Risk of stillbirth, preterm delivery, and fetal growth restriction following exposure in a previous birth: systematic review and meta-analysis.

BACKGROUND: Little is known about the risk of non-recurrent adverse birth outcomes. OBJECTIVES: To evaluate the risk of stillbirth, preterm birth (PTB), and small for gestational age (SGA) as a proxy for fetal growth restriction (FGR) following exposure to one or more of these factors in a previous birth. SEARCH STRATEGY: We searched MEDLINE, EMBASE, Maternity and Infant Care, and Global Health from inception to 30 November 2016. SELECTION CRITERIA: Studies were included if they investigated the association between stillbirth, PTB, or SGA (as a proxy for FGR) in two subsequent births. DATA COLLECTION AND ANALYSIS: Meta-analysis and pooled association presented as odds ratios (ORs) and adjusted odds ratios (aORs). MAIN RESULTS: Of the 3399 studies identified, 17 met the inclusion criteria. A PTB or SGA (as a proxy for FGR) infant increased the risk of subsequent stillbirth ((pooled OR 1.70; 95% confidence interval, 95% CI, 1.34-2.16) and (pooled OR 1.98; 95% CI 1.70-2.31), respectively). A combination of exposures, such as a preterm SGA (as a proxy for FGR) birth, doubled the risk of subsequent stillbirth (pooled OR 4.47; 95% CI 2.58-7.76). The risk of stillbirth also varied with prematurity, increasing three-fold following PTB <34 weeks of gestation (pooled OR 2.98; 95% CI 2.05-4.34) and six-fold following preterm SGA (as a proxy for FGR) <34 weeks of gestation (pooled OR 6.00; 95% CI 3.43-10.49). A previous stillbirth increased the risk of PTB (pooled OR 2.82; 95% CI 2.31-3.45), and subsequent SGA (as a proxy for FGR) (pooled OR 1.39; 95% CI 1.10-1.76). CONCLUSION: The risk of stillbirth, PTB, or SGA (as a proxy for FGR) was moderately elevated in women who previously experienced a single exposure, but increased between two- and three-fold when two prior adverse outcomes were combined. Clinical guidelines should consider the inter-relationship of stillbirth, PTB, and SGA, and that each condition is an independent risk factor for the other conditions. TWEETABLE ABSTRACT: Risk of adverse birth outcomes in next pregnancy increases with the combined number of previous adverse events. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Each year, around 2.6 million babies are stillborn, 15 million are born preterm (<37 weeks of gestation), and 32 million are born small for gestational age (less than tenth percentile for weight, smaller than usually expected for the relevant pregnancy stage). Being born preterm or small for gestational age can increase the chance of long-term health problems. The effect of having a stillbirth, preterm birth, or small-for-gestational-age infant in a previous pregnancy on future pregnancy health has not been summarised. We identified 3399 studies of outcomes of previous pregnancies, and 17 were summarised by our study. What were the main findings? The outcome of the previous pregnancy influenced the risk of poor outcomes in the next pregnancy. Babies born to mothers who had a previous preterm birth or small-for-gestational-age birth were more likely to be stillborn. The smaller and the more preterm the previous baby, the higher the risk of stillbirth in the following pregnancy. The risk of stillbirth in the following pregnancy was doubled if the previous baby was born both preterm and small for gestational age. Babies born to mothers who had a previous stillbirth were more likely to be preterm or small for gestational age. What are the limitations of the work? We included a small number of studies, as there are not enough studies in this area (adverse birth outcomes followed by adverse cross outcomes in the next pregnancy). We found very few studies that compared the risk of small for gestational age after preterm birth or stillbirth. Definitions of stillbirth, preterm birth categories, and small for gestational age differed across studies. We did not know the cause of stillbirth for most studies. What are the implications for patients? Women who have a history of poor pregnancy outcomes are at greater risk of poor outcomes in following pregnancies. Health providers should be aware of this risk when treating patients with a history of poor pregnancy outcomes.

School performance for children with cleft lip and palate: a population-based study.

BACKGROUND: Educational attainment is important in shaping young people's life prospects. To investigate whether being born with orofacial cleft (OFC) affects school performance, we compared school test results between children born with and without OFC. METHODS: Using record-linked datasets, we conducted a population-based cohort study of children liveborn in Western Australia 1980-2010 with a diagnosis of OFC on the Register of Developmental Anomalies, and a random sample of 6603 children born without OFC. We compared odds ratios for meeting national minimum standards in five domains (reading, numeracy, writing, spelling, grammar and punctuation), and adjusted OR (aOR) for children with cleft lip only (CLO), cleft lip and palate (CL + P) and cleft palate only (CPO) for each domain. RESULTS: Results from two testing programs (WALNA and NAPLAN) were available for 3238 (89%) children expected to participate. Most met the national minimum standards. Compared with children without OFC, children with CPO were less likely to meet minimum standards for NAPLAN reading (aOR 0.57 [95%CI 0.34, 0.96]) grammar and punctuation (aOR 0.49 [95%CI 0.32, 0.76]), WALNA writing (aOR 0.66 [95%CI 0.47, 0.92]), and WALNA and NAPLAN numeracy (aOR 0.64 [95%CI 0.43, 0.95] and aOR 0.47 [95%CI 0.28, 0.82]), respectively. Children with CL + P had significantly lower odds for reaching the spelling standard in NAPLAN tests (aOR 0.52 [95%CI 0.29, 0.94]). Children with CLO had similar odds for reaching all minimum standards. CONCLUSION: Children born with OFC, particularly children with CPO, should be monitored to identify learning difficulties early, to enable intervention to maximize school attainment.

Antenatal predictors and body composition of large-for-gestational-age newborns: perinatal health outcomes.

OBJECTIVE: To compare body composition of large-for-gestational-age (LGA) with appropriate-for-gestational-age (AGA) newborns and to identify antenatal predictors of LGA. STUDY DESIGN: This cross-sectional study included 536 term, singleton infants. Anthropometric measurements were performed within 48 h of birth and included determination of body fat percentage (%BF) by air displacement plethysmography. Associations were investigated using logistic regression. RESULT: LGA infants had greater %BF (P<0.001) compared with AGA infants. Significant predictors of LGA infants included parity (odds ratio (OR)=1.98, (95% confidence interval (CI) 1.00, 4.02)), paternal height (OR=1.08, (95% CI 1.03, 1.14)), maternal pregravid weight (65 to 74.9 kg: OR=2.77, (95% CI 1.14, 7.06)) and gestational weight gain (OR=1.09, 95% CI (1.03, 1.16)). Gestational diabetes mellitus was not associated with LGA infants (P=0.598). CONCLUSION: Paternal height, parity, maternal pregravid weight and gestational weight gain were strongly associated with LGA infants. These results may allow early prediction and potential modification, thereby optimising clinical outcomes.

Evaluation of a decision aid for women with breech presentation at term: a randomised controlled trial [ISRCTN14570598].

OBJECTIVES: To evaluate the effectiveness of a decision aid for women with a breech presentation compared with usual care. DESIGN: Randomised controlled trial. SETTING: Tertiary obstetric hospitals offering external cephalic version (ECV). POPULATION: Women with a singleton pregnancy were diagnosed antenatally with a breech presentation at term, and were clinically eligible for ECV. METHODS: Women were randomised to either receive a decision aid about the management options for breech presentation in addition to usual care or to receive usual care only with standard counselling from their usual pregnancy care provider. The decision aid comprised a 24-page booklet supplemented by a 30-minute audio-CD and worksheet that was designed for women to take home and review with a partner. MAIN OUTCOME MEASURES: Decisional conflict (uncertainty), knowledge, anxiety and satisfaction with decision making, and were assessed using self-administered questionnaires. RESULTS: Compared with usual care, women reviewing the decision aid experienced significantly lower decisional conflict (mean difference -8.92; 95% CI -13.18, -4.66) and increased knowledge (mean difference 8.40; 95% CI 3.10, 13.71), were more likely to feel that they had enough information to make a decision (RR 1.30; 95% CI 1.14, 1.47), had no increase in anxiety and reported greater satisfaction with decision making and overall experience of pregnancy and childbirth. In contrast, 19% of women in the usual care group reported they would have made a different decision about their care. CONCLUSIONS: A decision aid is an effective and acceptable tool for pregnant women that provides an important adjunct to standard counselling for the management of breech presentation.

Discontinuation of epidural analgesia late in labour for reducing the adverse delivery outcomes associated with epidural analgesia.

BACKGROUND: Although epidural analgesia provides the most effective labour analgesia, it is associated with some adverse obstetric consequences, including an increased risk of instrumental delivery. Many centres discontinue epidural analgesia late in labour to improve a woman's ability to push and reduce the rate of instrumental delivery. OBJECTIVES: To assess the impact of discontinuing epidural analgesia late in labour on: i) rates of instrumental deliveries and other delivery outcomes; and ii) analgesia and satisfaction with labour care. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (1 September 2003). SELECTION CRITERIA: Randomised controlled trials of epidurals discontinued late in labour compared with continuation of the same epidural protocol until birth, in women who receive an epidural for analgesia in the first stage of labour. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed study eligibility and quality and extracted the data. We analysed categorical data using relative risk (RR), and continuous data using weighted mean difference. MAIN RESULTS: We identified six studies, of which five were included (462 participants). Three of these were high quality studies whilst the other two were judged to be of lower quality because placebo was not used and the method of randomisation not described. All studies used different epidural analgesia protocols (type of drug, dosage or method of administration). Overall, the reduction in instrumental delivery rate was not statistically significant (23% versus 28%, RR 0.84, 95% confidence interval (CI) 0.61 to 1.15) nor was there any statistically significant difference in rates of other delivery outcomes. The only statistically significant result was an increase in inadequate pain relief when the epidural was stopped (22% versus 6%, RR 3.68, 95% CI 1.99 to 6.80). REVIEWERS' CONCLUSIONS: There is insufficient evidence to support the hypothesis that discontinuing epidural analgesia late in labour reduces the rate of instrumental delivery. There is evidence that it increases the rate of inadequate pain relief in the second stage of labour. The practice of discontinuing epidurals is widespread and the size of the reduction in instrumental delivery rate could be clinically important; therefore, we recommend a larger study than those included in this review be undertaken to determine whether this effect is real or has occurred by chance, and to provide stronger evidence about the safety aspects.

Antibiotics for ureaplasma in the vagina in pregnancy.

BACKGROUND: Preterm birth is a significant obstetric problem in high-income countries. Genital infection including ureaplasmas are suspected of playing a role in preterm birth and preterm rupture of the membranes. Antibiotics are used to treat women with preterm prelabour rupture of the membranes and results in prolongation of pregnancy and lowers the risks of maternal and neonatal infection. However, antibiotics may be beneficial earlier in pregnancy to eradicate potentially causative agents. OBJECTIVES: The objective of this review is to assess whether antibiotic treatment of pregnant women with ureaplasma in the vagina reduces the incidence of preterm birth and other adverse pregnancy outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (April 2003). SELECTION CRITERIA: All randomised controlled trials that compared any antibiotic regimen with placebo or no treatment in pregnant women with ureaplasma detected in the vagina. DATA COLLECTION AND ANALYSIS: Three reviewers independently assessed eligibility and trial quality and extracted data. MAIN RESULTS: One trial involving 1071 women was included. Of these, 644 randomly received antibiotic treatment (174 erythromycin estolate, 224 erythromycin sterate, and 246 clindamycin hydrochloride) and 427 received placebo. This trial did not report data on preterm birth. Incidence of low birthweight less than 2500 grams was only evaluated for erythromycin (combined) (n = 398 ) compared to placebo (n = 427) and there was no statistically significant difference between those treated and those not treated (relative risk (RR) 0.70, 95% confidence interval (CI) 0.46 to 1.07). In regards to side-effects sufficient to stop treatment, data were available for all women, and there were no statistically significant differences between any antibiotic (combined) and the placebo group (RR 1.25, 95% CI 0.85 to 1.85). REVIEWER'S CONCLUSIONS: There is insufficient evidence to show whether giving antibiotics to women with ureaplasma in the vagina will prevent preterm birth.

Mechanical ventilation for newborn infants with respiratory failure due to pulmonary disease.

BACKGROUND: Before the 1960s newborn infants with severe lung disease, usually due to respiratory distress syndrome (RDS), had a very high mortality rate. Standard treatment consisted of supportive measures including supplemental oxygen and correction of metabolic acidosis. Mechanical ventilation (MV) was introduced in the 1960s to correct hypoxaemia and respiratory acidosis in infants who were likely to die. MV is now standard treatment for infants with severe RDS but the degree to which this made a contribution to the outcome of such infants compared with standard neonatal care, is uncertain. OBJECTIVES: To evaluate the effects of the use of MV compared with no MV on mortality and morbidity in newborn infants with severe respiratory failure due to pulmonary disease. SEARCH STRATEGY: Searches were last updated in March 2002 on the Cochrane Controlled Trials Register (Cochrane Library Issue 1, 2002), MEDLINE from 1966 and EMBASE from 1980. In order to detect trials that may not have been published in full, searches carried out of the Oxford Database of Perinatal Trials and for abstracts published by the Society for Pediatric Research (1967 to 2001) and the European Society for Pediatric Research 1970 to 1977. Experts were consulted with emphasis on those who were in active neonatal practice in the 1960s and 1970s when the majority of these trials were likely to have been done. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials in newborn infants with respiratory failure due to pulmonary disease evaluating the use of MV versus standard neonatal care without MV. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Two authors independently assessed eligibility, methodological quality of each trial and extracted the data. Additional information was obtained from all trial authors on methodology or data. The data were analysed using relative risk and risk difference and their 95% confidence intervals. A fixed effect model was used for meta-analyses. MAIN RESULTS: The five trials reported on a total of 359 infants with RDS. In one study there is a higher neonatal mortality in the mechanical ventilation group [7/10 vs 1/10; RR 7.00 (1.04, 46.95)]. Overall any reported mortality is less frequent in the mechanical ventilation group with the upper 95% confidence limit on 1.00 [summary RR 0.86 (0.74, 1.00), RD -0.10 (-0.20, -0.01), NNT 10 (5, 100)]. In infants with a birth weight of 1 - 2 kg, no significant difference in mortality is found [summary RR for two trials 0.86 (0.70, 1.07)]. In infants with a birth weight of more than 2 kg, one study reports a significant reduction in mortality in the MV group compared with control [RR 0.67 (0.51, 0.86)]; overall for this birth weight group there is a significant reduction in mortality with MV in the two trials [summary RR 0.67 (0.52, 0.87), RD -0.27 (-0.45, -0.10), NNT 4 (2, 10)]. Any IVH at autopsy is not significantly different between the groups in any study or overall in four studies reporting on 202 infants who had an autopsy. Pneumothorax was reported in two studies of 275 infants and there is a non-significant trend towards an increase in the mechanical ventilation group [summary RR 2.75 (0.72, 10.45)]. REVIEWER'S CONCLUSIONS: When MV was introduced in the 1960s to treat infants with severe respiratory failure due to pulmonary disease, trials showed an overall reduction in mortality which was most marked in infants born with a birthweight of more than 2 kg. This review does not provide information to evaluate the relative benefits or harms of MV in the setting of modern perinatal care. In settings without modern neonatal care, the introduction of MV should ideally be evaluated in randomised controlled trials for its relative benefits, harms and costs.

HLA and other host factors in transfusion-acquired HIV-1 infection.

The host and viral factors that underlie infection with HIV-1 vary considerably with some individuals progressing to AIDS within 3 to 5 years after infection, whereas others remain clinically asymptomatic for over 10 years. Host factors that may contribute to disease progression include HLA and allelic variants of the chemokine receptors CCR5 and CCR2, which have been shown to influence both long-term survival and rapid progression. In this study, we have examined the contribution of HLA and polymorphisms in CCR5 and CCR2 to long-term survival in transfusion-acquired HIV-1-infected individuals. We have found a higher number of HLA-A32 and -A25 alleles but a lower number of the HLA-B8 allele in the study group compared with the frequencies seen in the HIV-1-negative Australian caucasian population. However, there was no apparent contribution by allelic variants of CCR5 and CCR2 to long-term survival and the combined influence of HLA and CCR polymorphisms could not be evaluated in this relatively small (n = 20) group of study subjects. The results of this work support a role for HLA in long-term nonprogression though the presence in the Sydney Blood bank Cohort of nef-defective HIV-1 may confound associations between certain HLA alleles and long-term survival in the face of infection with HIV-1.

Effect of long-term infection with nef-defective attenuated HIV type 1 on CD4+ and CD8+ T lymphocytes: increased CD45RO+CD4+ T lymphocytes and limited activation of CD8+ T lymphocytes.

Members of the Sydney Blood Bank Cohort (SBBC) have been infected with an attenuated strain of HIV-1 with a natural nef/LTR mutation and have maintained relatively stable CD4+ T lymphocyte counts for 14-18 years. Flow cytometric analysis was used to examine the phenotype of CD4+ and CD8+ T lymphocytes in these subjects, including the immunologically important naive (CD45RA+CD62L+), primed (CD45RO+), and activated (CD38+HLA-DR+ and CD28-) subsets. The median values were compared between the SBBC and control groups, comprising age-, sex-, and transfusion-matched HIV-1-uninfected subjects; transfusion-acquired HIV-1-positive LTNPs; and sexually acquired HIV-1-positive LTNPs. Members of the SBBC not only had normal levels of naive CD4+ and CD8+ T lymphocytes, but had primed CD45RO+ CD4+ T lymphocytes at or above normal levels. Furthermore, these primed cells expressed markers suggesting recent exposure to specific antigen. SBBC members exhibited variable activation of CD8+ T lymphocytes. In particular, SBBC members with undetectable plasma HIV-1 RNA had normal levels of activated CD8+ T lymphocytes. Therefore, the result of long-term infection with natural nef/LTR mutant HIV-1 in these subjects suggests a decreased cytopathic effect of attenuated HIV-1 on susceptible activated CD4+ T lymphocyte subsets in vivo, and minimal activation of CD8+ T lymphocytes.

Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort.

BACKGROUND AND METHODS: The Sydney Blood Bank Cohort consists of a blood donor and eight transfusion recipients who were infected before 1985 with a strain of human immunodeficiency virus type 1 (HIV-1) with a deletion in the region in which the nef gene and the long terminal repeat overlap. Two recipients have died since 1994, at 77 and 83 years of age, of causes unrelated to HIV infection; one other recipient, who had systemic lupus erythematosus, died in 1987 at 22 years of age of causes possibly related to HIV. We present longitudinal immunologic and virologic data on the six surviving members and one deceased member of this cohort through September 30, 1998. RESULTS: The five surviving recipients remain asymptomatic 14 to 18 years after HIV-1 infection without any antiretroviral therapy; however, the donor commenced therapy in February 1999. In three recipients plasma concentrations of HIV-1 RNA are undetectable (<200 copies per milliliter), and in two of these three the CD4 lymphocyte counts have declined by 9 and 30 cells per cubic millimeter per year (P=0.3 and P=0.5, respectively). The donor and two other recipients have median plasma concentrations of HIV-1 RNA of 645 to 2850 copies per milliliter; the concentration has increased in the donor (P<0.001). The CD4 lymphocyte counts in these three cohort members have declined by 16 to 73 cells per cubic millimeter per year (P<0.001). In the recipient who died after 12 years of infection, the median plasma concentration of HIV-1 RNA was 1400 copies per milliliter, with a decline in CD4 lymphocyte counts of 17 cells per cubic millimeter per year (P=0.2). CONCLUSIONS: After prolonged infection with this attenuated strain of HIV-1, there is evidence of immunologic damage in three of the four subjects with detectable plasma HIV-1 RNA. The CD4 lymphocyte counts appear to be stable in the three subjects in whom plasma HIV-1 RNA remains undetectable.