Jennifer Donnelly

A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy.

OBJECTIVES:Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19).METHODS:ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case–control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitages trend test.RESULTS:Cochran–Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10−4 (rs3815676) and for ABCB4 it was 4.6×10−7(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings.CONCLUSIONS:Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.

The placenta in infants >36 weeks gestation with neonatal encephalopathy: a case control study

Objective To determine placental characteristics associated with neonatal encephalopathy (NE) and correlate these with short- and long-term neurodevelopmental outcome. Design Case/control study. Setting Neonatal Intensive Care Unit, Rotunda Hospital, Dublin, Ireland. Patients Newborns ≥36 weeks gestation, with NE (cases). Healthy term newborns (controls). Interventions Placental pathology was obtained from the official placental report. Brain MRI was blindly reviewed. Children were assessed using a variety of standardised assessments. Data were analysed using multinomial logistic regression analysis. Main outcome measures RRR for grade of encephalopathy. OR for neurodevelopmental outcome. Results Placental reports were available on 141 cases (76 grade 1; 46 grade 2; 19 grade 3) and 309 control infants. Meconium phagocytosis, haemorrhage, raised placental to birth weight ratio and/or markers of infection/inflammation were independently associated with NE and showed a synergistic effect, when combined, for short- and long-term impairments. Conclusions Evaluation of the mechanisms leading to the placental characteristics identified may help to characterise the causal pathway of NE.

Laboratory assessment of iron status in pregnancy.

Abstract Background: Efforts to improve maternal nutrition during pregnancy prompted an observational study of the occurrence of maternal iron deficiency and its laboratory diagnosis in almost 500 pregnancies. Methods: In this longitudinal study, the biochemical and haematological iron indices of women (n=492) attending a prenatal clinic in a Dublin maternity hospital were assessed at first booking (mean 15.9 weeks), and after 24 weeks, and 36 weeks of gestation. Full blood counts were measured. Serum ferritin (SF), zinc protoporphyrin (ZPP), and transferrin receptor (sTfR) concentrations were assayed and transferrin receptor index (sTfR-Index) was calculated. The occurrence of low values and their diagnostic values were considered. Results: A high occurrence iron deficiency (ID) at first booking (SF<12 μg/L) had increased over six-fold by 24 weeks, and all biochemical iron indices reflected progressive iron depletion right up to term. The WHO recommended anaemia “cut-off” (Hb<110 g/L) was insensitive to biochemical iron deficiency at booking, missing over 90% of the low SF values (SF<12 μg/L) which were mostly associated with much higher Hb levels. Conclusions: This study stresses the importance of including a biochemical index of iron status in prenatal screening and supports SF as the best indicator of biochemical ID overall. sTfR was insensitive to iron deficiency in early pregnancy, whereas the sTfR-Index, as a ratio, has the potential to distinguish between ID and physiological anaemia, and may offer stability in the assessment of iron stores from early pregnancy to full term. A policy of early screening of both Hb and SF concentrations is recommended as the minimum requirement for surveillance of maternal iron status in pregnancy.

Illegal drug use, smoking and alcohol consumption in a low-risk Irish primigravid population.

Abstract To evaluate the prevalence of illegal drug use, smoking and alcohol consumption in Irish primigravidas, we interviewed 1011 women at their booking visit. A total of 23.5% (235) of women had used illegal drugs prior to their first pregnancy, 28.9% were ex-smokers and 27.9% were still smoking during pregnancy. A total of 53.9% admitted to drinking alcohol during pregnancy. Smokers are 2.8 times more likely to have used drugs in the past than non-smokers. Level of alcohol consumption appears to be a significant predictor of drug use.

The incidence and impact of increased body mass index on maternal and fetal morbidity in the low-risk primigravid population.

Objective. To determine the incidence and impact of increased body mass index (BMI) on maternal and fetal morbidity in the low-risk primigravid population. Methods. This was a prospective study with retrospective analysis of delivery outcome data. All low-risk primigravida who met the inclusion criteria during the recruitment period were approached. BMI was calculated using the formula weight/height squared. The participants were divided into five categories: ‘underweight’ (BMI <20 kg/m2), ‘normal’ (BMI 20.01–25 kg/m2), ‘overweight’ (BMI 25.01–30 kg/m2), ‘obese’ (BMI 30.01–40 kg/m2), and ‘morbidly obese’ (BMI >40 kg/m2). Maternal outcomes evaluated included gestation at delivery, onset of labor (spontaneous/induced/elective cesarean section), length of labor, use of oxytocin and epidural, mode of delivery, and estimated blood loss. Perinatal outcome measures included infant birth weight (kg) and centile, gestational age, ponderal index, Apgar score <7 at 5 minutes, cord pH <7.1, presence of meconium grade 3 at delivery, degree of resuscitation required, admission to neonatal intensive care unit (NICU), and duration of stay. Results. One thousand and eleven women participated in the study. Complete outcome data were available for 833 women (82%). A significant difference was identified in gestation at delivery between the subgroups (p < 0.004). A significant positive correlation was identified between cesarean section rates with increasing BMI, even when gestation was controlled for (p = 0.004). Similarly, women in the normal BMI group remained significantly less likely to have an infant requiring NICU admission than obese women (2.2% vs. 8.6%; p = 0.011). Conclusion. High BMI is associated with longer gestations, higher operative delivery rates, and an increased rate of neonatal intensive care admission.

The impact of ultrasonographic placental architecture on antenatal course, labor and delivery in a low-risk primigravid population

Objective. To ascertain the impact of placental architecture on antenatal course and labor delivery in a low-risk primigravid population. Methods. This study involves prospective recruitment of 1011 low-risk primigravids with placental ultrasound at 22–24 weeks and 36 weeks. Detailed postnatal review of all mothers and infants was undertaken. Retrospective analysis of ultrasound and clinical outcome data was performed. Results. Eight hundred ten women with complete outcome data were available. Anterior placentation was statistically associated with intrauterine growth restriction (IUGR) and preterm birth and fundal placentation was significantly associated with a higher incidence of pregnancy-induced hypertension and infants with a birthweight less than the 9th centile. Placental infarcts in the third trimester was significantly increased in cases complicated by pre-eclampsia (PET) and in cases with fetal acidosis. Placental calcification was associated a 40-fold increase in the incidence of IUGR. Placental lakes in the second trimester were more prevalent in patients with threatened miscarriage. Increased placental thickness was associated with a higher rate of fetal acidosis. The Grannum grade of the placenta was higher with threatened first or second trimester loss, PET and in infants born less than 9th centile for gestation. Conclusion. Placental site and architecture impact on the incidence of maternal and fetal disease.

Subclinical hypothyroidism as a risk factor for placental abruption: evidence from a low-risk primigravid population.

Subclinical thyroid hypofunction in pregnancy has been shown to have an association with neurodevelopmental delay in the offspring. It is unclear whether obstetric factors may account for this observation.

Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not affect outcomes in pregnant patients with venous thromboembolism

Venous thromboembolism (VTE) remains a leading cause of maternal morbidity and mortality in the developed world. Low molecular weight heparins (LMWH) are routinely used to provide therapeutic anticoagulation during pregnancy for women with VTE, with measurement of plasma anti-FXa activity used to guide dosing in certain patient groups. There is limited evidence to support the use of anti-FXa monitoring in pregnant patients. This study seeks to ascertain whether anti-FXa monitoring of pregnant patients with VTE influences patient outcomes. We performed a single-centre case series including two consecutive groups of pregnant patients treated with LMWH for VTE sustained in the index pregnancy with and without monitoring of anti-FXa levels. 35,394 patients delivered during the study period in a large urban stand-alone maternity hospital, with 26 cases of VTE eligible for inclusion. There was no significant difference between the two groups in any clinical outcome; including maternal blood loss at delivery, recurrent thromboembolic events or rates of planned delivery. These data provide clinical evidence to support current international guideline recommendations that measurement of plasma anti-FXa activity in the majority of patients receiving therapeutic-intensity antenatal LMWH is not warranted.

Early fetal anatomical sonography.

Over the past decade, prenatal screening and diagnosis has moved from the second into the first trimester, with aneuploidy screening becoming both feasible and effective. With vast improvements in ultrasound technology, sonologists can now image the fetus in greater detail at all gestational ages. In the hands of experienced sonographers, anatomic surveys between 11 and 14 weeks can be carried out with good visualisation rates of many structures. It is important to be familiar with the normal development of the embryo and fetus, and to be aware of the major anatomical landmarks whose absence or presence may be deemed normal or abnormal depending on the gestational age. Some structural abnormalities will nearly always be detected, some will never be and some are potentially detectable depending on a number of factors.

The relationship between body mass index and mid-arm circumference in a pregnant population

Our objective was to correlate body mass index (BMI) with mid-arm circumference (MAC) and also to ascertain whether maternal BMI could be calculated from MAC at booking. We approached all Caucasian women who met the inclusion criteria attending the University College Hospital, London between 1 April 1996 and 30 June 1997 and the Rotunda Hospital, Dublin, Ireland between 15 April 2003 and 19 May 2004. A total of 2,912 women agreed to participate in the research. The participants’ maternal height and weight were measured. Their BMI was calculated using the formula: BMI = weight (kg) ÷ height (m2). The MAC was measured in cm. Statistical analysis was performed using SPSS for Windows version 11 with p < 0.05 as significant. We found that BMI is directly correlated with MAC (r = 0.836) and estimates of BMI may be calculated from the simple equation BMI = MAC ± 2. Alternatively, a MAC of ≥ 27 cm allowed for a detection rate for overweight patients of 75%, with a false positive rate of 15%.