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Drug on Radar - New Drug Caralluma fimbriata for treatment of Obese PCOS Zinc supplementation for improving pregnancy and infant outcome [Intervention Review] Kassam Mahomed1, Zulfiqar A Bhutta2, Philippa Middleton3 (1Ipswich Hospital, Ipswich, Australia. 2Department of Pediatrics & Child Health, The Aga Khan University Hospital, Karachi, Pakistan. 3ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynecology, The University of Adelaide, Adelaide, Australia) Contact address: Kassam Mahomed, Ipswich Hospital, Ipswich, Queensland, 4305, Australia. kassam_mahomed@health.qld.gov.au. Editorial group: Cochrane Pregnancy and Childbirth Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009. Review content assessed as up-to-date: 31 January 2007. Citation: Mahomed K, Bhutta ZA, Middleton P. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD000230. DOI: 10.1002/14651858.CD000230.pub3. Thanks to: The Cochrane Collaboration and John Wiley & Sons, Ltd. ________________________________________ Abstract Background It has been suggested that low serum zinc levels may be associated with suboptimal outcomes of pregnancy such as prolonged labour, atonic postpartum hemorrhage, 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 strategy We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 2007). Selection criteria Randomized or quasi-randomized trials of zinc supplementation in pregnancy. Data collection and analysis Two review authors applied the study selection criteria, assessed trial quality and extracted data. When necessary, study authors were contacted for additional information. Main results We included 17 randomized controlled trials (RCTs) involving over 9000 women and their babies. Zinc supplementation resulted in a small but significant reduction in preterm birth (relative risk (RR) 0.86, 95% confidence interval (CI) 0.76 to 0.98 in 13 RCTs; 6854 women). This was not accompanied by a similar reduction in numbers of babies with low birth weight (RR 1.05 95% CI 0.94 to 1.17; 11 studies of 4941 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 a small effect favoring zinc for caesarean section (four trials with high heterogeneity) and 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 14% relative reduction in preterm birth for zinc compared with placebo was primarily in the group of studies 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. Plain language summary: Zinc supplementation for improving pregnancy and infant outcome Taking zinc during pregnancy helps to slightly reduce preterm births, but does not help prevent other problems such as low birth weight babies. Many women of childbearing age may have mild to moderate zinc deficiency. Low zinc levels may cause preterm birth or they may prolong labour. It is also possible that zinc deficiency may affect infant growth as well. The review of 17 trials, involving over 9000 women and their babies, found that although zinc supplementation has a small effect on reducing preterm births, it does not help to prevent low birth weight babies. Finding ways to improve women's overall nutritional status, particularly in low-income areas, will do more to improve the health of mothers and babies than supplementing pregnant women with zinc. Background The overall nutritional status of the mother during pregnancy is a significant contributor to both maternal and perinatal mortality and morbidity (Koblinsky 1995). This is likely to be even more crucial in developing countries where anemia and infections, such as malaria and hookworm, compound the issue even further. Zinc is known to play an important role in many biological functions, including protein synthesis and nucleic acid metabolism (Valee 1993). Although severe zinc deficiency is now considered rare, mild to moderate deficiency may be relatively common throughout the world (Sanstead 1991). In a review of literature published between 1970 and 1991, Parr 1996 noted that, on average, pregnant and lactating women worldwide consumed 9.6 mg zinc per day, well below the recommended 15 mg daily, during the last two trimesters of pregnancy (Sanstead 1996; WHO 1996). In animal studies, zinc deficiency during the early stages of pregnancy is associated with reduced fertility (Apgar 1970), fetal neurological malformations and growth retardation (McKenzie 1975), and deficiency in later stages of pregnancy negatively affects neuronal growth and may also be associated with impaired brain function and behavioral abnormalities (Golub 1995). In humans, pregnant women with acrodermatitis enteropathica (an inherited defect in zinc absorption from the bowel) show association with increased risk of congenital malformations and pregnancy losses (Verburg 1974). Numerous reports have noted low serum zinc levels to be linked with abnormalities of labour such as prolonged labour and atonic postpartum hemorrhage (Prema 1980), pregnancy-induced hypertension (Jameson 1976; Jameson 1993), preterm labour (Jones 1981) and post-term pregnancies (Simmer 1985). Others (Cherry 1981; Chesters 1982) have failed to show any such association. Some have also reported an association between low zinc and small-for-gestational age babies, and poor perinatal outcome (Kiilholma 1984a; Kiilholma 1984b). Kirksey 1994 reported low maternal serum zinc levels during pregnancy to be associated with an increased risk of low birth weight and preterm birth. Low birth weight babies have higher rates of morbidity and mortality due to infectious disease and impaired immunity and, thus, it is possible that zinc deficiency may affect infant growth and wellbeing too. Studies of the effects of zinc supplementation have differed in their findings. These inconsistencies in study findings could be due to lack of consensus on accurate assessment of zinc status (Aggett 1991) and to differences in populations studied. Randomized controlled trials of zinc supplementation in pregnancy would help to address the association, if any, between zinc deficiency and pregnancy outcome and neonatal and infant health and wellbeing. The fetal nervous system also develops progressively during pregnancy influencing motor and autonomic functions. Change in the pattern of fetal heart rate and movements monitored electronically have been related to fetal neurobehavioral development (DiPietro 1996) and atypical neurodevelopment has been shown in fetuses that exhibit other indicators of neurologic compromise (Hepper 1995). In a publication from Egypt, Kirskey 1991 also reported a positive association between maternal zinc status during the second trimester of pregnancy and newborn behavior. It is plausible that the effect of zinc supplementation would vary among different population groups depending on their nutritional status, with any effect likely to be more apparent in women from the developing world. Currently, UNICEF is already promoting antenatal use of multiple-micronutrient supplementation, including zinc, to all pregnant women in developing countries (Nepal 2003). The aim of this review is to systematically review all randomized controlled trials of zinc supplementation in pregnancy and to evaluate the role of zinc as it relates to pregnancy, labour and birth as well as to maternal and infant health and wellbeing. Objectives (1) To compare the effects on maternal, fetal, neonatal and infant outcomes in healthy pregnant women, supplemented with zinc, with those supplemented with either placebo or no zinc. (2) To assess the above outcomes in a subgroup analysis reviewing studies performed in women who are or are likely to be zinc deficient. Methods Criteria for considering studies for this review
Types of studies Randomized trials of zinc supplementation versus no zinc supplementation or placebo administration during pregnancy, earlier than 27 weeks' gestation. Types of participants Normal pregnant women with no systemic illness. Women who may have had normal zinc levels or they may have been, or likely to have been, zinc deficient. Routine zinc supplementation versus no zinc supplementation or placebo. Types of outcome measures We have included outcomes related to clinical complications of pregnancy on maternal, fetal, neonatal and infant outcomes. We have not included data related to biochemical outcomes or studies reporting only biochemical outcomes. Primary outcomes Maternal and pregnancy outcomes ?? Preterm labour or birth (less than 37 weeks), or both ?? Antepartum hemorrhage ?? Pregnancy induced hypertension ?? Prelabour rupture of membranes ?? Post-term pregnancy ?? Induction of labour ?? Any maternal infection ?? Meconium in liquor ?? Caesarean section ?? Instrumental vaginal birth ?? Retained placenta ?? Postpartum hemorrhage Neonatal outcomes ?? Gestational age at birth ?? Stillbirth or neonatal death ?? Birth weight ?? Small-for-gestational age (birth weight less than 10th centile for gestational age) ?? Low birth weight (less than 2.5 kg) ?? High birth weight (more than 4.5 kg) ?? Apgar score of less than five at five minutes Secondary outcomes ?? Maternal and pregnancy outcomes ?? Smell dysfunction ?? Taste dysfunction ?? Fetal neurodevelopmental assessment ?? Baseline fetal heart rate ?? Baseline variability ?? Number of accelerations ?? Number of fetal movements ?? Fetal activity level (minutes) ?? Movement amplitude Neonatal outcomes ?? Head circumference ?? Hypoxia ?? Neonatal sepsis ?? Neonatal jaundice ?? Respiratory distress syndrome ?? Neonatal intraventricular hemorrhage ?? Necrotising enterocolitis ?? Neonatal length of hospital stay Infant/child outcomes ?? Episodes of disease ?? Weight for age Z-score ?? Weight for height Z-score ?? Mid-upper arm circumference ?? Mental development index ?? Psychomotor development index ?? Other measures of infant or child development Search methods for identification of studies We searched the Cochrane Pregnancy and Childbirth Group's Trials Register by contacting the Trials Search Coordinator (February 2007). The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co-coordinator and contains trials identified from: (1) Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); (2) Monthly searches of MEDLINE; (3) Handsearches of 30 journals and the proceedings of major conferences; (4) Weekly current awareness search of a further 37 journals. Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group. Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co-coordinator searches the register for each review using these codes rather than keywords. Unpublished studies were identified from a review article (Osendarp 2003). We did not apply any language restrictions. Selection of studies
Two review authors (K Mahomed, P Middleton) applied the inclusion and exclusion criteria to all identified trials. Disagreements were resolved through discussion. Data extraction and management
We developed a form for data extraction and two authors independently extracted the data using this form. We contacted, or attempted to contact, authors of the original reports when information regarding a study was unclear. Assessment of methodological quality of included studies
We assessed the methodological quality of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). (1) Selection bias (randomization and allocation concealment) We coded each trial as: (A) adequate concealment of allocation (such as telephone randomization, consecutively numbered sealed opaque envelopes); (B) unclear allocation concealment (such as list or table of numbers used, sealed envelopes or trial does not report any approach for concealing allocation); (C) inadequate concealment of allocation (such as open list of random numbers, dates of birth or days of the week). (2) Performance bias (blinding of participants, researchers and outcome assessment) We assessed blinding using the following criteria: (1) blinding of participants (yes/no/unclear); (2) blinding of caregivers (yes/no/unclear); (3) blinding of outcome assessment (yes/no/unclear). (3) Attrition bias (loss of participants, for example, withdrawals, dropouts, protocol deviations) We have presented numbers of losses for each study when these have been reported. We conducted statistical analysis using the Review Manager software (RevMan 2003). At least two authors independently extracted data. We used a fixed-effect model to combine data since trials appeared to be sufficiently similar (as measured by I2), except for head circumference and caesarean section where we also calculated this outcome on the basis of a random-effects model. For dichotomous data, we presented results as a summary relative risk with 95% confidence intervals. For continuous data, we presented results as mean differences with 95% confidence intervals. One trial (Nepal 2003) used a cluster-randomization design. The trial was reported with relative risks adjusted to take account of the fact that sectors rather than individuals were randomized to groups. We adjusted the raw data from two of the five arms of this study (in order to compare zinc and no zinc groups). Using the methods outlined in section 8.11.2 of the Handbook (Higgins 2005), we calculated a design effect of 1.067. The average cluster size was 7.66 and we assumed an intra-class coefficient [r] of 0.01 and so the design effect was calculated as 1 + (1-7.66) x 0.01 = 1.067. Numerators and denominators of dichotomous outcomes and the sample sizes of the continuous outcomes in Nepal 2003 were reduced by dividing them by the design effect. We applied tests of heterogeneity between trials using the I2 statistic. In the event of high levels of heterogeneity among the trials (exceeding 50%), we explored this by prespecified subgroup analysis and performed sensitivity analysis. A random-effects meta-analysis was used as an overall summary when considered appropriate. The following prespecified subgroup analyses were performed: ??? Zinc supplementation compared with no zinc or placebo in women likely or shown to be zinc deficient; ??? Zinc supplementation compared with no zinc or placebo in women in whom compliance with supplementation was good (more than 80%). We included 17 randomized controlled trials involving 8273 women and their babies. See table of 'Characteristics of included studies' for details. Thirteen studies included women from low-income settings. One of the four studies in higher-income or mixed-income settings only recruited women at risk for giving birth to small-for-gestational age babies. Baseline zinc and nutritional levels Women in most of the studies had, or were likely to have low zinc levels and low nutritional status. It is difficult to assess zinc status and most studies have assumed that pregnant women from low-income groups would be low in zinc as part of their overall poor nutritional status. Where studied, the improvement in serum zinc levels in the supplemented group support this assumption (Bangladesh 2000; Peru 1999). The only studies likely to have included women with normal zinc levels were UK 1989; UK 1991a; UK 1991b. Dosage of zinc supplementation The dose of daily zinc supplementation ranged from 15 mg (Peru 1999) to 44 mg zinc per day (Denmark 1996). Some women in S Africa 1985 had doses of up to 90 mg zinc per day. Women were supplemented from before conception in Nepal 2003 with the shortest duration being from 26 completed weeks' gestation in some women in USA 1983; and USA 1985. Most trials (11/17) compared zinc with placebo (Bangladesh 2000; Chile 2001; Denmark 1996; Pakistan 2005; S Africa 1985; UK 1989; UK 1991a; USA 1983; USA 1985; USA 1989; USA 1995). In some trials (see Characteristics of included studies table) all women were also given iron, folate or vitamins or combinations of these. Three trials (Indonesia 1999; Indonesia 2001; Nepal 2003) had more than two arms, so these trials were analyzed to compare women who received zinc with women who did not. Two studies (Chile 2001; Denmark 1996) excluded non-compliers (85% and 60% compliance respectively) and the other 15 studies included or probably included non-compliers in the analysis. Of the latter group, two studies (UK 1991a; USA 1983) presented at least some results separately for compliers and non-compliers. Compliance levels were generally reported to be over 70%, except for Pakistan 2005; UK 1989; UK 1991a, where compliance was 50% to nearly 70%. We excluded eleven studies. See table of Characteristics of included studies for details. Risk of bias in included studies Randomization - generation of schedule and allocation concealment Allocation concealment was considered adequate (third party randomization) in seven trials (Indonesia 1999; Nepal 2003; Peru 1999; Peru 2004; S Africa 1985; UK 1989; USA 1985). Allocation concealment was rated as unclear in 10 studies: Bangladesh 2000; Chile 2001; Denmark 1996; Pakistan 2005; UK 1991a; UK 1991b; USA 1983; USA 1985; USA 1995 (method not described); and in Indonesia 2001 there was third party randomization but no details of how allocations were concealed. All trials stated that both investigators and mothers were blinded or that the trial was double-blinded. Losses to follow up ranged from 1% in UK 1989 to 40% in Denmark 1996. We included 17 randomized controlled trials (RCTs) involving over 9000 women and their babies. There was a 14% reduction in preterm birth in zinc groups compared with no zinc groups (relative risk (RR) 0.86, 95% confidence interval (CI) 0.76 to 0.98; 13 RCTs, 6854 women) No significant differences were seen for pregnancy hypertension or pre-eclampsia (RR 0.83, 95% CI 0.64 to 1.08; seven RCTs, 2975 women) or prelabour rupture of membranes, antepartum hemorrhage, post-term birth, prolonged labour, retention of placenta, meconium in liquor, instrumental vaginal birth and smell or taste dysfunction, but these outcomes were measured in only one or two trials. In one trial of women at risk for small-for-gestational age babies (UK 1991a), significantly fewer women in the zinc group than in the no-zinc group were induced (RR 0.27, 95% CI 0.10 to 0.73, 52 women). Pooling of four RCTs (1924 women) showed significantly fewer caesarean sections in the zinc groups compared with the no-zinc groups (RR 0.72, 95% CI 0.53 to 0.98, random- effects model). There was a high level of heterogeneity in this result and was affected by one study with a small sample size (UK 1991a), but it still remained statistically significant under a random-effects model. No differences were seen for postpartum hemorrhage or maternal infections (three RCTs each) or gestational age at birth (weighted mean difference (WMD) 0.07 weeks, 95% CI -0.08 to 0.22; six RCTS, 2773 women). Birth weight and associated outcomes There was no significant difference in birth weight for zinc and no-zinc groups (WMD -10.59 g, 95% CI -36.71 to 15.54; 14 RCTs, 5802 babies); nor were significant differences seen for low birth weight (RR 1.05 95% CI 0.94 to 1.17; 11 RCTs, 4941 women), small-for-gestational age (five RCTs), high birth weight (five RCTs), head circumference (seven RCTs) or mid-upper arm circumference (three RCTs). A high level of heterogeneity was apparent in the results for head circumference (I2 = 45%). A random-effects model did not change the conclusion of no significant difference between the zinc and no-zinc groups. No significant difference was seen for any of the perinatal mortality subgroups (seven RCTs; 3446 babies) or congenital malformations (five RCTs). None of the following outcomes showed significant differences between the zinc and no-zinc groups: Apgar scores less than five at five minutes, neonatal hypoxia, jaundice, fever, infant umbilical infection, neonatal sepsis, respiratory distress syndrome, neonatal intraventricular hemorrhage, necrotizing enterocolitis, neonatal hospital stay and lack of tubercular response. Each of these outcomes was only available from one or two RCTs. In one RCT of 176 babies (Peru 2004), four measures of fetal heart rate (fetal heart rate, number of fetal movement bouts, fetal activity level, and fetal movement amplitude) showed no differences between the zinc and no-zinc groups, while fetal heart rate variability and number of fetal accelerations were significantly higher in the zinc groups. In one RCT of 196 infants (Bangladesh 2000), the zinc group had significantly less episodes of acute diarrhea over six months (mean difference -0.4 episodes, 95% CI -0.79 to -0.01), but no differences were seen for episodes of persistent diarrhea, dysentery, cough, acute lower respiratory infection and impetigo) over the same period. Infant weight-for-age (Z-score) was similar at six months for the zinc and no-zinc groups in two RCTs (304 infants), but by 13 months, the no-zinc group showed significantly higher scores (in one RCT of 168 infants, Bangladesh 2000). No difference was seen for weight-for-height at six months in one RCT of 136 infants (Indonesia 2001). Infant/child development Two RCTs (Bangladesh 2000; USA 1995) measured child development outcomes. A subset of 168 infants from Bangladesh 2000 assessed at 13 months found that the zinc group had significantly worse mental development, psychomotor development index scores, emotional tone and cooperation than the no-zinc group, with infant approach, activity, and vocalization showing no differences. The other RCT (USA 1995) followed up 355 infants at five years, finding no significant differences between zinc and no-zinc groups for differential abilities, visual or auditory sequential memory scores, Knox cube, gross motor scale and grooved pegboard scores. No differing patterns were evident in the subgroups of women with low versus normal zinc and nutrition levels (with the possible exception of hypertension or pre-eclampsia, where women with low zinc levels may show benefit), or in women who complied with their treatment versus those who did not (latter subgroup analysis not presented in the graphs). Discussion Many studies have demonstrated some positive response on biochemical parameters such as serum zinc status of mother or baby, or both, with supplementation (Bangladesh 2000; Peru 1999) as have studies of iron supplementation in pregnancy (Pena-Rosas 2006). It is now crucial to focus on the impact of any intervention on outcomes that are of clinical significance and particularly those that may be related to maternal, fetal, neonatal and infant mortality and morbidity. This is relevant because of the limited resources, financial and human, currently available worldwide but in particular to the developing countries where such morbidity and mortality is high. This review of 17 RCTs, including over 9000 women and their babies, has not provided compelling evidence for routine zinc supplementation during pregnancy, although the finding of a reduction in preterm births warrants further investigation. Subgroup analysis of the 14 studies involving women who are or are likely to be zinc deficient, such as populations from developing countries or from low socioeconomic groups from western countries, also did not make a case for zinc supplementation in those groups of women. This is consistent with a review of maternal zinc supplementation in developing countries (Osendarp 2003). The small but significant reduction in preterm birth in the zinc group deserves further attention; is it possible that improving nutrition would cause an even greater reduction? The Cochrane Review on micronutrient supplementation also shows a trend in the same direction (Haider 2006). Some results of our review, such as the reduction in caesarean section rate are influenced by a single study (UK 1991a) of highly selective population and very small sample size and may be due to a chance effect. Although dosage of zinc may play a role, no dose response pattern was evident in this review (with the possible exception of pre-eclampsia). It is possible that zinc used in conjunction with iron may dilute the effect of supplementation. Intrauterine growth effect seen in UK 1991a, where women were selected on the basis of being at risk for giving birth to a small-for-gestational age (SGA) baby, have not been replicated. In the Bangladesh 2000 studies, where incidence of SGA was 75% and low birth weight was 43%, supplementation with 30 mg zinc daily did not improve pregnancy outcome. This is most likely due to the presence of other concurrent nutrient deficiencies. The Peru (Peru 1999; Peru 2004); Bangladesh 2000 and USA 1995 studies attempted to assess the neurodevelopmental effect of zinc supplementation on infants. The inconsistencies in their results probably reflect the dependence of such outcomes on many variables. Zinc is likely to be only one micronutrient in the overall picture of maternal nutrition prior to and during the course of pregnancy, although the Cochrane review on micronutrient supplementation concludes that there is "no added benefit of multiple-micronutrient supplements compared with iron folic acid supplementation" (Haider 2006). In order to make any significant impact on morbidity and mortality we really need to address the underlying problem of poor nutrition, due to low socioeconomic status (Peru 1999). Villar and colleagues (Villar 2003) indicated that while zinc supplementation may be promising, they go on to say that "it is unlikely that any specific nutrient on its own ... will prevent .... preterm delivery or death during pregnancy". Although improving birth weight particularly in women from low-income countries is desirable, data from Nepal 2003 imply a degree of caution. In the overall Nepal 2003 study, multiple-micronutrient supplementation (but not other combinations of micronutrients) compared with controls was associated with more babies with a birth weight greater than 3.3 kg; and this high birth weight was associated with an increased risk of symptoms of birth asphyxia (relative risk 1.49, 95% confidence interval 1.04 to 2.13). Despite uncertainty about the effects of maternal zinc supplementation, many pharmaceutical companies have added zinc to their multivitamin preparations. In the latest version of Physicians??? Desk Reference (Physicians Desk 2006) all listed multivitamin and mineral products contain zinc. Lack of any significant benefit from zinc supplementation of mothers suggests that we should now not waste valuable resources looking at zinc in isolation. In addition, infant micronutrient supplementation (including zinc) may be more effective than maternal supplementation (Shrimpton 2005). Any future research aimed at improving outcomes related to maternal nutrition should address ways of modifying the overall nutritional status of pregnant women particularly in developing countries. This may not come from the scientific but from the political community where more resources need to be put into improving the overall socioeconomic status of impoverished populations and also to improve the status of the women in such populations. Future research should also address other interventions such as work reduction in populations at high risk of nutritional deficiency. Authors' conclusions
Bangladesh 2000 {published data only}
Chile 2001 {published data only}
Denmark 1996 {published data only}
Indonesia 1999 {published data only}
Indonesia 2001 {published data only}
Nepal 2003 {published data only}
Pakistan 2005 {published data only}
Peru 1999 {published data only}
Peru 2004 {published data only}
S Africa 1985 {published data only}
UK 1991a {published data only}
UK 1991b {published data only}
USA 1983 {published data only}
USA 1985 {published data only}
USA 1989 {published data only}
USA 1995 {published data only}
* Indicates the major publication for the study |
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