DS is similar in both genders. This information could be useful for calculating gender-specific DS risk; however, this would require ultrasonographic determination of fetal sex.

Prenatal diagnosis of cloacal dysgenesis sequence : Differential diagnosis from other forms of fetal obstructive uropathy

Cloacal dysgenesis sequence (CDS) is a rare cause of fetal obstructive uropathy (FOU). The prenatal differentiation of CDS from other FOU is important because CDS is not amenable to in utero surgical intervention in the form of vesicoamniotic shunts. We evaluated the prenatal characteristics of 8 fetuses with CDS, including a pair of monozygotic twins concordant for CDS, in order to identify features that would enable differentiation from other forms of FOU. Pathologic examination in each of the 8 fetuses confirmed characteristic features of absent anal, genital, and urinary orifices associated with a smooth perineum and abnormal phallic development. Associated abnormalities included dysplastic kidneys in 6, hydroureters in 5, intraluminal colonic calcifications in 2, and hypoplastic lungs in 5. Five of these fetuses initially presented as posterior urethral valve syndrome. Six fetuses had megacystis, and 4 underwent vesicocenteses to evaluate urinary electrolytes, all of which were in the ‘poor-risk’ category. Six fetuses were male and 2 female, contradicting earlier claims that CDS occurs only in females. Evaluation of candidates for in utero surgical intervention should include fetal karyotype, and CDS should be suspected in cases of FOU in whom the karyotype reveals a male fetus and sonographic evaluation demonstrates colonic calcifications or abnormal phallic development. Diagnostic microendoscopy may be of benefit in such cases.

Trisomy 21 Placentas: Histopathological and Immunohistochemical Findings using Proliferating Cell Nuclear Antigen

OBJECTIVE The cause of growth retardation in trisomy 21 and other autosomal trisomies is not known, but may be the result of defective cell proliferation, slowing of the cell cycle, or placental structural abnormalities. Abnormalities of the fetal cell cycle may be reflected in placental growth and can be detected using proliferating cell nuclear antigen (PCNA). METHODS Twelve second-trimester and six third-trimester trisomy 21 placentas were examined histopathologically and stained immunohistochemically using antibodies to PCNA. Normal age-matched placentas were used as controls. RESULTS The second-trimester trisomy 21 placentas all exhibited many large irregular hypovascular villi. The third-trimester trisomy 21 placentas showed two patterns: (i) many large, irregular hypovascular villi, and (ii) relatively normal-appearing villi with only a few abnormal villi and focal hypervascularity. PCNA staining was significantly greater in second-trimester placentas when compared to third-trimester placentas for both trisomy 21 and controls. There was no significant difference in PCNA staining in trisomy 21 placentas when compared to the normal age-matched controls. CONCLUSIONS PCNA staining indicates no significant differences in proliferation between normal and trisomy 21 placentas. Trisomy 21 placentas show villus abnormalities, including hypovascularity.

Effect of adjustment of maternal serum α‐fetoprotein levels in insulin‐dependent diabetes mellitus

Our objective was to determine the effect of the 20% upward adjustment of maternal serum alphafetoprotein (MSAFP) in patients with insulin-dependent diabetes mellitus (IDDM) on the number of patients that would be classified at increased risk for pregnancy complicated by either Down syndrome (DS) or neural tube defect (NTD). We retrospectively evaluated a database containing 63,110 patients who underwent multiple serum marker screening between 14 and 22 weeks gestation; 620 patients with IDDM had measurements of MSAFP of which 479 also had measurements of beta-HCG, allowing calculation of DS risk. Increased NTD risk was defined as MSAFP >2.5 MOM while increased DS risk was defined as a calculated risk > or =1/270. One IDDM patient delivered an infant with a NTD; it was not detected on serum screening. No infants were born with DS. Of the 620 patients with MSAFP determinations, 9 had values >2.5 MOM before adjustment. After upward adjustment, 7 additional patients were identified. Sixteen patients were identified at increased risk for DS before and after adjustment. Our data suggest that the 20% upward adjustment of MSAFP increases by 78%, the number of patients who would require further evaluation for NTDs. Although we were able to identify 620 women with IDDM who underwent serum screening for NTD, the low prevalence of NTDs did not allow us to demonstrate an increased detection rate. The effect of upward adjustment of MSAFP on the number of patients categorized at increased DS risk appears to be minimal.

10 Multifetal pregnancy reduction

Multifetal pregnancy reduction (MFPR) has become a mainstay of infertility therapy as its development has allowed physicians to become more aggressive in treating patients resistant to more conservative therapies. Over the course of the past decade, MFPR has become practised in a limited number of tertiary specialty centres, which have improved its performance and very substantially lowered its risks. The majority of physicians performing MFPR employ a transabdominal needle injection of potassium chloride into the fetal thorax. Risks for pregnancy losses of patients starting with triplets and/or quadruplets reduced to twins have improved over the past decade and are not substantially different from those in patients whose pregnancy began as twins. There have been no substantiated risks of coagulopathies or damage to surviving fetuses.

Differences in Measurements of the Atria of the Lateral Ventricle: Does Gender Matter?

OBJECTIVE To evaluate possible differences in measurements of the width of atria of the lateral cerebral ventricles of male and female fetuses. STUDY DESIGN A prospectively entered database was reviewed to identify patients undergoing ultrasound examination at > 13 weeks between July 1, 1994 and June 30, 1995. Inclusion criteria included identification of fetal gender, measurement of the atria, and the absence of fetal anomalies. RESULTS The atrial width of the lateral ventricles was statistically greater in male than in female fetuses (7.1 vs. 7.0 mm, p < 0.001). CONCLUSION Although statistically significant, the difference between genders in the measurement of the ventricular atria is too small to be of clinical utility.

Age-specific variation in aneuploidy incidence among biochemical screening programs

OBJECTIVE Our purpose was to compare the observed age-related incidence of Down syndrome in two large screening programs with the commonly quoted incidences used in biochemical screening programs. STUDY DESIGN Data from two large prenatal screening programs were stratified in 5-year age groups. The age-related incidence of Down syndrome was compared with the commonly used incidence as reported by Cuckle. RESULTS No significant differences were found in age-related incidences of Down syndrome in any age group between the screening groups or among women ages 15 through 29 in any of the three groups. However, for women 30 to 34 and > or = 40 years old, a trend was noted toward a higher incidence in the screening groups. For women ages 35 to 39, the observed incidence was significantly greater in the screening groups compared with the data of Cuckle. CONCLUSION Our data suggest an underascertainment in Down syndrome risk built into the Cuckle model, particularly in high-risk patients.

Gene therapy : Is the future here yet ?

Despite the overwhelming number of articles on gene therapy that have been published in the last few years, there is a paucity of trials that have successfully demonstrated the clinical usefulness of this modality. The enthusiasm characterizing some of the earlier studies has given way to a more realistic approach. The next step is to develop more efficient vectors for effective targeting and persistent gene expression.