Screening for sickle cell and thalassaemia in primary care: a cost-effectiveness study

Background

Haemoglobinopathies, including sickle cell disease and thalassaemia (SCT), are inherited disorders of haemoglobin. Antenatal screening for SCT rarely occurs before 10 weeks of pregnancy.

Aim

To explore the cost-effectiveness of offering SCT screening in a primary care setting, during the pregnancy confirmation visit.

Design and setting

A model-based cost-effectiveness analysis of inner-city areas with a high proportion of residents from ethnic minority groups.

Method

Comparison was made of three SCT screening approaches: ‘primary care parallel’ (primary care screening with test offered to mother and father together); ‘primary care sequential (primary care screening with test offered to the mother and then the father only if the mother is a carrier); and ‘midwife care’ (sequential screening at the first midwife consultation). The model was populated with data from the SHIFT (Screening for Haemoglobinopathies In First Trimester) trial and other sources.

Results

Compared to midwife care, primary care sequential had a higher NHS cost of £34 000 per 10 000 pregnancies (95% confidence interval [CI] = £15 000 to £51 000) and an increase of 2623 women screened (95% CI: 1359 to 4495), giving a cost per additional woman screened by 10 weeks of £13. Primary care parallel was dominated by primary care sequential, with both higher costs and fewer women screened.

Conclusion

The policy judgement is whether an earlier opportunity for informed reproductive choice has a value of at least £13. Further work is required to understand the value attached to earlier informed reproductive choices.     

Counselling for prenatal diagnosis of sickle cell disease and beta thalassaemia major: a four year experience.

A non-directive programme of prenatal counselling was used during a four year period. Forty-three couples at risk for having a baby with a haemoglobinopathy were identified. Prenatal diagnosis was offered in 19 pregnancies to 14 couples at risk of having a baby with sickle cell anaemia and in two pregnancies in two couples at risk of a baby with beta thalassaemia major, who presented before the 18th week of pregnancy. Six couples at risk for sickle cell anaemia accepted prenatal diagnosis in 10 pregnancies, as did both couples at risk for thalassaemia. Couples who were eligible for prenatal diagnosis but refused it tended not to have been informed about sickle cell disease before counselling, one partner was more frequently absent at the time of the initial counselling session, or they either had no children with sickle cell disease or the children were not severely affected. Other factors influencing their decision included a poor obstetric history and rejection of abortion, mainly on moral grounds. The approximately 50% uptake of prenatal diagnosis in this initial study highlights the complex issues involved. Our experience indicates that with systematic screening and counselling in the antenatal clinic, and with increased awareness of the haemoglobinopathies, couples at risk will be in a better position to make informed decisions.     

Offering antenatal sickle cell and thalassaemia screening to pregnant women in primary care: a qualitative study of GPs' experiences

Background

Timely antenatal sickle cell and thalassaemia (SC&T) screening for all women in primary care facilitates informed decision making, but little is known about its implementation.

Aim

To assess the feasibility of offering antenatal SC&T screening in primary care at the time of pregnancy confirmation.

Design of study

Cross-sectional investigation of GPs'' beliefs and perceived practices.

Method

Informal face-to-face interviews with 34 GPs.

Setting

Seventeen inner-city general practices that offered antenatal SC&T screening as part of a trial.

Results

GPs identified both barriers and facilitators. Organisational barriers included inflexible appointment systems and lack of interpreters for women whose first language was not English. Professional barriers included concerns about raising possible adverse outcomes in the first antenatal visit. Perceived patient barriers included women''s lack of awareness of SC&T. Hence, GPs presented the test to women as routine, rather than as a choice. Organisational facilitators included simple and flexible systems for offering screening in primary care, practice cohesion, and training. Professional facilitators included positive attitudes to screening for SC&T. Perceived patient facilitators included women''s desire for healthy children.

Conclusion

GPs reported barriers, as well as facilitators, to successful implementation but the extent to which screening could be regarded as offering ‘informed choice’ remained fundamental when making sense of these barriers and facilitators.     

Anthropometry of Malawian live births between 35 and 41 weeks of gestation

The aim of this analysis was to construct cross-sectional gestational age specific percentile curves for birthweight, length, head and mid-arm circumference for Malawian babies, and to compare these percentiles with reference values for babies born to women with normal pregnancies, from a developed country. A cross-sectional study which enrolled pregnant women attending two study hospitals between March 1993 and July 1994 was undertaken. Data on maternal socio-economic status, newborn anthropometry, previous obstetric history and current pregnancy were collected. Smoothed percentile values were derived using the LMS method. Malawian reference percentiles were constructed for fetal growth from 35 weeks' gestation for singleton births. Mean birthweight, length and head circumference were lower at all gestational ages for Malawian compared with Swedish newborns. Fetal growth per completed gestational week was higher by 60 g in weight, 0.5 cm in length and 0.2 cm in head circumference in Swedish compared with Malawian babies. Growth restriction was present from 35 to 41 weeks' gestation. The pattern for the 10th percentile suggested that this was occurring from well before 35 weeks' gestation in a proportion of babies.     

Antenatal screening for haemoglobinopathies in primary care: a whole system participatory action research project

BACKGROUND: The usual system for antenatal screening for haemoglobinopathies permits termination only late in the second trimester of pregnancy. AIM: To evaluate a system where pregnant women are screened in general practice, and to develop a model of care pathway or whole system research able to bring into view unexpected effects of health service innovation. DESIGN OF STUDY: A whole system participatory action research approach was used. Six purposefully chosen general practices screened women who attended with a new pregnancy. Data of gestational age of screening were compared with two control groups. Qualitative data were gathered through workshops, interviews and feedback to the project steering group. At facilitated annual workshops participants from all parts of the care pathway produced a consensus about the meaning of the data as a whole. SETTING: Six general practices in north London. METHOD: A whole system participatory action research approach allowed stakeholders from throughout the care pathway to pilot the innovation and reflect on the meaning and significance of quantitative and qualitative data. RESULTS: The gestational age of screening in general practice was 4.1 weeks earlier (95% confidence interval (CI) = 3.41 to 4.68) than in hospital clinics (P<0.001), and 2.9 weeks earlier (95% CI = 2.07 to 3.65) than in community midwife clinics (P <0.001). However, only 35% of pregnant women in the study were screened in the practices. Changes required throughout the whole care pathway make wider implementation more difficult than at first realised. The cost within general practice is greater than initially appreciated owing to a perceived need to provide counselling about other issues at the same time. Practitioners considered that other ways of early screening should be explored, including preconceptual screening. The research approach was able to bring into view unexpected effects of the innovation, but health workers were unfamiliar with the participatory processes. CONCLUSION: Antenatal screening for haemoglobinopathies in general practice lowers the gestational age at which an at-risk pregnancy can be identified. However, widespread implementation of such screening may be too difficult.     

A prospective study of the incidence, time of appearance and significance of anti-paternal lymphocytotoxic antibodies in human pregnancy

The incidence and natural history of serum anti-paternal cytotoxic antibody (APCA) in normal pregnancy and spontaneous abortion was investigated prospectively in 306 women (64 primigravidae and 242 multigravidae), in order to establish whether serum APCA is a useful screening test in the diagnosis, treatment and prognosis for patients with recurrent pregnancy loss. Pre-pregnancy, serial pregnancy and post delivery serum samples were tested against partner's lymphocytes, using a microdroplet lymphocytotoxicity assay. The incidence of serum APCA in the 256 pregnancies successfully completed was 32%, compared with 10% amongst the 50 pregnancies ending in spontaneous abortion. The lower incidence of positive APCA tests in unsuccessful pregnancies was explained by our finding that positive APCA tests are related to the gestational age of the pregnancy and are rarely demonstrable before 28 weeks gestation. Since APCA usually disappears between pregnancies, its usefulness as a diagnostic test for immunotherapy against recurrent abortion should be questioned.     

Bleeding following pregnancy loss before 6 weeks' gestation

BACKGROUND: Pregnancy loss before 6 weeks' gestation is common, but little has been reported about the associated bleeding. We compared women's bleeding following a pregnancy loss before 6 weeks' gestation with their typical menstruation. METHODS: Women provided daily urine samples while trying to become pregnant and recorded the number of pads and tampons used each day. Thirty-six women had complete bleed data for a loss before 6 weeks' gestation and one or more non-pregnant cycles. RESULTS: Mean bleed length following a pregnancy loss was 0.4 days longer than the woman's average menstrual bleed (P = 0.01), primarily because of more days of light bleeding. Although there was no overall increase in the total number of pads plus tampons used, women with losses bled less than their typical menses following pregnancies of very short duration and more than usual for the pregnancies lasting the longest. CONCLUSIONS: Overall, the bleeding associated with pregnancy loss before 6 weeks' gestation is similar to menstrual bleeding and unlikely to be recognized as pregnancy loss. The intriguing finding that pregnancies of very short duration were associated with less bleeding than the woman's typical menses might reflect endometrial factors associated with loss.     

Vascular endothelial growth factor (VEGF) and discrimination between abnormal intrauterine and ectopic pregnancy

BACKGROUND: This study evaluated serum vascular endothelial growth factor (VEGF) levels in women with abnormal intrauterine and ectopic pregnancies (EP) at 6 weeks gestation. METHODS: We conducted a prospective case-control study comparing serum VEGF concentrations among 84 women with abnormal intrauterine and EP matched for gestational age (42 women in each group). We analysed whether serum VEGF levels >200 pg/ml would discriminate between abnormal intrauterine pregnancies and EP at 6 weeks gestation, and we calculated sensitivity, specificity and positive predictive values. RESULTS: Serum VEGF concentrations did not show statistically significant differences between women with abnormal intrauterine pregnancies (median, 198.5 pg/ml; range, 0-701.6) and EP (median, 211.2 pg/ml; range 0-628.8). When threshold concentrations of a serum VEGF level >200 pg/ml were used, abnormal intrauterine pregnancy could be distinguished from EP with a sensitivity of 56%, a specificity of 51%, and a positive predictive value of 53%. CONCLUSIONS: VEGF does not discriminate ectopic from abnormal intrauterine pregnancies at 6 weeks gestation, and thus should not be used in clinical management.     

Reducing delay in booking for antenatal care

The study compared two schemes of booking for antenatal care: booking at a health centre by general practitioners in conjunction with a hospital consultant or booking in a hospital clinic by hospital staff. the health centre scheme reduced the proportion of women booking late at 16 or more weeks gestation from 44% to 11% and at 20 weeks or more from 28% to 6%. There was no improvement in delay in booking owing to late confirmation of pregnancy. The benefits of this scheme were due to improved attendance and reduced delays in booking among women who confirmed pregnancy before 16 weeks gestation.     

Serum müllerian-inhibiting substance in Down's syndrome pregnancies

BACKGROUND: To examine whether maternal serum levels of müllerian-inhibiting substance (MIS) differ in Down's syndrome and unaffected pregnancies. METHODS: Case-control study was conducted using stored serum from an antenatal screening programme. Sera from 25 Down's syndrome pregnancies were retrieved from -20 degrees C storage together with 125 unaffected controls individually matched for maternal age, weeks of gestation and duration of storage. Results were expressed in multiples of the gestation-specific median value (MoM) in controls. RESULTS: The median value in Down's syndrome pregnancies was 0.83 MoM (P = 0.77, two-tail Wilcoxon rank sum test). Among unaffected pregnancies, there was a statistically significant correlation between MIS and pregnancy-associated plasma protein-A (P < 0.05). MIS levels were elevated in pregnancies where assisted reproduction techniques had been used. CONCLUSION: There is no evidence for a substantial reduction in maternal serum MIS levels in Down's syndrome pregnancies. This study provides useful information regarding serum MIS levels in pregnancy.     

Etiologic factors of prematurity in Ziguinchor maternity hospital center (Senegal)

A case-control study was conducted between September 2003 and January 2004. Fifty four newborn babies born before 37 weeks of gestation resulting from 47 pregnancies including 7 multiple pregnancies were compared to 105 newborn babies born between 37 and the 42 weeks of gestation. Parturient geographical origin, marital status, age, alcohol or tea consumption and height were not significantly associated to premature birth (p > 0.05). On the other hand, a higher parity or equal to 3, a number of antenatal care lower than 3 were significantly associated with the risk of premature birth (p < 0.05). But a gestity and a parity lower than 3 and a number of antenatal consultations higher or equal to 3 had a protective effect (OR < 1; p < 0.05). We recommend a reinforcement of malarial prevention during pregnancy according to WHO recommendations and the improvement of the quality of the antenatal care in the Ziguinchor medical district.     

Serum levels of CA 125 during the first trimester of normal outcome, ectopic and anembryonic pregnancies

Single serum samples were obtained during the first trimester of pregnancies with a retrospectively normal outcome (n = 150), ectopic pregnancies (n = 38) and anembryonic pregnancies (n = 78). Serial samples during the first trimester were also obtained from 43 women achieving pregnancy following successful treatment for infertility and with a retrospectively defined normal outcome. Significant variation in serum CA 125 levels in relation to gestational age was observed in pregnancies with a normal outcome (P less than 0.0001). Peak serum CA 125 levels were observed at 6-7 weeks, the mean level at this gestation being 40.1 U/ml (range 31.7-50.7 U/ml) in the normal conception/normal outcome group and 36.5 U/ml (range 25.6-52.0 U/ml) in the assisted conception/normal outcome group. A rise and fall in serum CA 125 levels during the first trimester was observed in 42 of 43 assisted conceptions monitored serially, with peak levels ranging from 7 to 1398 U/ml (median 48.8 U/ml) occurring at 28-61 days (median 45 days) gestation. Mean serum CA 125 levels were higher in the anembryonic pregnancy group at 4-5 and 6-7 weeks gestation than in both normal pregnancy outcome groups (P less than 0.01).     

The course of pregnancy and delivery and the use of maternal healthcare services after standard IVF in Northern Finland 1990-1995

BACKGROUND: The objective of this study was to evaluate the course of pregnancy and delivery and the use of maternal healthcare after IVF. METHODS: This population-based cohort study included all women who had undergone IVF treatment in Northern Finland leading to delivery in 1990-1995 (n = 225) and control pregnancies derived from the Finnish Medical Birth Register (n = 671) matched for sex of the child, year of birth, area, maternal age, parity, social class and fetal plurality. The analyses were stratified by plurality. Outcome measures were pregnancy complications, mode of delivery, gestational length and the level of use of antenatal care. RESULTS: The results showed an increased risk for vaginal bleeding throughout pregnancy [relative risk (RR) 4.1, 95% confidence interval (CI) 2.5-6.7 for singletons; RR 6.9, 95% CI 2.5-19.2 for twins], threatened preterm birth (RR 1.8, 95% CI 1.1-2.9, singletons) and intrahepatic cholestasis of pregnancy (RR 3.8, 95% CI 1.0-15.0, singletons) in IVF pregnancies, as well as an increase in the use of specialized antenatal care. CONCLUSIONS: IVF pregnancies following standard, fresh ova IVF treatments are at greater risk of obstetric problems than spontaneously conceived pregnancies, and hence IVF mothers use more specialized antenatal care than others. The pregnancy complications after IVF are likely to be due to maternal characteristics regarding infertility and to a high incidence of multiple pregnancies.     

Parents' experiences of universal screening for haemoglobin disorders: implications for practice in a new genetics era.

BACKGROUND: England is the only country in the world that currently has universal population screening for haemoglobin disorders through linked antenatal and newborn screening. Little is known about the acceptability of such screening. AIM: To explore parents' experiences of, and attitudes towards, new universal genetic screening for haemoglobin disorders. DESIGN OF STUDY: Narrative interview study. SETTING: Primary and community care settings across England. METHOD: Narrative interviews were undertaken with a maximum variation sample of 39 people who had experienced gene-carrier identification through antenatal and newborn screening for sickle cell, thalassaemia, and other haemoglobin variants within the previous 2 years. RESULTS: Most parents were unaware screening had occurred or had given it little consideration and so were surprised or shocked by results. However, they were glad to learn of their carrier status, reproductive genetic risk, or their newborn's carrier status. Participants emphasised that antenatal screening should happen as early as possible. Many would rather have known their carrier status before pregnancy or before entering a relationship. Although most were satisfied with the information they received, significant misunderstandings remained. There were culturally diverse attitudes towards prenatal diagnosis and termination. These procedures were acceptable to some parents with strong religious beliefs, including Christians and Muslims. CONCLUSION: Parents support screening for haemoglobin disorders but need to be better informed and better prepared for results and what they mean. Sensitivity to patient diversity in attitudes and choices is also required. Universal screening for genetic reproductive risk will increasingly involve generalists, particularly in primary care, presenting opportunities for screening before or earlier in pregnancy, which is likely to be welcomed by patients.     

Uterine artery Doppler velocimetry and the outcome of pregnancies resulting from ICSI.

BACKGROUND: An increased incidence of pregnancy complications following assisted reproduction has been reported. The use of uterine artery Doppler ultrasound may aid the prediction of such complications. METHODS: Doppler was performed at 18-24 weeks gestation in 114 singleton and 32 twin pregnancies after intracytoplasmic sperm injection (ICSI) and compared with a control group matched for age, parity and plurality. Outcome variables included gestational age at delivery, prematurity, preterm premature rupture of membrane (PPROM), birth weight, birth weight discordance of >20% in twins, small for gestational age (SGA), mode of delivery, development of pre-eclampsia and placental abruption. RESULTS: Compared with the controls, there were no significant differences concerning uterine Doppler parameters, pregnancy complications and the neonatal outcome, either in singleton or in twin pregnancies. According to Doppler results and/or risk factors by medical history, 42% of singleton ICSI and 39% of spontaneous singleton pregnancies were considered as high risk. In singletons, abnormal Doppler findings were associated with pre-eclampsia in 22% and SGA in 26% of ICSI patients, compared with 33 and 21% in controls; in contrast, 0 and 10% in ICSI and 3 and 6% in controls showed these complications but no risk factors respectively. No correlation was found between PPROM, prematurity, the rate of Caesarean section and pathological Doppler results. CONCLUSIONS: Uterine Doppler examination holds the potential to identify patients with an increased risk for developing pregnancy complications. According to our results, this risk is not elevated after ICSI treatment, therefore the decision of offering an intensified antenatal care should be based on the results of Doppler examination or risks by medical history rather than the mode of conception.     

Embryo reduction in multifetal pregnancies using saline injection: comparison between the transvaginal and the transabdominal approach.

A total of 30 patients with multifetal pregnancies, all resulting from treatment with superovulatory agents or assisted reproductive techniques, underwent embryo reduction. All patients had three or more fetuses (one sextuplet, two quintuplets, seven quadruplets and 20 triplets). The procedure was carried out using intra-embryonal injection of 0.9% sodium chloride solution. Embryo reduction was carried out via the transabdominal approach in 10 patients, performed at 11-12 weeks of gestation, and via the transvaginal route in 20 other patients, at 8-10 weeks of gestation. In the transabdominal group, one patient aborted following repeated attempts at embryo reduction while the other nine gave birth to healthy newborns (eight twins and one triplet). In the transvaginal group, four pregnancies are currently ongoing (all beyond 28 weeks of gestation), 14 pregnancies resulted in a delivery of at least one live newborn (13 twins and one singleton), one patient had a late abortion at 24 weeks' gestation and another was delivered at 27 weeks' gestation due to severe pre-eclampsia. Transvaginal ultrasound-guided needle procedures are commonly practised in most in-vitro fertilization units. The employment of this route for embryo reduction, performed at an earlier gestational age and with the use of a non-toxic substance such as 0.9% saline solution, is advocated.     

兰州地区孕中期产前筛查血清指标MoM值分析

目的分析兰州地区孕中期唐氏综合征（Down syndrome,Ds）筛查人群中位数分布并探讨其临床应用价值。方法采用时间分辨荧光分析法检测7172例妊娠14—20“周妊娠女性血清甲胎蛋白（alpha fetoprotein,AFP）和游离绒毛促性腺激素（free—beta human chorionic gonadotropin,Freeβ—HCG）的浓度。利用DS筛查风险评估软件（LifeCycle3．0,LC3．0）的MediansTool统计不同孕用AFP和Freeβ-HCG的人群中位数、体质量,对LC3．0的中位数方程、体质量校正方程系数进行修正。结果各孕周血清AFP中位数平均水平均比软件内嵌值低,而Freeβ-HCG中位数水平在孕17周前中位数高于软件内嵌值而孕17周后中位数则低于软件内嵌值。各体重血清AFP与软件内嵌值几乎吻合,而Freeβ-HCG中位数平均水平比软件内嵌值低。结论不同地区血清中位数的筛查切割值制定标准可能存在差异,有必要进一步建立本地区孕中期产前筛查人群中位数系统。     

Macrophage colony-stimulating factor levels in amniotic fluid before and after the onset of labor do not differ in normal pregnancies

PROBLEM: Macrophage colony-stimulating factor (M-CSF) promotes placental growth and maintenance. M-CSF also regulates trophoblast invasion into the placental bed. We evaluated whether M-CSF levels in amniotic fluid during labor contributing to subsequent delivery differed from those before the onset of labor in normal pregnancies. METHOD OF STUDY: This study enrolled 48 Japanese women experiencing normal pregnancies with single fetuses who had no infection. Of these pregnancies, 24 were women during labor: 22 led to subsequent term delivery (labors); two had premature delivery. The other 24 were women without labor underwent cesarean section (controls). These two groups (22 labors and 24 controls) were compared. The average gestational age at entry was 38 weeks of gestation. The women's ages and gestational ages did not differ significantly between the two groups. Amniotic fluid was collected and the M-CSF levels were compared between two groups. The M-CSF level was determined by the sandwich enzyme-linked immunosorbent assay (ELISA) method. RESULTS: The levels of M-CSF in amniotic fluid did not differ significantly between the women during labor and those without labor. CONCLUSIONS: M-CSF in amniotic fluid may not contribute to the onset of labor in term pregnancy and/or labor resulting in subsequent delivery may not induce the production and secretion of M-CSF into amniotic cavity.