Vitamin D deficiency and supplementation during pregnancy.

OBJECTIVE: Vitamin D is essential for skeletal health and prolonged deficiency results in infantile rickets and adult osteomalacia. The aim of this study is to determine the vitamin D status in pregnancy and to evaluate the effects of daily and of single-dose vitamin D supplementation. DESIGN: A prospective randomized study at St Mary's Hospital London. PATIENTS: A total of 180 women (Indian Asian, Middle Eastern, Black and Caucasian) were recruited at 27 weeks gestation and randomized into three treatment groups: a single oral dose of 200,000 IU vitamin D, a daily supplement of 800 IU vitamin D from 27 weeks until delivery and a no treatment group. MEASUREMENTS: Vitamin D (25-hydroxyvitamin D), PTH and corrected calcium levels in mothers at 27 weeks and at delivery and cord 25-hydroxyvitamin D and corrected calcium levels. RESULTS: The final maternal 25-hydroxyvitamin D levels were significantly higher in the supplemented group [daily dose (median) 42 (IQR 31-76) nmol/l, stat dose (median) 34 (IQR 30-46) nmol/l vs. median 27 (IQR 27-39) nmol/l in the no treatment; P < 0.0001] and significantly fewer women with secondary hyperparathyroidism in the supplemented group (10% in daily dose vs. 12% in stat dose vs. 27% in the no treatment; P < 0.05). Cord 25-hydroxyvitamin D levels were significantly higher with supplementation [daily dose median 26 (IQR 17-45) nmol/l, stat dose median 25 (IQR 18-34) nmol/l vs. median 17 (IQR 14-22) nmol/l in no treatment; P = 0.001]. CONCLUSION: Single or daily dose improved 25-hydroxyvitamin D levels significantly. However, even with supplementation, only a small percentage of women and babies were vitamin D sufficient. Further research is required to determine the optimal timing and dosing of vitamin D in pregnancy.

Outcome of pregnancy in sickle cell disease patients attending a combined obstetric and haematology clinic.

This study aims to determine the pregnancy outcomes in women attending the combined obstetric sickle cell clinic at King's College Hospital, London from June 2000 to July 2006. There were 71 pregnancies in 65 women with sickle cell disease. Sickle crisis requiring admission occurred in 47% of the antenatal patients. The first admission occurred most frequently in the third trimester (23 vs 6 and 5 admissions in the second and first trimester; p < 0.001). There were no maternal deaths; other complications include anaemia requiring blood transfusion (32%), proteinuric hypertension (9%), infections (28%) and emergency caesarean section (30%). There was one fetal demise due to abruption. Pre-term delivery before 34 weeks occurred in 8% and 24% before 37 weeks. A total of 18% of infants had reduced growth velocity with the measurements crossing below the 10th centile.

Prediction of pre-eclampsia by uterine artery Doppler imaging: relationship to gestational age at delivery and small-for-gestational age.

OBJECTIVES: To determine the relationship between pre-eclampsia, small-for-gestational age (SGA) and gestational age at delivery, and the effect of this relationship on the prediction of pre-eclampsia by uterine artery Doppler imaging. METHODS: This was a multicenter prospective Doppler study of the uterine artery at 22-24 weeks of gestation in unselected women with singleton pregnancies. RESULTS: In the 30,639 pregnancies examined, the median uterine artery pulsatility index (PI) was 1.0 and the 95(th) centile was 1.58. In 614 (2%) cases the woman developed pre-eclampsia and in this group there was an inverse significant association between the gestational age at delivery and prevalence of SGA (r = - 0.99, P < 0.0001), and between the gestational at delivery and mean uterine artery PI (r = - 0.51, P < 0.0001) and prevalence of mean uterine artery PI above the 95(th) centile (r = - 0.99, P < 0.0001). The mean uterine artery PI was above the 95(th) centile in 77.2% of women who developed pre-eclampsia requiring delivery before 34 weeks, in 35.9% of those delivering at 34-37 weeks and in 21.9% of those delivering after 37 weeks. The respective percentages were 82.3%, 46.9% and 28.8% for those with pre-eclampsia and SGA, and 43.8%, 21.2% and 8.4% for those with SGA but without pre-eclampsia. CONCLUSIONS: Pre-eclampsia requiring early delivery is more likely to be associated with SGA than less severe pre-eclampsia in women who deliver at term. Doppler ultrasound assessment of the uterine arteries is more effective in identifying pre-eclampsia requiring preterm than term delivery.

Prediction of pre-eclampsia by a combination of maternal history, uterine artery Doppler and mean arterial pressure.

OBJECTIVES: To determine the value of combined screening for pre-eclampsia by maternal history, and mid-trimester uterine artery (UtA) Doppler imaging and maternal blood pressure. METHODS: In 3529 singleton pregnancies attending for routine care at 22-24 weeks' gestation we recorded maternal variables, and made UtA Doppler and mean arterial pressure (MAP) measurements. Multiple regression analysis was used to determine the significant predictors of pre-eclampsia, gestational hypertension and small-for-gestational age (SGA) among maternal characteristics, UtA pulsatility index (PI) and MAP. RESULTS: Complete pregnancy outcomes were available in 3359/3529 (95.2%) cases. Pre-eclampsia developed in 101 (3.0%) pregnancies, including 23 (0.7%) in which delivery was before 34 weeks (early pre-eclampsia) and 78 (2.3%) with delivery at 34 weeks or more (late pre-eclampsia); 74 (2.2%) developed gestational hypertension, 366 (10.9%) delivered SGA newborns with no hypertensive disorders, and 2806 (83.8%) were unaffected by pre-eclampsia, gestational hypertension or SGA. Multiple regression analysis demonstrated that maternal characteristics, UtA-PI and MAP provided a significant independent contribution in the prediction of pre-eclampsia, gestational hypertension and SGA. For a false-positive rate of 10%, the estimated detection rates of early and late pre-eclampsia were 100% and 56.4%, respectively. CONCLUSIONS: The combination of maternal demographic characteristics, and UtA Doppler and maternal blood pressure measurements is an effective screening tool for the prediction of pre-eclampsia.

Second-trimester sex hormone-binding globulin and subsequent development of pre-eclampsia.

OBJECTIVE: To investigate whether maternal plasma sex hormone-binding globulin (SHBG) concentrations are reduced in women who subsequently develop pre-eclampsia. METHODS: This was a cross-sectional study, carried out at antenatal clinics in seven hospitals in and around London. Healthy women underwent uterine artery Doppler velocimetry as a screening method for pre-eclampsia at 22-24 weeks of gestation. The first group (408 women) had normal uterine artery Doppler waveforms (mean uterine artery pulsatility index (PI) below 1.6). The second group (274 women) had increased impedance to flow in the uterine arteries (mean PI above the 95th centile, 1.6). Maternal plasma SHBG concentrations were measured retrospectively using a competitive chemiluminescent immunoassay. Pre-eclampsia was as defined by the International Society for the Study of Hypertension in Pregnancy. RESULTS: Plasma SHBG concentrations in the 80 (11.7%) women who subsequently developed pre-eclampsia were significantly lower than in the 585 (85.8%) women with normal pregnancy outcomes (median 336, range 142-674 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.001). There was a strong correlation between SHBG concentrations and body mass index (r =-0.232246, p < 0.0001). There were no significant differences in maternal plasma SHBG concentrations in women with abnormal uterine artery Doppler (n = 274) compared with controls (n = 408) (median 324, range 101-635 nmol/l vs. median 336, range 142-674 nmol/l, p = 0.09). CONCLUSION: Maternal plasma SHBG concentrations are reduced in women who subsequently develop pre-eclampsia.

Second-trimester uterine artery Doppler screening in unselected populations: a review.

OBJECTIVE: Doppler ultrasound provides a non-invasive method for the study of the uteroplacental circulation. In normal pregnancy, impedance to flow in the uterine arteries decreases with gestation, which may be the consequence of trophoblastic invasion of the spiral arteries and their conversion into low-resistance vessels. Pre-eclampsia and fetal growth restriction are associated with failure of trophoblastic invasion of spiral arteries, and Doppler studies, in these conditions, have shown that impedance to flow in the uterine arteries is increased. A series of screening studies involving assessment of impedance to flow in the uterine arteries have examined the potential value of Doppler in identifying pregnancies at risk of the complications of impaired placentation. This review examines the findings of Doppler studies in unselected populations. METHODS: Searches of a computerized medical database were performed to identify relevant studies. Only those studies that provided sufficient data to allow calculation of the performance of the test were included in the analysis. Likelihood ratios were calculated for each study and are reported for pre-eclampsia, fetal growth restriction and perinatal death as well as for more severe forms of pre-eclampsia and fetal growth restriction. RESULTS: The literature search identified 19 relevant studies, four of which were excluded from the further analysis. The main characteristics and results of the 15 remaining studies provided discrepant results, which may be the consequence of differences in Doppler technique for sampling, the definition of abnormal flow velocity waveform, differences in the populations examined, the gestational age at which women were studied and different criteria for the diagnosis of pre-eclampsia and fetal growth restriction. Nevertheless, the studies provided evidence that increased impedance to flow in the uterine arteries is associated with increased risk for subsequent development of pre-eclampsia, fetal growth restriction and perinatal death. In addition, women with normal impedance to flow in the uterine arteries constituted a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency. CONCLUSIONS: The review suggests that increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 40% of those who subsequently develop pre-eclampsia and about 20% of those who develop fetal growth restriction. Following a positive test, the likelihood of these complications is increased by about 6 and 3.5 times, respectively.

Uterine artery Doppler and mid-trimester maternal plasma homocysteine in subsequent pre-eclampsia.

OBJECTIVE: To investigate whether mid-trimester maternal plasma homocysteine concentration is elevated in women who develop pre-eclampsia and in those women identified at high risk by abnormal uterine artery Doppler examination. METHODS: This was a multicenter study involving healthy women undergoing screening for pre-eclampsia by uterine artery Doppler velocimetry at 22-24 weeks' gestation. Abnormal uterine artery blood flow was defined as a mean pulsatility index (PI) above the 95th centile (1.6). Controls (mean PI < 1.6) were matched for gestational age and date of blood sample collection. Maternal plasma homocysteine concentration was measured retrospectively using a chemiluminescent immunoassay. RESULTS: In total, 683 women were recruited. Maternal plasma homocysteine concentration did not vary with gestation. Maternal plasma homocysteine concentration in women who subsequently developed pre-eclampsia (n = 80, 12%) was not significantly different from women with uncomplicated pregnancies (n = 536, 78%) (median 5.1, range 2.7-14.1 micromol/l vs. median 5.5, range 1.9-27.9 micromol/l, p = 0.44). There were no significant differences in the maternal plasma homocysteine concentration in women with abnormal uterine artery Doppler findings (n = 275) compared with controls (n = 408), (median 5.6, range 2.6-17.7 micromol/l vs. median 5.4, range 1.9-27.9 micromol/l, p = 0.13). CONCLUSION: Mid-trimester maternal plasma homocysteine concentration is not elevated in women who developed pre-eclampsia even in those at high risk defined by abnormal uterine artery Doppler velocimetry.

Maternal serum vitamin D levels at 11-13 weeks of gestation in preeclampsia.

This study is aimed to determine whether the maternal serum levels of vitamin D in the first trimester of pregnancy are altered in cases that develop preeclampsia (PE) and whether the levels are related to biochemical and biophysical markers of impaired placental perfusion and function. Maternal total serum vitamin D, pregnancy-associated plasma protein-A (PAPP-A), uterine artery pulsatility index (PI) and mean arterial pressure (MAP) were measured at 11-13 week gestation in 90 cases that developed PE, including 30 that required delivery before 34 weeks (early PE) and 1000 unaffected controls. The median values of vitamin D, PAPP-A, uterine artery PI and MAP expressed as a multiple of the unaffected median (MoM), in the patients developing early PE and late PE were compared with the controls. There was no significant difference in the median serum vitamin D MoM or raw values within the outcome groups (P=141 and P=0.231, respectively) whereas the median PAPP-A MoM, uterine PI MoM and MAP MoM were significantly different (P=0.031, P=0.001 and P<0.0001, respectively). Serum PAPP-A was decreased in both early PE and late PE (0.54 and 0.88 versus 1.03 MoM, P<0.0001 and P=0.010, respectively), MAP was increased in both early PE and late PE (1.09 and 1.06 versus 0.99 MoM, P<0.0001 and P<0.0001, respectively) and uterine artery PI was increased in early PE but not in late PE (1.32 and 1.12 versus 1.01 MoM, P<0.0001 and P=0.083, respectively). In pregnancies that subsequently develop PE maternal serum total vitamin D levels at 11-13 weeks are not altered.

Obesity in pregnancy.

Overweight and obesity are common findings in women of reproductive age in the UK; as 32% of 35- to 64-year-old women are overweight and 21% obese. Obesity causes major changes in many features of maternal intermediary metabolism. Insulin resistance appears to be central to these changes and may also be involved in increased energy accumulation by the fetus. Maternal obesity is associated with many risks to the pregnancy, with increased risk of miscarriage (three-fold) and operative delivery (20.7 versus 33.8% in the obese and 47.4% in the morbidly obese group). Other risks to the mother include an increased risk of pre-eclampsia (3.9 versus 13.5% in the obese group) and thromboembolism (0.05 versus 0.12% in the obese group). There are risks to the fetus with increased perinatal mortality (1.4 per 1000 versus 5.7 per 1000 in the obese group) and macrosomia (>90th centile; 9 versus 17.5% in the obese group). Maternal obesity is associated with an increased risk of obesity in the long term. Obese woman should try to lose weight before pregnancy but probably not during pregnancy. There is no real evidence base for the management of maternal obesity but some practical suggestions are made.

Prediction of patient-specific risk of early preterm delivery using maternal history and sonographic measurement of cervical length: a population-based prospective study.

OBJECTIVE: To develop a model for calculating the patient-specific risk of spontaneous early preterm delivery by combining maternal factors and the transvaginal sonographic measurement of cervical length at 22 + 0 to 24 + 6 weeks, and to compare the detection rate of this method to that achieved from screening by cervical length or maternal characteristics alone. METHODS: This was a population-based prospective multicenter study involving 40,995 unselected women with singleton pregnancies attending for routine hospital antenatal care in London, UK. Complete follow-up was obtained from 39,284 (95.8%) cases. The main outcomes were detection rate, false-positive rate and accuracy of predicting spontaneous delivery before 32 weeks' gestation. RESULTS: Spontaneous delivery before 32 weeks occurred in 235 (0.6%) cases. The detection rate of screening for early preterm delivery, at a fixed false-positive rate of 10%, was 38% for maternal factors, 55% for cervical length and 69% for combined testing. There was good agreement between the model estimates and the observed probabilities of preterm delivery. CONCLUSIONS: This study provides a model that can give an accurate patient-specific risk of preterm delivery. The detection rate of screening by a combination of maternal factors and the measurement of cervical length was substantially higher than that of screening by each method alone.

Prediction of pre-eclampsia by uterine artery Doppler ultrasonography and maternal serum pregnancy-associated plasma protein-A, free beta-human chorionic gonadotropin, activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation.

OBJECTIVE: To investigate the potential value of combining uterine artery Doppler ultrasonography with the measurement of maternal serum pregnancy-associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (beta-hCG), activin A and inhibin A at 22 + 0 to 24 + 6 weeks' gestation, in the prediction of pregnancies that subsequently develop pre-eclampsia. METHODS: The maternal serum PAPP-A, free beta-hCG, activin A and inhibin A concentrations at 22 + 0 to 24 + 6 weeks' gestation were measured in samples obtained from women with singleton pregnancies who participated in a screening study for pre-eclampsia by transvaginal color flow Doppler measurement of the uterine artery pulsatility index (PI). A search was made of the database to identify those who subsequently developed pre-eclampsia (n = 24) and a group of controls with normal outcome (n = 144). Regression analysis was performed to establish any relationship between the biochemical markers themselves and between the biochemical markers and uterine artery mean PI. A multivariate Gaussian model combining various biochemical markers with uterine artery mean PI was developed using standard statistical modeling techniques and the performance of such models in discriminating cases with pre-eclampsia was evaluated by receiver-operating characteristics curve (ROC) analysis. RESULTS: In the pre-eclampsia group, compared to the controls, the uterine artery mean PI and the maternal serum levels of PAPP-A, free beta-hCG, activin A and inhibin A were significantly increased. The predicted detection rates of pre-eclampsia, for a false positive rate of 5%, was 50% by uterine artery mean PI, 5% by PAPP-A, 10% by free beta-hCG, 35% by inhibin A and 44% by activin A. Screening by a combination of uterine artery mean PI and maternal serum activin A and inhibin A could detect 75% and 92% of patients who subsequently developed pre-eclampsia, for false positive rates of 5% and 10%, respectively. CONCLUSION: Screening for pre-eclampsia by uterine artery PI at 22 + 0 to 24 + 6 weeks' gestation can be improved by measurement of activin A and inhibin A levels.

Relationship between second-trimester uterine artery Doppler and spontaneous early preterm delivery.

OBJECTIVE: To evaluate the relationship between impedance to flow in the uterine arteries at 22-24 weeks and subsequent spontaneous delivery before 33 weeks. METHODS: The pulsatility index (PI) in the uterine arteries was measured by transvaginal sonography at 22-24 weeks in 33,629 women with singleton pregnancies attending for routine antenatal care. The distribution of PI in the 237 patients with live births before 33 weeks, after spontaneous onset of labor, was compared to that in 31,633 patients with live births at or after 33 weeks. RESULTS: The median uterine artery mean PI was significantly higher in those women delivering before 33 weeks than in those delivering at or after 33 weeks. The mean PI was 1.57, which is the 95th centile, in 1525 (4.8%) of those delivering at or after 33 weeks and in 19 (8.0%) of the deliveries before 33 weeks. Multiple regression analysis demonstrated that the significant predictors of spontaneous delivery before 33 weeks were ethnic origin, smoking status, previous obstetric history and uterine artery mean PI. However, the prediction of spontaneous early preterm delivery by a combination of maternal characteristics and uterine artery Doppler was not significantly higher than maternal characteristics alone (area under the receiver-operating characteristics curve: 0.704, 95% CI 0.669-0.740 vs. 0.684, 95% CI 0.647-0.722; P = 0.062). CONCLUSIONS: Uterine artery PI in spontaneous deliveries before 33 weeks is higher than in those women delivering at or after 33 weeks. However, uterine artery Doppler does not provide a significant improvement in the prediction of spontaneous early delivery provided by maternal demographic characteristics and previous obstetric history.

Total laparoscopic hysterectomy as a primary surgical treatment for endometrial cancer in morbidly obese women.

To evaluate the feasibility of total laparoscopic hysterectomy as the primary treatment for endometrial cancer in morbidly obese women, an audit was carried out during an 18-month period in a tertiary referral centre for gynaecological oncology. Four women who had laparoscopic surgery were compared with a similar cohort who had open surgery. The mean operating time was equivalent, without evidence of excess morbidity with the laparoscopic approach. However, inpatient stay was longer with open versus laparoscopic surgery (11.5 vs 4 days). Laparoscopic surgery is safe to use in morbidly obese women with endometrial cancer.

Screening for pre-eclampsia and fetal growth restriction in twin pregnancies at 23 weeks of gestation by transvaginal uterine artery Doppler.

OBJECTIVE: To assess the value of transvaginal uterine artery Doppler at 23 weeks of gestation in predicting the development of adverse perinatal outcomes in twin pregnancies. PATIENTS AND METHODS: Women with twin pregnancies attending for routine ultrasound examination at 23 weeks in any one of seven hospitals underwent Doppler assessment of the uterine arteries. The right and left uterine arteries were identified using color flow mapping and velocity waveforms were obtained using pulsed Doppler. The mean pulsatility index (PI) of the two arteries was determined and the presence of uterine artery notching noted. Results were compared between monochorionic and dichorionic twins, and with our previously reported data from singleton pregnancies. Screening characteristics in the prediction of pre-eclampsia, fetal growth restriction (FGR), placental abruption, fetal death and early preterm delivery were calculated. RESULTS: Uterine artery Doppler at 22-24 weeks of gestation was performed in 360 twin pregnancies, including 324 dichorionic and 36 monochorionic diamniotic twins. Complete outcome data were available in 351 (97.5%). The mean uterine artery PI did not change significantly with gestation and there was no significant difference in mean PI between the dichorionic and monochorionic groups. However, the mean PI was significantly lower in twin pregnancies than in singletons. The pregnancy was complicated by pre-eclampsia in 6.0% of cases, FGR below the 5th centile of both twins in 8.8%, abruption in 0.9%, intrauterine fetal death in 1.7% and early preterm delivery at less than 32 completed weeks of gestation in 5.7% of cases. The respective sensitivities of uterine artery mean PI above the 95th centile for these complications were 33.3%, 9.7%, 66.6%, 33.3% and 18.6%. CONCLUSIONS: In twin pregnancies PI in the uterine arteries is lower than that in singleton pregnancies, but there is no significant difference between dichorionic and monochorionic twins. Doppler assessment of the uterine arteries at 23 weeks identifies a large proportion of twin pregnancies destined to develop adverse outcomes related to uteroplacental insufficiency.

Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks' gestation.

OBJECTIVE: Pre-eclampsia, which is a major cause of perinatal and maternal morbidity and mortality, is thought to be due to impaired perfusion of the placenta. There is contradictory evidence that the administration of low-dose aspirin may provide effective prophylaxis against the subsequent development of pre-eclampsia. In this study we tested the hypothesis that in women identified as being at high-risk for pre-eclampsia, because of impaired flow in the uterine arteries, the prophylactic use of low-dose aspirin from 23 weeks of gestation can reduce the incidence of pre-eclampsia. METHODS: We used color and pulsed Doppler to measure the flow in the uterine arteries in 19,950 singleton pregnancies at 22-24 weeks of gestation. Those women exhibiting increased impedance were recruited into a randomized study of aspirin 150 mg per day or placebo. We compared the two groups for the incidence of pre-eclampsia and the other consequences of impaired placentation. RESULTS: The screening study identified 844 women (4.2%) as being at high risk of uteroplacental insufficiency. After exclusion and refusal, 560 women were randomly allocated to aspirin 150 mg or placebo per day until 36 weeks' gestation. There were no significant differences between the aspirin and placebo groups in either the incidence of pre-eclampsia (18% vs. 19%, P = 0.6) or pre-eclampsia requiring delivery below 34 weeks (6% vs. 8%, P = 0.36). Furthermore, the administration of aspirin did not significantly alter the incidence of preterm delivery (24% vs. 27%, P = 0.46), birth weight below the 5th centile (22% vs. 24%, P = 0.4), perinatal death (3% vs. 1%, P = 0.33) or placental abruption (4% vs. 2%, P = 0.12). CONCLUSION: In pregnancies with impaired placentation, as demonstrated by increased impedance to flow in the uterine arteries, the daily administration of 150 mg aspirin after 23 weeks of gestation does not prevent the subsequent development of pre-eclampsia.