Antenatal interventions for preventing stillbirth, fetal loss and perinatal death: an overview of Cochrane systematic reviews.

BACKGROUND: Stillbirth is generally defined as a death prior to birth at or after 22 weeks' gestation. It remains a major public health concern globally. Antenatal interventions may reduce stillbirths and improve maternal and neonatal outcomes in settings with high rates of stillbirth. There are several key antenatal strategies that aim to prevent stillbirth including nutrition, and prevention and management of infections. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews on the effects of antenatal interventions for preventing stillbirth for low risk or unselected populations of women. METHODS: We collaborated with Cochrane Pregnancy and Childbirth's Information Specialist to identify all their published reviews that specified or reported stillbirth; and we searched the Cochrane Database of Systematic Reviews (search date: 29 Feburary 2020) to identify reviews published within other Cochrane groups. The primary outcome measure was stillbirth but in the absence of stillbirth data, we used perinatal mortality (both stillbirth and death in the first week of life), fetal loss or fetal death as outcomes. Two review authors independently evaluated reviews for inclusion, extracted data and assessed quality of evidence using AMSTAR (A Measurement Tool to Assess Reviews) and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm; clear evidence of no effect or equivalence; possible benefit or harm; or unknown benefit or harm or no effect or equivalence. MAIN RESULTS: We identified 43 Cochrane Reviews that included interventions in pregnant women with the potential for preventing stillbirth; all of the included reviews reported our primary outcome 'stillbirth' or in the absence of stillbirth, 'perinatal death' or 'fetal loss/fetal death'. AMSTAR quality was high in 40 reviews with scores ranging from 8 to 11 and moderate in three reviews with a score of 7. Nutrition interventions Clear evidence of benefit: balanced energy/protein supplementation versus no supplementation suggests a probable reduction in stillbirth (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.94, 5 randomised controlled trials (RCTs), 3408 women; moderate-certainty evidence). Clear evidence of no effect or equivalence for stillbirth or perinatal death: vitamin A alone versus placebo or no treatment; and multiple micronutrients with iron and folic acid versus iron with or without folic acid. Unknown benefit or harm or no effect or equivalence: for all other nutrition interventions examined the effects were uncertain. Prevention and management of infections Possible benefit for fetal loss or death: insecticide-treated anti-malarial nets versus no nets (RR 0.67, 95% CI 0.47 to 0.97, 4 RCTs; low-certainty). Unknown evidence of no effect or equivalence: drugs for preventing malaria (stillbirth RR 1.02, 95% CI 0.76 to 1.36, 5 RCTs, 7130 women, moderate certainty in women of all parity; perinatal death RR 1.24, 95% CI 0.94 to 1.63, 4 RCTs, 5216 women, moderate-certainty in women of all parity). Prevention, detection and management of other morbidities Clear evidence of benefit: the following interventions suggest a reduction: midwife-led models of care in settings where the midwife is the primary healthcare provider particularly for low-risk pregnant women (overall fetal loss/neonatal death reduction RR 0.84, 95% CI 0.71 to 0.99, 13 RCTs, 17,561 women; high-certainty), training versus not training traditional birth attendants in rural populations of low- and middle-income countries (stillbirth reduction odds ratio (OR) 0.69, 95% CI 0.57 to 0.83, 1 RCT, 18,699 women, moderate-certainty; perinatal death reduction OR 0.70, 95% CI 0.59 to 0.83, 1 RCT, 18,699 women, moderate-certainty). Clear evidence of harm: a reduced number of antenatal care visits probably results in an increase in perinatal death (RR 1.14 95% CI 1.00 to 1.31, 5 RCTs, 56,431 women; moderate-certainty evidence). Clear evidence of no effect or equivalence: there was evidence of no effect in the risk of stillbirth/fetal loss or perinatal death for the following interventions and comparisons: psychosocial interventions; and providing case notes to women. Possible benefit: community-based intervention packages (including community support groups/women's groups, community mobilisation and home visitation, or training traditional birth attendants who made home visits) may result in a reduction of stillbirth (RR 0.81, 95% CI 0.73 to 0.91, 15 RCTs, 201,181 women; low-certainty) and perinatal death (RR 0.78, 95% CI 0.70 to 0.86, 17 RCTs, 282,327 women; low-certainty). Unknown benefit or harm or no effect or equivalence: the effects were uncertain for other interventions examined. Screening and management of fetal growth and well-being Clear evidence of benefit: computerised antenatal cardiotocography for assessing infant's well-being in utero compared with traditional antenatal cardiotocography (perinatal mortality reduction RR 0.20, 95% CI 0.04 to 0.88, 2 RCTs, 469 women; moderate-certainty). Unknown benefit or harm or no effect or equivalence: the effects were uncertain for other interventions examined. AUTHORS' CONCLUSIONS: While most interventions were unable to demonstrate a clear effect in reducing stillbirth or perinatal death, several interventions suggested a clear benefit, such as balanced energy/protein supplements, midwife-led models of care, training versus not training traditional birth attendants, and antenatal cardiotocography. Possible benefits were also observed for insecticide-treated anti-malarial nets and community-based intervention packages, whereas a reduced number of antenatal care visits were shown to be harmful. However, there was variation in the effectiveness of interventions across different settings, indicating the need to carefully understand the context in which these interventions were tested. Further high-quality RCTs are needed to evaluate the effects of antenatal preventive interventions and which approaches are most effective to reduce the risk of stillbirth. Stillbirth (or fetal death), perinatal and neonatal death need to be reported separately in future RCTs of antenatal interventions to allow assessment of different interventions on these rare but important outcomes and they need to clearly define the target populations of women where the intervention is most likely to be of benefit. As the high burden of stillbirths occurs in low- and middle-income countries, further high-quality trials need to be conducted in these settings as a priority.

Antenatal dietary education and supplementation to increase energy and protein intake.

BACKGROUND: Gestational weight gain is positively associated with fetal growth, and observational studies of food supplementation in pregnancy have reported increases in gestational weight gain and fetal growth. OBJECTIVES: To assess the effects of education during pregnancy to increase energy and protein intake, or of actual energy and protein supplementation, on energy and protein intake, and the effect on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015), reference lists of retrieved studies and contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials of dietary education to increase energy and protein intake, or of actual energy and protein supplementation, during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and checked for accuracy. Extracted data were supplemented by additional information from the trialists we contacted. MAIN RESULTS: We examined 149 reports corresponding to 65 trials. Of these trials, 17 were included, 46 were excluded, and two are ongoing. Overall, 17 trials involving 9030 women were included. For this update, we assessed methodological quality of the included trials using the standard Cochrane criteria (risk of bias) and the GRADE approach. The overall risk of bias was unclear. Nutritional education (five trials, 1090 women) Women given nutritional education had a lower relative risk of having a preterm birth (two trials, 449 women) (risk ratio (RR) 0.46, 95% CI 0.21 to 0.98, low-quality evidence), and low birthweight (one trial, 300 women) (RR 0.04, 95% CI 0.01 to 0.14). Head circumference at birth was increased in one trial (389 women) (mean difference (MD) 0.99 cm, 95% CI 0.43 to 1.55), while birthweight was significantly increased among undernourished women in two trials (320 women) (MD 489.76 g, 95% CI 427.93 to 551.59, low-quality evidence), but did not significantly increase for adequately nourished women (MD 15.00, 95% CI -76.30 to 106.30, one trial, 406 women). Protein intake increased significantly (three trials, 632 women) (protein intake: MD +6.99 g/day, 95% CI 3.02 to 10.97). No significant differences were observed on any other outcomes such as neonatal death (RR 1.28, 95% CI 0.35 to 4.72, one trial, 448 women, low-quality evidence), stillbirth (RR 0.37, 95% CI 0.07 to 1.90, one trial, 431 women, low-quality evidence), small-for-gestational age (RR 0.97, 95% CI 0.45 to 2.11, one trial, 404 women, low-quality evidence) and total gestational weight gain (MD -0.41, 95% CI -4.41 to 3.59, two trials, 233 women). There were no data on perinatal death. Balanced energy and protein supplementation (12 trials, 6705 women)Risk of stillbirth was significantly reduced for women given balanced energy and protein supplementation (RR 0.60, 95% CI 0.39 to 0.94, five trials, 3408 women, moderate-quality evidence), and the mean birthweight was significantly increased (random-effects MD +40.96 g, 95% CI 4.66 to 77.26, Tau² = 1744, I² = 44%, 11 trials, 5385 women, moderate-quality evidence). There was also a significant reduction in the risk of small-for-gestational age (RR 0.79, 95% CI 0.69 to 0.90, I² = 16%, seven trials, 4408 women, moderate-quality evidence). No significant effect was detected for preterm birth (RR 0.96, 95% CI 0.80 to 1.16, five trials, 3384 women, moderate-quality evidence) or neonatal death (RR 0.68, 95% CI 0.43 to 1.07, five trials, 3381 women, low-quality evidence). Weekly gestational weight gain was not significantly increased (MD 18.63, 95% CI -1.81 to 39.07, nine trials, 2391 women, very low quality evidence). There were no data reported on perinatal death and low birthweight. High-protein supplementation (one trial, 1051 women)High-protein supplementation (one trial, 505 women), was associated with a significantly increased risk of small-for-gestational age babies (RR 1.58, 95% CI 1.03 to 2.41, moderate-quality evidence). There was no significant effect for stillbirth (RR 0.81, 95% CI 0.31 to 2.15, one trial, 529 women), neonatal death (RR 2.78, 95% CI 0.75 to 10.36, one trial, 529 women), preterm birth (RR 1.14, 95% CI 0.83 to 1.56, one trial, 505 women), birthweight (MD -73.00, 95% CI -171.26 to 25.26, one trial, 504 women) and weekly gestational weight gain (MD 4.50, 95% CI -33.55 to 42.55, one trial, 486 women, low-quality evidence). No data were reported on perinatal death. Isocaloric protein supplementation (two trials, 184 women)Isocaloric protein supplementation (two trials, 184 women) had no significant effect on birthweight (MD 108.25, 95% CI -220.89 to 437.40) and weekly gestational weight gain (MD 110.45, 95% CI -82.87 to 303.76, very low-quality evidence). No data reported on perinatal mortality, stillbirth, neonatal death, small-for-gestational age, and preterm birth. AUTHORS' CONCLUSIONS: This review provides encouraging evidence that antenatal nutritional education with the aim of increasing energy and protein intake in the general obstetric population appears to be effective in reducing the risk of preterm birth, low birthweight, increasing head circumference at birth, increasing birthweight among undernourished women, and increasing protein intake. There was no evidence of benefit or adverse effect for any other outcome reported.Balanced energy and protein supplementation seems to improve fetal growth, and may reduce the risk of stillbirth and infants born small-for-gestational age. High-protein supplementation does not seem to be beneficial and may be harmful to the fetus. Balanced-protein supplementation alone had no significant effects on perinatal outcomes.The results of this review should be interpreted with caution. The risk of bias was either unclear or high for at least one category examined in several of the included trials, and the quality of the evidence was low for several important outcomes. Also, as the anthropometric characteristics of the general obstetric population is changing, those developing interventions aimed at altering energy and protein intake should ensure that only those women likely to benefit are included. Large, well-designed randomised trials are needed to assess the effects of increasing energy and protein intake during pregnancy in women whose intake is below recommended levels.

Zinc supplementation for improving pregnancy and infant outcome.

BACKGROUND: It has been suggested that low serum zinc levels may be associated with suboptimal outcomes of pregnancy such as prolonged labour, atonic postpartum haemorrhage, pregnancy-induced hypertension, preterm labour and post-term pregnancies, although many of these associations have not yet been established. OBJECTIVES: To assess the effects of zinc supplementation in pregnancy on maternal, fetal, neonatal and infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of zinc supplementation in pregnancy. We excluded quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, assessed trial quality and extracted data. When necessary, we contacted study authors for additional information. The quality of the evidence was assessed using GRADE. MAIN RESULTS: We included 21 randomised controlled trials (RCTs) reported in 54 papers involving over 17,000 women and their babies. One trial did not contribute data. Trials were generally at low risk of bias. Zinc supplementation resulted in a small reduction in preterm birth (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.76 to 0.97 in 16 RCTs; 16 trials of 7637 women). This was not accompanied by a similar reduction in numbers of babies with low birthweight (RR 0.93, 95% CI 0.78 to 1.12; 14 trials of 5643 women). No clear differences were seen between the zinc and no zinc groups for any of the other primary maternal or neonatal outcomes, except for induction of labour in a single trial. No differing patterns were evident in the subgroups of women with low versus normal zinc and nutrition levels or in women who complied with their treatment versus those who did not. The GRADE quality of the evidence was moderate for preterm birth, small-for-gestational age, and low birthweight, and low for stillbirth or neonatal death and birthweight. AUTHORS' CONCLUSIONS: The evidence for a 14% relative reduction in preterm birth for zinc compared with placebo was primarily represented by trials involving women of low income and this has some relevance in areas of high perinatal mortality. There was no convincing evidence that zinc supplementation during pregnancy results in other useful and important benefits. Since the preterm association could well reflect poor nutrition, studies to address ways of improving the overall nutritional status of populations in impoverished areas, rather than focusing on micronutrient and or zinc supplementation in isolation, should be an urgent priority.

Antenatal dietary advice and supplementation to increase energy and protein intake.

BACKGROUND: Gestational weight gain is positively associated with fetal growth, and observational studies of food supplementation in pregnancy have reported increases in gestational weight gain and fetal growth. OBJECTIVES: To assess the effects of advice during pregnancy to increase energy and protein intake, or of actual energy and protein supplementation, on energy and protein intakes, and the effect on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (22 July 2011) and contacted researchers in the field. We updated the search on 12 July 2012 and added the results to the awaiting classification section of the review. SELECTION CRITERIA: Randomised controlled trials of dietary advice to increase energy and protein intake, or of actual energy and protein supplementation, during pregnancy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and checked for accuracy. Extracted data were supplemented by additional information from the trialists we contacted. MAIN RESULTS: We examined 110 reports corresponding to 46 trials. Of these trials, 15 were included, 30 were excluded, and one is ongoing. Overall, 15 trials involving 7410 women were included.Nutritional advice (four trials, 790 women)Women given nutritional advice had a lower relative risk of having a preterm birth (two trials, 449 women) (risk ratio (RR) 0.46, 95% CI 0.21 to 0.98 ), head circumference at birth was increased in one trial (389 women) (mean difference (MD) 0.99 cm, 95% CI 0.43 to 1.55) and protein intake increased (three trials, 632 women) (protein intake: MD +6.99 g/day, 95% CI 3.02 to 10.97). No significant differences were observed on any other outcomes.Balanced energy and protein supplementation (11 trials, 5385 women)Risk of stillbirth was significantly reduced for women given balanced energy and protein supplementation (RR 0.62, 95% CI 0.40 to 0.98, five trials, 3408 women), mean birthweight was significantly increased (random-effects MD +40.96 g, 95% CI 4.66 to 77.26 , Tau(2)= 1744, I(2) = 44%, 11 trials, 5385 women). There was also a significant reduction in the risk of small-for-gestational age (RR 0.79, 95% CI 0.69 to 0.90, I(2) = 16%, seven trials, 4408 women). No significant effect was detected for preterm birth or neonatal death.High-protein supplementation (one trial, 1051 women)High-protein supplementation (one trial, 505 women), was associated with a significantly increased risk of small-for-gestational age babies (RR 1.58, 95% CI 1.03 to 2.41).Isocaloric protein supplementation (two trials, 184 women)Isocaloric protein supplementation (two trials,184 women) had no significant effect on birthweight and weekly gestational weight gain. AUTHORS' CONCLUSIONS: This review provides encouraging evidence that antenatal nutritional advice with the aim of increasing energy and protein intake in the general obstetric population appears to be effective in reducing the risk of preterm birth, increasing head circumference at birth and increasing protein intake, there was no evidence of benefit or adverse effect for any other outcome reported.Balanced energy and protein supplementation seems to improve fetal growth, and may reduce the risk of stillbirth and infants born small-for-gestational age. High-protein supplementation does not seem to be beneficial and may be harmful to the fetus. Balanced-protein supplementation alone had no significant effects on perinatal outcomes.The results of this review should be interpreted with caution, the risk of bias was either unclear or high for at least one category examined in several of the included trials and the quality of the evidence was low for several important outcomes. Also the anthropometric characteristics of the general obstetric population is changing, therefore, those developing interventions aimed at altering energy and protein intake should ensure that only those women likely to benefit are included. Large, well designed randomised trials are needed to assess the effects of increasing energy and protein intake during pregnancy in women whose intake is below recommended levels.

Zinc supplementation for improving pregnancy and infant outcome.

BACKGROUND: It has been suggested that low serum zinc levels may be associated with suboptimal outcomes of pregnancy such as prolonged labour, atonic postpartum haemorrhage, pregnancy-induced hypertension, preterm labour and post-term pregnancies, although many of these associations have not yet been established. OBJECTIVES: To assess the effects of zinc supplementation in pregnancy on maternal, fetal, neonatal and infant outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2011) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of zinc supplementation in pregnancy. We excluded quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, assessed trial quality and extracted data. When necessary, we contacted study authors for additional information. MAIN RESULTS: We included 20 randomised controlled trials (RCTs) reported in 51 papers involving over 15,000 women and their babies. Trials were generally at low risk of bias. Zinc supplementation resulted in a small but significant reduction in preterm birth (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.76 to 0.97 in 16 RCTs; 16 trials of 7637 women). This was not accompanied by a similar reduction in numbers of babies with low birthweight (RR 0.93, 95% CI 0.78 to 1.12; 14 trials of 5643 women). No significant differences were seen between the zinc and no zinc groups for any of the other primary maternal or neonatal outcomes, except for induction of labour in a single trial. No differing patterns were evident in the subgroups of women with low versus normal zinc and nutrition levels or in women who complied with their treatment versus those who did not. AUTHORS' CONCLUSIONS: The evidence for a 14% relative reduction in preterm birth for zinc compared with placebo was primarily represented by trials involving women of low income and this has some relevance in areas of high perinatal mortality. There was no convincing evidence that zinc supplementation during pregnancy results in other useful and important benefits. Since the preterm association could well reflect poor nutrition, studies to address ways of improving the overall nutritional status of populations in impoverished areas, rather than focusing on micronutrient and or zinc supplementation in isolation, should be an urgent priority.