Lipopolysaccharide-binding protein in microbial invasion of the amniotic cavity and human parturition.

OBJECTIVE: Lipopolysaccharide-binding protein (LBP) is an acute-phase protein of predominantly hepatic origin, capable of binding the lipid A fraction of bacterial lipopolysaccharide (LPS). The complex LBP-LPS binds to CD14, and has been implicated in the host response to gram-negative infection. The purpose of this study was to determine whether microbial invasion of the amniotic cavity (MIAC) and parturition (term and preterm) are associated with changes in the amniotic fluid concentration of LBP. STUDY DESIGN: Amniotic fluid was retrieved by amniocentesis from 343 patients in the following groups: (1) those in mid-trimester with a subsequent normal pregnancy outcome (n = 84); (2) those in mid-trimester with a fetal loss after the procedure (n = 10); (3) those with preterm labor and intact membranes without MIAC who delivered at term (n = 36) or prematurely (n = 52), and those with preterm labor with MIAC (n = 26); (4) those with preterm premature rupture of membranes (PROM) with (n = 26) and without (n = 26) MIAC; and (5) those delivering at term with intact membranes in the absence of MIAC, in labor (n = 52) and not in labor (n = 31). The concentration of LBP in amniotic fluid was determined with a specific and sensitive immunoassay. Non-parametric statistics were used. A p value of < 0.05 was considered significant. RESULTS: LBP was detected in 98% (335/343) of the amniotic fluid samples. MIAC was associated with a significant increase in amniotic fluid concentration of LBP in women with preterm labor and intact membranes, but not in preterm PROM. Spontaneous preterm parturition was associated with a significant increase in amniotic fluid concentration of LBP. Patients who had a spontaneous fetal loss after a mid-trimester amniocentesis had a significantly higher median amniotic fluid LBP concentration than those who had a mid-trimester amniocentesis and a normal perinatal outcome. CONCLUSION: Preterm labor with MIAC and preterm parturition are associated with higher amniotic fluid concentrations of LBP than those with sterile amniotic fluid.

Prenatal diagnosis from cystic hygroma fluid: the value of fluorescence in situ hybridization.

OBJECTIVE: We sought to determine the optimal approach to the prenatal chromosome analysis of cystic hygroma fluid using traditional cytogenetic analysis and fluorescence in situ hybridization. STUDY DESIGN: A retrospective evaluation of our experience with traditional cytogenetic and fluorescence in situ hybridization analysis on cystic hygroma fluid was performed through a systematic review of the Genzyme Genetics database from January 1995 to July 2000. Information on gestational age, sample volume, clinical ultrasound findings (including fetal viability), cytogenetic results, fluorescence in situ hybridization results, and turn-around-time were queried. RESULTS: Eighty-three specimens were included in the investigation. The mean gestational age was 18.1 weeks (range, 13-27 weeks), and the mean sample volume was 20.7 mL (range, 0.1-101 mL). Of the 72 samples in which > 5 mL of cystic hygroma fluid was available, the success rate for cytogenetic analysis was 76% (55/72 samples). In 11 specimens of < or = 5 mL of cystic hygroma fluid, cytogenetic analysis was successful in only 1 case (9%). Fluorescence in situ hybridization was attempted on 23 samples, 18 of which were successful (78%), including 6 of 9 cases of cell culture failure (67%). Both traditional cytogenetic analysis and fluorescence in situ hybridization were performed in 21 instances when a sample of > 5 mL was available. A successful result was obtained by either cytogenetic testing or fluorescence in situ hybridization analysis or both in 19 of 21 of these cases (90%). Samples of > 5 mL from viable fetuses had a higher cytogenetic success rate (80%) and fluorescence in situ hybridization success rate (89%) than samples from fetuses with intrauterine death (38% and 50% cytogenetic and fluorescence in situ hybridization success rates, respectively.) The mean turn-around time was 8.2 days (range, 4-17 days). Results were available in < or = 12 days in 91% of cases. There was a 91% aneuploidy rate identified, with 45,X occurring in 86% of the samples. CONCLUSION: We conclude that the optimal approach for the prenatal diagnosis of chromosome abnormalities from cystic hygroma samples is to perform both traditional cytogenetic studies and interphase prenatal fluorescence in situ hybridization evaluation for the most common aneuploidies that involve chromosomes 13, 18, 21, X, and Y. With this combined approach, our data indicate that, in viable pregnancies with a fluid sample of >5 mL, a 90% diagnostic success rate can be achieved.

Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome.

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

Issues in implementing prenatal screening for cystic fibrosis: results of a working conference.

PURPOSE: To summarize a conference convened to examine how cystic fibrosis screening might appropriately be introduced into routine prenatal practice. METHODS: Participants included experts from various relevant disciplines. Systematic reviews and data from individual trials were presented; issues were identified and discussed. RESULTS: Judged by published criteria, prenatal cystic fibrosis screening is suitable for introduction. Screening can be performed cost-effectively by identifying racial/ethnic groups at sufficient risk and then using either of two models for delivering laboratory services. Validated educational materials exist. Ethical issues are not unique. CONCLUSIONS: Once adequate facilities for patient and provider education, testing, counseling, quality control, and monitoring are in place, individual programs can begin prenatal screening for cystic fibrosis.

Success rate of cytogenetic analysis at the time of second-trimester dilation and evacuation.

OBJECTIVE: The aim of this study was to determine the success rate of cytogenetic analysis from specimens obtained at the time of second-trimester termination of pregnancy by dilation and evacuation. STUDY DESIGN: All second-trimester dilation and evacuations performed by a single practitioner at a single institution from 1993 through 1995 were evaluated to pick out those patients in whom biopsy specimens were submitted for cytogenetic analysis. The main outcome studied was the ability to obtain karyotype results for these specimens. RESULTS: Cytogenetic studies were performed on 258 dilation and evacuation specimens with a median gestational age of 18 weeks (range 13-25 weeks). The indications for termination were fetal aneuploidy (n = 88, 34%), sonographically diagnosed fetal malformations (n = 82, 32%), intrauterine fetal death (n = 67, 26%), oligohydramnios or premature rupture of membranes (n = 16, 6%), and others (hematologic and metabolic disorders, n = 5, 2%). Successful karyotyping was achieved for 99% of specimens obtained at second-trimester dilation and evacuation, with 3 failures of growth (1% failure rate). The failures included a 14-week molar pregnancy, an 18-week fetus with Dandy-Walker malformation, and a 19-week intrauterine fetal death. Of the samples obtained in cases of intrauterine fetal death, 99% (66/67) provided adequate cytogenetic information. CONCLUSIONS: Karyotyping for abnormal second-trimester pregnancies and intrauterine fetal deaths at the time of a dilation and evacuation procedure has a success rate nearing 100%. In contrast to previous reports, our data indicate that it is unnecessary to perform pretermination invasive karyotyping in patients with abnormal second-trimester pregnancies or intrauterine fetal death who elect to undergo dilation and evacuation. Chromosome analysis at the time of termination of pregnancy by dilation and evacuation reduces patient discomfort, risk of infection, and cost while still providing reliable and vital cytogenetic information for future genetic counseling.

Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.

Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (+/- 3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.

The genetics of ovarian cancer: molecular biology and clinical application.

Ovarian cancer is the fifth most common malignancy among American women and the fourth leading cause of cancer death. The rapid advances in molecular genetic analysis, presymptomatic detection, and treatment of ovarian cancer are staggering. In this review, both the genetic component and the molecular biology of ovarian cancer are discussed, as well as current recommendations for genetic counseling. It is important for the practicing obstetrician and gynecologist to become familiar with these concepts, for it is he or she who will likely serve as a primary resource of information for these patients.

Therapeutic amniocentesis using a vacuum bottle aspiration system.

BACKGROUND: Therapeutic amniocentesis has been performed traditionally by gravitational drainage or syringe aspiration. We describe a technique for relatively rapid, large-volume therapeutic amniocentesis using a negative-pressure vacuum bottle aspiration system. TECHNIQUE: The procedure involves insertion of a 20-gauge spinal needle into the amniotic cavity followed by connection to a 1-L vacuum bottle via noncollapsible tubing. EXPERIENCE: During a 5-year period, 86 therapeutic amniocenteses were performed on 26 women. The amniotic fluid removal rate was 89 mL/minute. There were three instances of transient preterm labor, three cases of ruptured membranes within a week of the procedure, and no cases of abruption, chorioamnionitis, or fetal distress. CONCLUSION: The vacuum bottle aspiration technique for therapeutic amniocentesis permits expeditious removal of large volumes of amniotic fluid safely and effectively.

Correlation of maternal triple screen values with fetal liver length.

Objective: To determine if a relationship exists between fetal liver length and any of the three serum markers (AFP, uE3, and hCG) that constitute the maternal triple marker screen.Methods: From March to November of 1996, 124 randomly selected women between 17.0 and 20.3 weeks gestation underwent serum triple screen testing on the same day that an anatomy sonogram was performed by a single sonographer. Fetal liver size was measured between the right hemidiaphragm and the tip of the right hepatic lobe. All triple marker screen results were obtained from the same commercial lab. Utilizing linear regression analysis, liver length adjusted for gestational age was plotted versus AFP, uE3, and hCG measurements (expressed as multiples of the median).Results: Of the 124 subjects, 17 (14%) were white and 97 (78%) were black; the remaining 10 (8%) were unknown or other. Neither hCG nor AFP measurements had a statistically significant association with liver length after taking into account gestational age (linear regression: R = -0.018, P =.848 and R = 0.100, P =.269 for hCG and AFP, respectively). Interestingly, a statistically significant correlation was identified between uE3 levels and fetal liver length (R = 0.205, P =.023).Conclusions: No statistical significance was identified between either maternal serum hCG or AFP and fetal liver size. A statistically significant correlation between maternal serum uE3 and liver size was observed. Although preliminary, sonographic evaluation of fetal liver size has little role in elucidating the etiology of abnormal hCG or AFP levels, but may be relevant in the interpretation of abnormal uE3 values.

Fragile X syndrome.

Fragile X syndrome is the most common familial form of mental retardation. This X-linked disorder affects one in every 1000 males and one in every 2000 females. The female carrier rate in the general population is estimated to be 1/600. A fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark cytogenetic feature of the syndrome. Clinical features include physical as well as cognitive and neuropsychological deficits. Although fragile X syndrome follows an X-linked pattern of inheritance (which explains the predominance of affected males), females can also be affected. Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked diseases. Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.

Concordant anencephaly in monoamniotic twins and an analysis of maternal serum markers.

Anomalies occur with greater frequency in twin gestations than in singleton pregnancies. Anencephaly is not an uncommon defect, but because of its multifactorial inheritance pattern, twins are usually discordant for this anomaly. We present a case of monoamniotic twins concordant for anencephaly. Monoamniotic anencephalic twins were diagnosed at 15 weeks' gestation. Normal interval growth occurred until intrauterine demise of both fetuses at 28 weeks. Maternal serum obtained at 16.5 weeks demonstrated low unconjugated oestriol (uE3) levels and elevated values of alpha-fetoprotein, although this result was lower than expected. Human chorionic gonadotropin (hCG) levels were significantly elevated. Monoamniotic twins concordant for anencephaly occur with extreme rarity. To our knowledge, maternal serum uE3 and hCG levels in fetuses concordant for neural tube defects have not been previously reported.

Haloperidol overdose during pregnancy.

BACKGROUND: Suicide attempts during pregnancy are rare. Over-the-counter and psychotropic medications are most commonly used. Although intentional overdose of haloperidol has been reported in nonpregnant adults, it has not, to our knowledge, been reported previously during pregnancy. In this case of suicide attempt by haloperidol overdose, maternal and fetal responses were studied extensively. CASE: Intentional ingestion of 300 mg haloperidol by a pregnant woman at 34 weeks' gestation caused maternal unresponsiveness, an extrapyramidal reaction, temporary fetal akinesia, and a nonreactive nonstress test. The mother recovered in 48 hours. The fetus did not reach a biophysical profile score of ten until 5 days after presentation. CONCLUSION: Haloperidol overdose during pregnancy causes a maternal extrapyramidal reaction, temporary fetal akinesia, and prolonged fetal neuromuscular depression.

The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study.

OBJECTIVE: Our purpose was to examine the potential teratogenicity of calcium channel blockers. STUDY DESIGN: Six teratogen information services prospectively collected and followed up 78 women with first-trimester exposure to calcium channel blockers. Pregnancy outcome was compared (by paired t text of chi2 analysis) with that of a control group matched for maternal age and smoking. RESULTS: There was no increase in major malformation (2/66=3.0% [calcium channel blockers] vs 0% [nonteratogenic controls], p=0.27); a fivefold increase was ruled out (baseline 2%, alpha = 0.05, beta = 0.20). The defects reported were attributable to maternal diabetes or coingestion of teratogens. The increase in preterm delivery 28% [calcium channel blockers] vs 9% [nonteratogenic controls], p=0.003), attributed to maternal disease by stepwise regression, was the most important factor responsible for the observed decrease in birth weight (mean -334 gm vs nonteratogenic controls, p=0.08). CONCLUSION: This study suggests that calcium channel blockers do not represent a major teratogenic risk.

Ultrasound-adjusted risk and spectrum of fetal chromosomal abnormality in women with elevated maternal serum alpha-fetoprotein.

OBJECTIVE: To determine the incidence of chromosomal abnormality in sonographically normal fetuses after amniocentesis for elevated maternal serum alpha-fetoprotein (MSAFP), and to compare the spectrum of abnormality with that seen in women undergoing amniocentesis for advanced maternal age. METHODS: Cytogenetic and sonographic findings from women undergoing amniocentesis for elevated MSAFP (at least 2.0 multiples of median) between 1988-1992 were reviewed retrospectively. The literature was reviewed and data compiled regarding the risk of chromosomal abnormality for women with elevated MSAFP levels. RESULTS: The incidence of abnormal karyotype among all women with elevated MSAFP was 1.23% (nine of 733). The risk of an abnormal karyotype with a normal ultrasound examination was 1.01% (seven of 696). This included three fetuses with sex chromosome abnormalities, three with de novo, apparently balanced rearrangements, and one with an unbalanced structural rearrangement. CONCLUSIONS: The risk of chromosomal abnormality in nonselected patients, predominantly younger than 35 years of age, with elevated MSAFP and a sonographically normal fetus is 0.6%, based on a compilation of our data and reports published previously. The spectrum of abnormality in women with elevated MSAFP differs from that in women of advanced maternal age. Patients should be specifically counseled regarding this difference.

Fetal akinesia.

Normal fetal growth and development during pregnancy is highly dependent upon adequate fetal movement. Limitation of movement, regardless of the underlying cause, can result in a particular pattern of abnormal fetal morphogenesis. This phenotype is termed the fetal akinesia deformation sequence (FADS). The etiology of fetal akinesia may be generally classified into one of five categories: neuropathy, myopathy, restrictive dermopathy, teratogen exposure, or restricted movement due to intrauterine constraint. In this article, the differential diagnosis of fetal akinesia is systematically reviewed and information regarding prenatal diagnosis, prognosis, perinatal management, and recurrence risks are discussed.