Spectrum of fetal limb anomalies.

PURPOSE: Antenatal detection of limb anomalies is not uncommon, and pregnancies are usually terminated in view of the expected physical handicap. The aim of this retrospective observational study is to delineate the spectrum of fetal limb anomalies and provide evidence in support of complete postnatal evaluation in establishing recurrence risk. METHODS: We present 54 cases of limb malformations detected antenatally and discuss the spectrum of abnormalities, the utility of fetal autopsy, and genetic testing to establish recurrence risk in subsequent pregnancies. RESULTS: 16/54 cases were isolated radial ray anomalies. There were five cases of amniotic band syndrome, five limb body wall complex cases, three VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities) associations, one case of sirenomelia, two cases of limb pelvis hypoplasia, and one case of OEIS (Omphalocele Exstrophy Imperforate anus and spinal defects). Four fetuses with non-isolated radial ray anomaly had trisomy 18. One case with bilateral radial ray defect had a mutation in the FANC-E gene confirming fanconi anemia. Twelve cases were unclassified. CONCLUSION: Autopsy is the most important investigation in fetuses with limb anomalies. We suggest chromosomal microarray (CMA) as a first-tier test after autopsy. However, in cases of bilaterally symmetrical limb anomalies, in case of previous similarly affected child, or history of consanguinity, whole exome sequencing (WES) can be offered as the primary investigation, followed by CMA if WES is normal.

Ultrasound detection of placental insufficiency in women with elevated second trimester serum alpha-fetoprotein or human chorionic gonadotropin.

OBJECTIVE: We evaluated the role of placental morphology ultrasound and uterine artery Doppler in predicting adverse perinatal outcomes in women with unexplained elevated serum alpha-fetoprotein (AFP) or human chorionic gonadotropin (hCG) levels in the second trimester of pregnancy. METHODS: Women with a serum AFP > 2.0 MoM (n = 83) or serum hCG > 2.5 MoM (n = 68) had placental imaging at 19-23 weeks' gestation. Abnormal placental morphology (i.e., a maximum thickness of > 4 cm or > 50% of length) and abnormal uterine artery Doppler [UTAD] (mean pulsatility index > 1.45) were related to placental complications of pregnancy. Relative risks were derived for all women. Likelihood ratios were derived for the subset (55/83) in the group with elevated AFP who had no medical and/or obstetrical risk factors. RESULTS: Compared with elevated serumh CG, an elevated serum AFP was associated with higher rates of perinatal mortality (15.6% vs. 4.3%), preterm birth at < 32 weeks' gestation (26.5% vs. 7.3%), small-for-gestational age (SGA) birth weight < 10th centile (24.1% vs. 10.3%) and severe intrauterine growth restriction (IUGR) (8.4% vs. 2.8%). Thirty-seven (44.5%) women with elevated serum AFP had an adverse perinatal outcome, and 23 of these women (67%) had no prior medical and/or obstetric risk factors. Abnormal tests of placental function were more common in the elevated serum AFP group than in the hCG group (UTAD 30.1% vs. 11.6%; placental morphology 30.2% vs. 16.2%). Abnormal UTAD and abnormal placental morphology had similar positive likelihood ratios for a range of adverse perinatal events in the elevated AFP group (1.3-4.4) and were increased when both tests were abnormal (likelihood ratio 5.0 for preeclampsia, 4.5 for preterm delivery < 32 weeks, 4.9 for intrauterine fetal demise). In the elevated hCG group abnormal UTAD and abnormal placental morphology predicted SGA (likelihood ratios 5.2 and 4.9) and IUGR (likelihood ratios 4.7 and 7.3) but did not predict preeclampsia or preterm birth. CONCLUSION: Assessment of placental function using either morphology or UTAD at 19-23 weeks' gestation identifies a subset of women at increased risk of adverse perinatal events with an elevated serum AFP. These tests have more limited value in women with an elevated serum hCG because of the lower prevalence of adverse perinatal events.

Usefulness of a placental profile in high-risk pregnancies.

OBJECTIVE: Test the hypothesis that a placental function profile can reassure most high-risk women with normal test results yet accurately can identify a subset of women who are destined for major complications that will be attributable to placental disease. STUDY DESIGN: This was a prospective study of 212 high-risk pregnancies that used the placental profile (16- to 18-week maternal serum screening, 18- to 23-week uterine artery Doppler imaging, and placental morphologic condition). Odds ratios (95% CI) were derived for intrauterine fetal death (IUFD), preterm delivery at < 34 weeks of gestation, preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP) syndrome, small for gestational age delivery, and early-onset intrauterine growth restriction (IUGR); all normal test results (n =125) were compared with > or = 1 abnormal test results. RESULTS: The odds of the development of adverse outcomes were significantly less in women with all normal test results (preeclampsia/HELLP [odds ratio, 0.2; 95% CI, 0.1-0.4]), preterm delivery (odds ratio, 0.1; 95% CI, 0.06-0.3), small for gestational age delivery (odds ratio, 0.2; 95% CI, 0.09-0.3), early-onset IUGR (0), and IUFD (odds ratio, 0.05 [0.01-0.2]). Combining those women with two (n = 21) of 3 (n = 15) abnormal test results together predicted 14 of 19 severe IUGR and 15 of 22 IUFD cases. CONCLUSION: This placental function profile at 16-23 weeks of gestation can reassure women with normal test results by identifying a smaller subset of women who are at reduced risk of perinatal morbidity or death from severe IUGR.

Second-trimester prediction of severe placental complications in women with combined elevations in alpha-fetoprotein and human chorionic gonadotrophin.

OBJECTIVE: The purpose of this study was to determine the ability of uterine artery Doppler and placental ultrasound to identify adverse clinical outcomes attributable to severe placental dysfunction in women with second-trimester unexplained elevated maternal serum screening of alpha-fetoprotein and human chorionic gonadotropin. STUDY DESIGN: Fifty singleton pregnancies with elevated alpha-fetoprotein (3.5 multiples of median [range 2.1 to 10.5]) and human chorionic gonadotropin (5.3 multiples of median [range 2.5 to 21.7]) and a normal fetal anatomical ultrasound were prospectively evaluated with placental ultrasound and uterine artery Doppler at referral between 19 and 23 weeks' gestation. RESULTS: Abnormalities in both placental ultrasound and uterine artery Doppler (n = 24) predicted preterm delivery less than 32 weeks from any cause (n = 24) (75% sensitivity, 75% positive predictive value; likelihood ratio positive 3.3 [1.6 to 6.8]), intrauterine fetal death (n = 12) (100% sensitivity, 50% positive predictive value; likelihood ratio positive 3.1 [2.0 to 5.0]), and intrauterine growth restriction with absent/reversed end-diastolic flow (n = 17) (sensitivity 94%, positive predictive value 67%, likelihood ratio positive 3.9 [2.0 to 6.2]) . Ischemic-thrombotic pathology was present in 88% of placentas examined (n = 32). CONCLUSION: Uterine artery Doppler and placental morphology identified most pregnancies with combined abnormal maternal serum screening destined to result in extremely premature delivery and/or perinatal death. Abnormal maternal serum screening reports could include a recommendation for placental ultrasound testing when no fetal explanation has been identified.

Fetal response to maternal exercise in pregnancies with uteroplacental insufficiency.

OBJECTIVE: The purpose of this study was to determine the fetal response to submaximal maternal exercise at 22 to 26 weeks in pregnancies with abnormal uterine artery Doppler. STUDY DESIGN: This was a prospective comparison of singleton pregnancies with uteroplacental vascular insufficiency (UPVI) (mean uterine pulsatility index [PI] values >1.45 [n = 12]) and those with normal uterine artery Doppler (n = 23). Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of predicted work rate maximum were studied. RESULTS: Umbilical artery Doppler deteriorated after exercise in patients with UPVI (pre PI 1.4 [0.35-2.14], post PI 1.64 [0.45-2.18]). Three (25%) had transient absent-end diastolic flow (AEDF) in umbilical artery, 2 of which developed early-onset intrauterine growth restriction (IUGR) with AEDF. Fetal cardiac output studies remained stable during the examinations. CONCLUSION: Submaximal steady state exercise had a transient deleterious effect in a subset of women with uteroplacental vascular insufficiency destined to develop early-onset IUGR.

Developmental biology of the placenta and the origins of placental insufficiency.

Defects in all the trophoblast-differentiating pathways--endovascular, interstitial and chorionic villous--play a role in the pathogenesis of early-onset intra-uterine growth restriction (IUGR). There are two types of extravillous trophoblast: endovascular trophoblast, that forms the definitive placenta by occlusion of the spiral arteriole at the implantation site, and interstitial extravillous trophoblast, responsible for the anatomical erosion of the distal spiral arteriole and the secretion of angiogenic and vasodilator signals to improve uterine blood flow. Defective endovascular erosion may render the basal plate inadequate to meet the demands of the fetus. Failed interstitial invasion of spiral arterioles could lead to failure of local angiogenic and systemic cardiovascular adaptation signals that could be the underlying basis for early-onset IUGR and pre-eclampsia. As debate persists regarding the relative importance of cord, stem and terminal villous pathology, the study of factors controlling trophoblast turnover from immature intermediate villi to conductance stem villi and gas-exchanging terminal villi, translation of our knowledge from mouse placental genetics into human placental development, and defining causes of thrombo-occlusive damage to the placenta would help our understanding of the pathophysiology of early-onset IUGR.

Absence of sperm meiotic segregation error of chromosomes 1, 9, 12, 13, 16, 18, 21, X and Y in a case of 100% necrozoospermia.

Varying degrees of necrozoospermia are common findings in cases of male sub-fertility; however, it is rare to find persistent and 100 % necrozoospermia. A case of persistent 100 % necrozoospermia was presented in this paper, where aneuploidy analysis was carried out on sperm. No known associations like thyrotoxicosis, genital infection, spinal injury and diabetes were found. Sperm fluorescent in situ hybridization (FISH) was carried out to evaluate sperm aneuploidy for chromosome 1, 9, 12, 13, 16, 18, 21, X and Y and did not show any excess of aneuploidy over controls. To the best of our knowledge, this is the first attempt on meiotic segregation analysis on 100 % necrozoospermic patients.

Low level of mosaicism in atypical Prader Willi syndrome: detection using fluorescent in situ hybridization.

Prader Willi syndrome (PWS) most commonly is due to paternal micro-deletion of 15q11-q13. Although PWS is not a rare condition, mosaic micro-deletion cases are reported rarely. FISH using PWS micro-deletion probe is the most useful method to detect deletion including mosaicism. In this report we describe a female child with clinical features of atypical PWS and FISH analysis showing mosaicism for deletion in the PWS critical region. This is first mosaic deletion case of PWS from Indian subcontinent.