MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface.

Many cancers are dependent on inappropriate activation of epidermal growth factor receptor (EGFR), and drugs targeting this receptor can improve patient survival, although benefits are generally short-lived. We reveal a novel mechanism linking EGFR and the membrane-spanning, cancer-promoting protein CDCP1 (CUB domain-containing protein 1). Under basal conditions, cell surface CDCP1 constitutively internalizes and undergoes palmitoylation-dependent degradation by a mechanism in which it is palmitoylated in at least one of its four cytoplasmic cysteines. This mechanism is functional in vivo as CDCP1 is elevated and palmitoylated in high-grade serous ovarian tumors. Interestingly, activation of the EGFR system with EGF inhibits proteasome-mediated, palmitoylation-dependent degradation of CDCP1, promoting recycling of CDCP1 to the cell surface where it is available to mediate its procancer effects. We also show that mechanisms inducing relocalization of CDCP1 to the cell surface, including disruption of its palmitoylation and EGF treatment, promote cell migration. Our data provide the first evidence that the EGFR system can function to increase the lifespan of a protein and also promote its recycling to the cell surface. This information may be useful for understanding mechanisms of resistance to EGFR therapies and assist in the design of treatments for EGFR-dependent cancers.

Surgical outcomes in steroid refractory acute severe ulcerative colitis: the impact of rescue therapy.

AIM: The advent of rescue medical therapy (cyclosporin or infliximab) and laparoscopic surgery has shifted the paradigm in managing steroid refractory acute severe ulcerative colitis (ASUC). We investigated prospectively the impact of rescue therapy on timing and postoperative complications of urgent colectomy and subsequent restorative surgery for steroid refractory ASUC. METHOD: All consecutive presentations of steroid refractory ASUC at the Royal Brisbane Hospital (1996-2009) were entered in the study. Data collated included demographics, clinical and laboratory parameters on admission, medical therapy and operative and postoperative details. Steroid refractory ASUC patients undergoing immediate colectomy were compared with those failing rescue therapy and requiring same admission colectomy. RESULTS: Of 108 steroid refractory ASUC presentations, 19 (18%) received intravenous steroids only and proceeded directly to colectomy. Rescue medical therapy was instituted in 89 (82%) patients with 30 (34%) failing to respond and proceeding to colectomy. There was no significant difference in the median time from admission to colectomy for rescue therapy compared with steroid-only cases (12 vs 10 days, P = 0.70) or 30-day complication rates (27%vs 47%, P = 0.22). The interval from colectomy to a subsequent restorative procedure was significantly longer for patients who failed rescue therapy (12 vs 5 months, P = 0.02). Furthermore 30-day complications following pouch surgery were significantly higher in patients who failed rescue therapy (32%vs 0%, P = 0.01). CONCLUSION: Rescue therapy in steroid refractory ASUC is not related to delay in urgent colectomy or increased post-colectomy complications.

The ideal ileal-pouch design: a long-term randomized control trial of J- vs W-pouch construction.

BACKGROUND: The IPAA has become established as the preferred technique for restoring intestinal continuity postproctocolectomy. The ideal pouch design has not been established. W-pouches may give better functional results owing to increased volume, whereas the J-pouch's advantage is its straightforward construction. We report short- and long-term results of an randomized control trial designed to establish the ideal pouch. DESIGN: Ninety-four patients were randomly assigned to J- and W-pouches (49:45) and assessed at 1 and 8.7 years postoperatively. Assessment was questionnaire based and designed to assess pouch function and patient quality of life. RESULTS: Eighty-five percent of patients were followed up at 1 year, and 68% were followed up at 8.7 years. At 1 year, there was a significant difference in 24-hour bowel movement frequency J- vs W-pouches 7 vs 5(p < 0.001) and in daytime frequency J- vs W-pouches 6 vs 4 (p < 0.001), with no difference in nocturnal function. At 9-year follow-up, function had equilibrated between the 2 groups: 24-hour bowel movement frequency J- vs W-pouches 6.5 vs 6 (p = 0.36), daytime frequency 5.5 vs 5 (p = 0.233), and nocturnal function 1 vs 1 (p = 0.987). Mean operating time of J- and W-pouches was 195 and 215 minutes (p < 0.05). All other parameters, pad usage, urgency, incontinence, and quality of life, did not differ significantly between groups. CONCLUSION: These data demonstrate that the theoretical functional advantage conferred on the W-pouch by its greater volume exists only in the short term and is of little consequence to patients' long-term quality of life. This advantage is attenuated as the pouches mature, resulting in no disparity in pouch function. This, combined with the more consistent, efficient, and easily taught construction of the J-pouch, should conclusively establish it as the optimum ileal-pouch design.

Surgical revascularisation for childhood moyamoya.

PURPOSE: Children with moyamoya disease/syndrome (MM) have a high rate of recurrent arterial ischaemic stroke (AIS) and associated neurological morbidity; surgical revascularisation (SR) has the potential to prevent this. Here we describe our experience of SR for childhood mm. METHODS: This study is a retrospective review of case notes and radiology of children with moyamoya who underwent SR at our centre. RESULTS: Seventy-three children with MM and who had SR were identified, with median age at presentation of 4.75 years (range 0.6-14.5). Children with >1 AIS or transient ischaemic attack (TIA) and who had not infarcted the whole territory of the diseased carotid artery were offered SR, with the primary aim of preventing further AIS. One hundred and thirty-four SR procedures were undertaken: 82 indirect (62.4 %) and 49 (37.6 %) direct procedures with 3 second SR procedures following initial SR. Median age at surgery was 7.3 (1-18.2) years. There was no perioperative mortality. One anticoagulated child developed an intracranial haemorrhage on the fifth post-operative day. Median duration of follow-up was 34 (5-166) months. Three children (4.1 %) had recurrent AIS (one silent) after SR; two with sickle cell disease had intracranial haemorrhage 1.5 and 11 months post-SR. TIAs improved in 42 out of 53 (79.2 %). CONCLUSION: Our experience of SR for paediatric MM is comparable to other large series. SR is safe, and the rate of recurrent AIS after SR is lower than would be anticipated, on the basis of known natural history of MM. There was no observed difference in outcome of recurrent AIS for direct versus indirect procedures in this series.

Laparoscopic resection of advanced colorectal cancer.

BACKGROUND: Palliative resection of the primary tumour in asymptomatic patients with stage IV colorectal cancer is associated with improved survival and fewer complications. Laparoscopic surgery is widely employed in the curative treatment of colorectal cancer, but its value in advanced colorectal cancer remains unclear. METHODS: All patients who underwent laparoscopic resection of primary colorectal cancer in this unit between June 1991 and Jan 2010 were entered into a prospective computerized database. Outcomes for patients with laparoscopic resection of stage IV colorectal cancer were compared with those of patients who had laparoscopic surgery for stage I disease. RESULTS: Some 185 patients with stage IV colorectal cancer who underwent laparoscopic resection were compared with 310 patients who had stage I colorectal cancer. Some 94·1 and 98·4 per cent of operations respectively were completed laparoscopically. Hospital stay was slightly longer in the group with stage IV disease (mean 6·2 versus 5·3 days; P = 0·091). The 30-day mortality rate was 2·7 per cent in patients with stage IV disease and 0·6 per cent in those with stage I tumours (P = 0·061). There was no difference in complications. One-year survival rates were 77·8 and 99·0 per cent respectively (P < 0·001). CONCLUSION: Short-term outcomes after laparoscopic surgery for stage IV colorectal cancer in selected patients are equivalent to those for stage I cancers.

Preservation of sexual and bladder function after laparoscopic rectal surgery.

BACKGROUND: There have recently been reports of higher levels of bladder and sexual dysfunction in men after laparoscopic rectal surgery when compared with those undergoing open surgery. This has led some surgeons to question the role of the laparoscopic approach to rectal surgery. METHOD: This study represents a retrospective analysis of a prospectively collected database for a single unit, comprising 2406 patients undergoing laparoscopic colorectal surgery. Bladder function, potency and ejaculation were assessed at postoperative clinic visits for men undergoing laparoscopic low or ultra-low anterior resection and abdominoperineal excision of the rectum. RESULTS: A total of 101 males were identified (median age 62 years: range 20-90 years). Urinary dysfunction was reported by six (6%) patients. Six (6%) patients had sexual dysfunction, manifesting as retrograde ejaculation in four patients and erectile dysfunction in a further two patients. CONCLUSIONS: The low rates of sexual dysfunction in this unit may be attributable to pelvic dissection only being undertaken by experienced, dedicated laparoscopic colorectal surgeons. Laparoscopic restorative surgery for rectal cancer has been performed here only since 2001 after considerable experience accrued in operating on benign rectal disease and colon cancer. Studies from elsewhere reporting poorer functional outcomes have probably included a significant number of patients on the surgeons''learning curve'.

Brief antenatal cognitive behaviour therapy group intervention for the prevention of postnatal depression and anxiety: a randomised controlled trial.

BACKGROUND: The majority of randomised controlled trials examining the effectiveness of antenatal group interventions at preventing postnatal depression in "at risk" women have used a "psychoeducational" intervention. The aim of the present study is to evaluate the effectiveness of an antenatal cognitive behavioural group intervention in a primary care setting for pregnant women identified with mild to moderate symptoms in pregnancy and/or at risk of developing depression or anxiety in the perinatal period. METHOD: Subjects were randomised to a CBT group intervention or control condition (information booklet) and administered the EPDS and STAI at pre (Time 1) and post intervention (Time 2), and at 2 months (Time 3) and 4 months postpartum (Time 4). MINIs were administered at Times 1, 3 and 4. RESULTS: Of the 774 women approached, 277 accepted and were suitable; thus 191 were randomised to the CBT intervention and 86 to the control condition. The subsequent 52% drop-out left 89 women "completing" the CBT groups and 43 in the control group; these two groups were well matched on demographic variables. Intention to treat analyses revealed relatively low mean baseline EPDS scores (means 6.88 -8.16) with no reduction in EPDS scores in either group from Time 1 to Time 4. MINI depression criteria were fulfilled by 19% of all participants at Time 1 but there was no reduction in depression in either group; in contrast those with MINI anxiety diagnoses reduced from 28% in late pregnancy to 16% at four months postpartum in the CBT group with similar reductions in the control group. Analyses on the 132 "completers" showed significant symptomatic improvement over time for both the CBT group and control condition. Depression scores in the most symptomatic women (EPDS>12; N=19) decreased steadily by over 50% over the total time course but there were no differences in improvement between the CBT and control groups. LIMITATIONS: A number of methodological factors may have obscured our results including a tendency to natural remission in mildly symptomatic subjects and the possibility that our control condition was therapeutic in itself. CONCLUSION: While a modest reduction in depression scores was noted in study "completers", both the CBT group intervention control condition were equally beneficial. The reasons for this finding include the low symptom level at baseline; the potential effectiveness of the control condition; and the brevity of the intervention.

Precancerous changes in the cervix and risk of subsequent preterm birth.

OBJECTIVE: The aims of this study were (i) to examine whether women referred for assessment of precancerous changes in the cervix had higher rates of preterm birth compared with those in the general population and (ii) to compare preterm birth rates for treated and untreated women adjusting for possible confounding factors. DESIGN: Retrospective cohort design. SETTING: Teaching hospital. POPULATION: All women referred to the Royal Women's Hospital, Melbourne (1982-2000), who subsequently had a birth recorded on the Victorian Perinatal Data Collection system (n = 5548). METHODS: Record linkage of hospital dysplasia clinic records and population-based birth records. MAIN OUTCOME MEASURES: Total preterm delivery (<37 weeks of gestation) and subtypes. RESULTS: Both treated and untreated women were at a significantly increased risk for preterm birth compared with those in the general population: treated--standardised prevalence ratio (SPR) 2.0, 95% CI 1.8-2.3 and untreated--SPR 1.5, 95% CI 1.4-1.7. Within the cohort, the treated women were significantly more likely to give birth preterm (adjusted OR 1.23, 95% CI 1.01-1.51). An increased risk of preterm birth was also associated with a history of induced or spontaneous abortions, illicit drug use during pregnancy or a major maternal medical condition. Cone biopsy, loop electrosurgical excision procedure and diathermy were associated with preterm birth. After adjusting for possible confounding factors, only diathermy remained significant (adjusted OR 1.72, 95% CI 1.36-2.17). Women treated using laser ablation were not at an increased risk for preterm birth (adjusted OR 1.1, 95% CI 0.8-1.4). CONCLUSIONS: Diagnosis of precancerous changes in the cervix (regardless of the treatment) was associated with an increased risk of preterm birth. Consideration should be given to the preferential use of ablative treatments.

Long term outcome of transcranial bypass.

OBJECTIVES: This study examines the long term outcome of transcranial bypass in a single centre. METHODS: In a prospective study, symptoms and angiographic findings were recoded on a database for 229 consecutive transcranial bypass procedures performed in 204 patients between 1976 and 1983. One hundred and seventy-seven had carotid territory symptoms, and the predominant angiogram finding was internal carotid artery (ICA) occlusion. RESULTS: At 5 years 87% (86 patients) were free from stroke. At 20 years 83% (29 patients) were stroke free but by this time the majority had died from other cardiovascular causes and 35 were lost to follow up. CONCLUSION: Stroke is uncommon five or more years after transcranial bypass but overall survival is poor.

Interventions for promoting smoking cessation during pregnancy.

BACKGROUND: Smoking remains one of the few potentially preventable factors associated with low birthweight, preterm birth and perinatal death. OBJECTIVES: To assess the effects of smoking cessation programs implemented during pregnancy on the health of the fetus, infant, mother, and family. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Tobacco Addiction Group trials register (July 2003), MEDLINE (January 2002 to July 2003), EMBASE (January 2002 to July 2003), PsychLIT (January 2002 to July 2003), CINAHL (January 2002 to July 2003), and AUSTHEALTH (January 2002 to 2003). We contacted trial authors to locate additional unpublished data. We handsearched references of identified trials and recent obstetric journals. SELECTION CRITERIA: Randomised and quasi-randomised trials of smoking cessation programs implemented during pregnancy. DATA COLLECTION AND ANALYSIS: Four reviewers assessed trial quality and extracted data independently. MAIN RESULTS: This review included 64 trials. Fifty-one randomised controlled trials (20,931 women) and six cluster-randomised trials (over 7500 women) provided data on smoking cessation and/or perinatal outcomes. Despite substantial variation in the intensity of the intervention and the extent of reminders and reinforcement through pregnancy, there was an increase in the median intensity of both 'usual care' and interventions over time. There was a significant reduction in smoking in the intervention groups of the 48 trials included: (relative risk (RR) 0.94, 95% confidence interval (CI) 0.93 to 0.95), an absolute difference of six in 100 women continuing to smoke. The 36 trials with validated smoking cessation had a similar reduction (RR 0.94, 95% CI 0.92 to 0.95). Smoking cessation interventions reduced low birthweight (RR 0.81, 95% CI 0.70 to 0.94) and preterm birth (RR 0.84, 95% CI 0.72 to 0.98), and there was a 33 g (95% CI 11 g to 55 g) increase in mean birthweight. There were no statistically significant differences in very low birthweight, stillbirths, perinatal or neonatal mortality but these analyses had very limited power. One intervention strategy, rewards plus social support (two trials), resulted in a significantly greater smoking reduction than other strategies (RR 0.77, 95% CI 0.72 to 0.82). Five trials of smoking relapse prevention (over 800 women) showed no statistically significant reduction in relapse. REVIEWERS' CONCLUSIONS: Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce low birthweight and preterm birth. The pooled trials have inadequate power to detect reductions in perinatal mortality or very low birthweight.

How useful is the concept of somatization in cross-cultural studies of maternal depression? A contribution from the Mothers in a New Country (MINC) study.

Somatization of depression symptoms has been assumed to characterize particular cultural groups, yet evidence for this has often been anecdotal. The Mothers in a New Country (MINC) study aimed to explore cultural assumptions about somatization in three groups of immigrant women who had recently given birth in Melbourne, Australia. Physical health (SF-36 physical health dimensions and a symptom list) and depression (EPDS, SF-36 mental health dimension and self assessment) data from personal interviews with Vietnamese (n = 104), Turkish (n = 107) and Filipino (n = 107) women, conducted in women's language of choice, six to nine months after childbirth were analyzed. Comparisons with data from a statewide postal survey of Victorian women are also made. Contrary to the study hypothesis that Turkish and Vietnamese women in particular would exhibit a high degree of somatization (leading to low depression scores on the standard measures and greater reporting of somatic symptoms), Turkish women were in fact most likely of the three groups to be assessed as depressed on the two psychological measures and by self-assessment, to report high levels of somatic symptoms, and Vietnamese and Filipino women had a low prevalence of depression on all measures and relatively lower levels of somatic symptom reporting. The MINC study findings thus call into question some common cultural assumptions about depression and demonstrate the importance of designing studies which can put hypothesized cultural differences to the test.

Antenatal screening for postnatal depression: a systematic review.

OBJECTIVE: To describe the screening properties of the antenatal tools which have been developed to predict depression after birth and to summarize the implications of the findings for antenatal screening. METHOD: Systematic review and secondary analysis of published papers. RESULTS: Sixteen studies including sufficient data for the calculation of screening properties were identified. The majority developed a study-specific screening instrument. Outcome assessments used the Edinburgh Postnatal Depression Scale or standardized diagnostic psychiatric interviews, or both. In the two largest population-based studies, the proportion of women screening as positive ('at risk' of postnatal depression) was 16 and 52%, respectively, and of these only 35 and 8% actually developed depression after birth. CONCLUSION: No screening instrument(s) met the criteria for routine application in the antenatal period. Factors that may have affected poor sensitivity and positive predictive values include the exclusion of key domains in predicting risk, particularly personality, a past history of abuse and postnatal events, the contribution of which may be being under-estimated in studies evaluating antenatal risk prediction tools.

Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects.

BACKGROUND: Neural tube defects arise during the development of the brain and spinal cord. OBJECTIVES: The objective of this review was to assess the effects of increased consumption of folate or multivitamins on the prevalence of neural tube defects periconceptionally (that is before pregnancy and in the first two months of pregnancy). SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. Date of last search: April 2001. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing periconceptional supplementation by multivitamins with placebo, folate with placebo, or multivitamins with folate; different dosages of multivitamins or folate; prepregnancy dietary advice and counselling in primary care settings to increase the consumption of folate-rich foods, or folate-fortified foods, with standard care; increased intensity of information provision with standard public health dissemination. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Four trials of supplementation involving 6425 women were included. The trials all addressed the question of supplementation and they were of variable quality. Periconceptional folate supplementation reduced the incidence of neural tube defects (relative risk 0.28, 95% confidence interval 0.13 to 0.58). Folate supplementation did not significantly increase miscarriage, ectopic pregnancy or stillbirth, although there was a possible increase in multiple gestation. Multivitamins alone were not associated with prevention of neural tube defects and did not produce additional preventive effects when given with folate. One dissemination trial, a community randomised trial, was identified involving six communities, matched in pairs, and where 1206 women of child-bearing age were interviewed following the dissemination intervention. This showed that the provision of printed material increased the awareness of the folate/neural tube defects association by 4%, (odds ratio 1.37, 95% confidence interval 1.33 to 1.42). REVIEWER'S CONCLUSIONS: Periconceptional folate supplementation has a strong protective effect against neural tube defects. Information about folate should be made more widely available throughout the health and education systems. Women whose fetuses or babies have neural tube defects should be advised of the risk of recurrence in a subsequent pregnancy and offered continuing folate supplementation. The benefits and risks of fortifying basic food stuffs, such as flour, with added folate remain unresolved.

What interventions may reduce postpartum depression.

Postnatal depression is a major public health problem affecting about one in seven women after childbirth. Depression is also common during pregnancy and throughout the perinatal period it is associated with symptoms of anxiety. Apart from the adverse consequences for women themselves becoming depressed when they are going through demanding physical and social changes, there are additional concerns. There is the possible negative impact of maternal depression on the relationship between mother and child and on the child's emotional, behavioural and cognitive development. Primary prevention and early intervention/secondary prevention strategies are potentially important in view of the frequent contact pregnant women, new mothers and infants have with health services, but the effectiveness of these strategies needs to be tested. In the past year there have been five new studies of antenatal screening for postnatal depression. These studies are consistent with nine earlier studies in showing that there is no evidence to support routine antenatal screening for postnatal depression. Seven new primary prevention/early intervention trials add evidence on a wide range of interventions ranging from practical support to individual interpersonal therapy, but without identifying significant differences in depression as an outcome. Two new trials of secondary prevention, one involving interpersonal therapy and the other including partners in a series of psychoeducational visits, show promise but neither is large enough to form a basis for practice change. Novel interventions, or promising findings, with a strong basis in theory need to be tested in trials which are appropriately sized and which comply with internationally accepted design and reporting guidelines.

Modelling the potential impact of population-wide periconceptional folate/multivitamin supplementation on multiple births.

OBJECTIVE: To develop a model of the impact of population-wide periconceptional folate supplementation on neural tube defects and twin births. DESIGN: A hypothetical cohort of 100,000 pregnancies > or =20 weeks, plus terminations of pregnancy after prenatal diagnosis before 20 weeks. METHODS: Application of pooled data on the relative risks for neural tube defects and twins following periconceptional folate from meta-analysis of the randomised trials. MAIN OUTCOME MEASURES: 1. Pregnancies with a neural tube defect (i.e. terminations of pregnancy, perinatal deaths, and surviving infants); 2. twin births (i.e. preterm births, perinatal deaths, postneonatal deaths, birth defects, cerebral palsy); 3. numbers needed to treat. RESULTS: The change in neural tube defects would be 75 fewer terminations (95% CI -47, -90), 30 fewer perinatal deaths (95% CI 18, -35), and 13 fewer surviving infants with a neural tube defect (95% CI -8, -16). The change in twinning would be an additional 572 twin confinements (95% CI -100, +1587), among whom there would be 63 very preterm twin confinements (95% CI -11, +174), 54 perinatal and postneonatal deaths (95% CI -9, +149), 48 surviving twins with a birth defect (95% CI -8, +133), and nine with cerebral palsy (95% CI -2, +26). The numbers needed to treat for the prevention of one pregnancy with a neural tube defect is 847, for the birth of one additional set of twins is 175, for the birth of one additional set of very preterm twins is 1587, and for the birth of an additional twin with any of the following outcomes (perinatal death, postneonatal death, survival with a birth defect, or survival with cerebral palsy) is 901. CONCLUSIONS: Monitoring rates of neural tube defects and twinning is essential as supplementation or fortification with folate is implemented.