Protocol citation

Overview of pre‐specified outcomes in protocol

Amorim 2011

Secondary pre‐specified perinatal and neonatal outcomes include:

• Long‐term disability: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

Bimbashi A, Duley L, Ndoni E, Dokle A. Amniotomy plus intravenous oxytocin for induction of labour. Cochrane Database of Systematic Reviews 2012, Issue 4.

Primary pre‐specified outcomes for the baby include:

• Serious neonatal morbidity or perinatal death (e.g. seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood).

Secondary pre‐specified outcomes for the baby include:

• Individual components of serious neonatal morbidity or perinatal death, as listed above (perinatal death, total baby death, seizures, birth asphyxia defined by trialists, neonatal encephalopathy, disability in childhood ‐ such as neurodevelopmental delay, blind, deaf, cerebral palsy).

Dodd JM, Grivell RM, O'Brien CM, Dowswell T, Deussen AR. Prenatal administration of progestogens for preventing preterm birth in women with a multiple pregnancy. Cochrane Database of Systematic Reviews 2016, Issue 1.

Primary pre‐specified outcomes for the infant include:

• Major neurodevelopmental disability at childhood follow‐up.

Secondary pre‐specified outcomes for the child include:

• Major sensorineural disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, developmental delay, or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below mean)).

• Cerebral palsy.

Dutta D, Sule M, Ray A. Epidural therapy for the treatment of severe pre‐eclampsia in non labouring women. Cochrane Database of Systematic Reviews 2012, Issue 1.

Secondary pre‐specified outcome for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

Eke AC, Ezebialu IU, Eleje GU. Hypnosis for preventing preterm labour. Cochrane Database of Systematic Reviews 2012, Issue 11.

Secondary pre‐specified outcomes for the child include:

• Major sensorineural disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, developmental delay, or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below mean)).

• Cerebral palsy.

Haruna M, Matsuzaki M, Ota E, Shiraishi M, Hanada N, Mori R. Guided imagery for treating hypertension in pregnancy. Cochrane Database of Systematic Reviews 2014, Issue 10.

Secondary pre‐specified outcomes for the neonate include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

Hobson SR, Mockler JC, Lim R, Alers NO, Miller SL, Wallace EM. Melatonin for preventing pre‐eclampsia. Cochrane Database of Systematic Reviews 2015, Issue 5.

Secondary pre‐specified outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

Hobson SR, Mockler JC, Lim R, Alers NO, Miller SL, Wallace EM. Melatonin for treating pre‐eclampsia. Cochrane Database of Systematic Reviews 2016, Issue 3.

Secondary pre‐specified outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

Martis R, Emilia O, Nurdiati DS. Intermittent auscultation (IA) of fetal heart rate in labour for fetal well‐being. Cochrane Database of Systematic Reviews 2010, Issue 9.

Secondary pre‐specified outcomes for the baby include:

• Cerebral palsy.

Review citation

Overview of pre‐specified outcomes in review with no outcome data

Main conclusion(s) of review

Abdel‐Latif 2010

Primary outcomes include:

• Neurodevelopmental disability at 18 months or more postnatal age, defined as neurological abnormality, including: cerebral palsy on clinical examination; developmental delay more than two standard deviations below population mean on any standard test of development; blindness (visual acuity less than 6/60); or deafness (any hearing impairment requiring amplification) at any time after term corrected age.

No included trials.

"We identified no randomised trials that evaluated the effect of intra‐amniotic instillation of surfactant for women at risk of preterm birth. Evidence from animal and observational human studies suggest that intra‐amniotic surfactant administration is potentially safe, feasible and effective. Well designed trials of intra‐amniotic instillation of surfactant for women at risk of preterm birth are needed."

Bain E, Heatley E, Hsu K, Crowther CA. Relaxin for preventing preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 8.

Secondary outcomes for the infant/child include:

• Cerebral palsy.

"There is limited randomised controlled trial evidence available on the effect of relaxin during pregnancy for preventing preterm birth for women in preterm labour. Evidence from one quasi‐randomised trial suggested a reduction in birth within seven days of treatment for women receiving relaxin, compared with women in a control group, however this trial was at a high risk of bias and included only 30 women. Thus, there is insufficient evidence to support or refute the use of relaxin in women in preterm labour for preventing preterm birth."

Bain E, Middleton P, Crowther CA. Different magnesium sulphate regimens for neuroprotection of the fetus for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2012, Issue 2.

Primary outcomes for the infant/child include:

• Cerebral palsy (abnormality of tone with motor dysfunction, or as defined by trialists).

• Death or cerebral palsy (as they are competing outcomes, this combined outcome is often considered the most clinically relevant for assessing neuroprotection).

Secondary outcomes for the infant/child include:

• Cerebral palsy (mild, moderate or severe, evaluated separately, as defined by trialists).

• Major neurologic disability (including: moderate or severe cerebral palsy (as defined by trialists)).

No included trials.

"Although strong evidence supports the use of antenatal magnesium sulphate for neuroprotection of the fetus prior to very preterm birth, no trials comparing different treatment regimens have been completed. Research should be directed towards comparisons of different dosages and other variations in regimens, evaluating both maternal and infant outcomes."

Bain E, Pierides KL, Clifton VL, Hodyl NA, Stark MJ, Crowther CA, et al. Interventions for managing asthma in pregnancy. Cochrane Database of Systematic Reviews 2014, Issue 10.

Secondary outcomes for the infant, child, and for the child as an adult include:

• Any neurodevelopmental disability (blindness, deafness, moderate or severe cerebral palsy (however defined by authors), or development delay or intellectual impairment (defined as developmental quotient or intelligence quotient more than two standard deviations below population mean)).

• Cerebral palsy (however defined by authors).

"Based on eight included trials, of moderate quality overall, no firm conclusions about optimal interventions for managing asthma in pregnancy can be made. Five trials assessing pharmacological interventions did not provide clear evidence of benefits or harms to support or refute current practice. While inhaled magnesium sulphate for acute asthma was shown to reduce exacerbations, this was in one small trial of unclear quality, and thus, this finding should be interpreted with caution. Three trials assessing non‐pharmacological interventions provided some support for the use of such strategies, however, were not powered to detect differences in important maternal and infant outcomes. While a FENO‐based algorithm reduced exacerbations, the effects on perinatal outcomes were less certain, and thus, widespread implementation is not yet appropriate. Similarly, though positive effects on asthma control were shown with PMR and pharmacist‐led management, the evidence to date is insufficient to draw definitive conclusions.

In view of the limited evidence base, further randomised trials are required to determine the most effective and safe interventions for asthma in pregnancy. Future trials must be sufficiently powered, and well‐designed, to allow differences in important outcomes for mothers and babies to be detected. The impact on health services requires evaluation. Any further trials assessing pharmacological interventions should assess novel agents or those used in current practice. Encouragingly, at least five trials have been identified as planned or underway."

Bricker L, Reed K, Wood L, Neilson JP. Nutritional advice for improving outcomes in multiple pregnancies. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes for the child include:

• Cerebral palsy.

No included trials.

"There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial."

Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database of Systematic Reviews 2013, Issue 1.

Secondary outcomes for the neonate include:

• Cerebral palsy at childhood follow‐up.

"Antibiotic treatment can eradicate bacterial vaginosis in pregnancy. The overall risk of PTB was not significantly reduced. This review provides little evidence that screening and treating all pregnant women with bacterial vaginosis will prevent PTB and its consequences. When screening criteria were broadened to include women with abnormal flora there was a 47% reduction in preterm birth, however, this is limited to two included studies."

Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2013, Issue 8.

Primary outcomes for the child include:

• Neurodevelopmental disability at follow‐up (blindness, deafness, moderate or severe cerebral palsy (however defined by authors), or developmental delay or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below population mean) or variously defined).

Primary outcomes for the child as an adult include:

• Neurodevelopmental disability at follow‐up (blindness, deafness, moderate or severe cerebral palsy (however defined by authors), or developmental delay or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below population mean), or variously defined.

Secondary outcomes for the child include:

• Cerebral palsy (however defined by authors);

"It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another. Dexamethasone may have some benefits compared with betamethasone, such as less IVH, and a shorter length of stay in the NICU. The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the suggestion that 12‐hour dosing may be as effective as 24‐hour dosing of betamethasone, based on one small trial, we were unable to make few other conclusions about optimal antenatal corticosteroid regimens. No long‐term results were available, except for a small subgroup of 18‐month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of dosages and other variations in treatment regimens."

Chawanpaiboon S, Laopaiboon M, Lumbiganon P, Sangkomkamhang US, Dowswell T. Terbutaline pump maintenance therapy after threatened preterm labour for reducing adverse neonatal outcomes. Cochrane Database of Systematic Reviews 2014, Issue 3.

Secondary outcomes for the neonate include:

• Neurological sequelae (general intelligence, hearing, vision, cerebral palsy, and disability).

"We found no evidence that terbutaline pump maintenance therapy decreased adverse neonatal outcomes. Taken together with the lack of evidence of benefit, its substantial expense, and the lack of information on the safety of the therapy, the evidence does not support its use in the management of arrested preterm labour. Future use should only be in the context of well‐conducted, adequately powered randomised controlled trials."

Cluett ER, Burns E. Immersion in water in labour and birth. Cochrane Database of Systematic Reviews 2009, Issue 2.

Primary outcomes for the neonate include:

• Neurological pathology, e.g. seizures, cerebral palsy.

"Evidence suggests that water immersion during the first stage of labour reduces the use of epidural or spinal analgesia and duration of the first stage of labour. There is limited information for other outcomes related to water use during the first and second stages of labour, due to intervention and outcome variability. There is no evidence of increased adverse effects to the fetus, neonate or woman from labouring in water or a water birth. However, the studies are very variable and considerable heterogeneity was detected for some outcomes. Further research is needed."

Devane D, Lalor JG, Daly S, McGuire W, Smith V. Cardiotocography versus intermittent auscultation of fetal heart on admission to labour ward for assessment of fetal well‐being. Cochrane Database of Systematic Reviews 2012, Issue 2.

Primary outcomes for the infant include:

• Severe neurodevelopmental disability assessed at greater than, or equal to, 12 months of age. We have defined severe neurodevelopmental disability as any one or a combination of the following: non‐ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory, and visual impairment. Development should have been assessed by means of a previously validated tool, such as Bayley Scales of Infant Development (Psychomotor Developmental Index and Mental Developmental Index).

"Contrary to continued use in some clinical areas, we found no evidence of benefit for the use of the admission cardiotocograph (CTG) for low‐risk women on admission in labour.

We found no evidence of benefit for the use of the admission CTG for low‐risk women on admission in labour. Furthermore, the probability is that admission CTG increases the caesarean section rate by approximately 20%. The data lacked power to detect possible important differences in perinatal mortality. However, it is unlikely that any trial, or meta‐analysis, will be adequately powered to detect such differences. The findings of this review support recommendations that the admission CTG not be used for women who are low risk on admission in labour. Women should be informed that admission CTG is likely associated with an increase in the incidence of caesarean section without evidence of benefit."

Dickinson H, Bain E, Wilkinson D, Middleton P, Crowther CA, Walker DW. Creatine for women in pregnancy for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2014, Issue 12.

Primary outcomes for the infant and child include:

• Death or any neurosensory disability (at latest time reported); this combined outcome recognises the potential for competing risks of death or survival with neurological problems.

• Neurosensory disability (any of cerebral palsy, blindness, deafness, developmental delay or intellectual impairment; at latest time reported).

Secondary outcomes for the infant/child include:

• Cerebral palsy (any, and graded as severe: including children who are non‐ambulant and are likely to remain so; moderate: including those children who have substantial limitation of movement; mild: including those children walking with little limitation of movement).

• Death or cerebral palsy.

• Major neurosensory disability (defined as any of: moderate or severe cerebral palsy, legal blindness, neurosensory deafness requiring hearing aids, or moderate or severe developmental delay, or intellectual impairment).

No included trials.

"As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a fetal neuroprotective role for creatine when administered to the mother during pregnancy, no trials assessing creatine in pregnant women for fetal neuroprotection have been published to date. If creatine is established as safe for the mother and her fetus, research efforts should first be directed towards randomised trials comparing creatine with either no intervention (ideally using a placebo), or with alternative agents aimed at providing fetal neuroprotection (including magnesium sulphate for the very preterm infant). If appropriate, these trials should then be followed by studies comparing different creatine regimens (dosage and duration of exposure). Such trials should be high quality and adequately powered to evaluate maternal and infant short and longer‐term outcomes (including neurodevelopmental disabilities, such as cerebral palsy), and should consider utilisation and costs of health care."

Dodd JM, Dowswell T, Crowther CA. Specialised antenatal clinics for women with a multiple pregnancy for improving maternal and infant outcomes. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes for the infant include:

• Disability at childhood follow‐up (including deafness, blindness, neurodisability, or cerebral palsy).

"There is currently limited information available from randomised controlled trials to assess the role of 'specialised' antenatal clinics for women with a multiple pregnancy compared with 'standard' antenatal care in improving maternal and infant health outcomes. The value of 'specialised' multiple pregnancy clinics in improving health outcomes for women and their infants requires evaluation in appropriately powered and designed randomised controlled trials."

Drakeley AJ, Roberts D, Alfirevic Z. Cervical stitch (cerclage) for preventing pregnancy loss in women. Cochrane Database of Systematic Reviews 2003, Issue 1.

Neonatal outcomes include:

• Infant and child development ‐ such as cerebral palsy; mental retardation, hearing and vision as assessed by paediatric follow‐up and attainment of developmental milestones (less than one year; less than two years; greater than two years.

"The use of a cervical stitch should not be offered to women at low or medium risk of mid trimester loss, regardless of cervical length by ultrasound. The role of cervical cerclage for women who have short cervix on ultrasound remains uncertain as the numbers of randomised women are too few to draw firm conclusions. There is no information available as to the effect of cervical cerclage or its alternatives on the family unit and long term outcome."

Duckitt K, Thornton S, O'Donovan OP, Dowswell T. Nitric oxide donors for treating preterm labour. Cochrane Database of Systematic Reviews 2014, Issue 5.

Primary outcomes for the infant include:

• Long‐term neurological development (general intelligence, hearing, vision, cerebral palsy, and disability, (serious infant outcome)).

"There is currently insufficient evidence to support the routine administration of nitric oxide donors in the treatment of threatened preterm labour."

Duley L, Gülmezoglu AM, Chou D. Magnesium sulphate versus lytic cocktail for eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 9.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"Magnesium sulphate, rather than lytic cocktail, for women with eclampsia reduces the risk ratio of maternal death, of further seizures and of serious maternal morbidity (respiratory depression, coma, pneumonia). Magnesium sulphate is the anticonvulsant of choice for women with eclampsia; the use of lytic cocktail should be abandoned."

Duley L, Henderson‐Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 10.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"Magnesium sulphate, rather than phenytoin, for women with eclampsia reduces the risk ratio of recurrence of seizures, probably reduces the risk of maternal death, and improves outcome for the baby. Magnesium sulphate is the drug of choice for women with eclampsia. The use of phenytoin should be abandoned."

Duley L, Henderson‐Smart DJ, Meher S. Altered dietary salt for preventing pre‐eclampsia, and its complications. Cochrane Database of Systematic Reviews 2005, Issue 4.

Outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"In the absence of evidence that advice to alter salt intake during pregnancy has any beneficial effect for prevention of pre‐eclampsia or any other outcome, salt consumption during pregnancy should remain a matter of personal preference."

Duley L, Henderson‐Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre‐eclampsia and its complications. Cochrane Database of Systematic Reviews 2007, Issue 2.

Outcomes for the child include:

• Infant and child development (such as cerebral palsy, cognitive delay, deafness, and blindness).

"Antiplatelet agents, largely low‐dose aspirin, have moderate benefits when used for prevention of pre‐eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose."

Duley L, Henderson‐Smart DJ, Walker GJA, Chou D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 12.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"Magnesium sulphate for women with eclampsia reduces the risk ratio of maternal death and of recurrence of seizures, compared with diazepam."

Duley L, Matar HE, Almerie MQ, Hall DR. Alternative magnesium sulphate regimens for women with pre‐eclampsia and eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 8.

Secondary outcomes for the baby include:

• Development in childhood: including cerebral palsy and major neurodevelopmental delay.

"Although strong evidence supports the use of magnesium sulphate for prevention and treatment of eclampsia, trials comparing alternative treatment regimens are too small for reliable conclusions."

Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database of Systematic Reviews 2013, Issue 7.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"Until better evidence is available, the choice of antihypertensive should depend on the clinician's experience and familiarity with a particular drug; on what is known about adverse effects; and on women's preferences. Exceptions are nimodipine, magnesium sulphate (although this is indicated for women who require an anticonvulsant for prevention or treatment of eclampsia), diazoxide and ketanserin, which are probably best avoided."

Duley L, Williams J, Henderson‐Smart DJ. Plasma volume expansion for treatment of pre‐eclampsia. Cochrane Database of Systematic Reviews 1999, Issue 4.

Outcomes for the baby include:

• Measures of infant and child development (such as cerebral palsy).

"There is insufficient evidence for any reliable estimates of the effects of plasma volume expansion for women with pre‐eclampsia."

Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DNM. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2014, Issue 6.

Primary outcomes include:

• Serious infant outcome (defined as death or chronic lung disease (need for supplemental oxygen at 28 days of life or later), grade three or four intraventricular haemorrhage or periventricular leukomalacia, major neurosensory disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment (defined as developmental quotient (DQ) or intelligence quotient (IQ) less than two standard deviations below mean))).

"This review did not demonstrate superiority of oxytocin receptor antagonists (ORA; largely atosiban) as a tocolytic agent compared with placebo, betamimetics, or calcium channel blockers (CCB; largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths, and more births before completion of 28 weeks of gestation in one placebo‐controlled study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well‐designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side‐effect profile than betamimetics) are needed. Consideration of further placebo‐controlled studies seems warranted. Future studies of tocolytic agents should measure all important short‐ and long‐term outcomes for women and infants, and costs."

Flenady V, Wojcieszek AM, Papatsonis DNM, Stock OM, Murray L, Jardine LA, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database of Systematic Reviews 2014, Issue 6.

Primary outcomes include:

• Serious infant outcome (defined as death or chronic lung disease (need for supplemental oxygen at 28 days of life or later), grade three or four intraventricular haemorrhage (IVH) or periventricular leukomalacia (PVL), major neurosensory disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment (defined as developmental quotient (DQ) or intelligence quotient (IQ) less than two standard deviations below mean))).

Secondary outcomes for the infant or child include:

• Blindness, deafness, cerebral palsy.

"Calcium channel blockers (CCB; mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth, thus, theoretically allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer‐term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well‐designed tocolytic trials are required to determine short‐ and longer‐term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence), and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer‐term effects into early childhood, and also costs."

Grivell RM, Alfirevic Z, Gyte GML, Devane D. Antenatal cardiotocography for fetal assessment. Cochrane Database of Systematic Reviews 2015, Issue 9.

Secondary outcomes include:

• Cerebral palsy at 12 months.

"There is no clear evidence that antenatal CTG improves perinatal outcome, but further studies focusing on the use of computerised CTG in specific populations of women with increased risk of complications are warranted."

Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired fetal growth. Cochrane Database of Systematic Reviews 2012, Issue 6.

Secondary outcomes for the infant include:

• Cerebral palsy.

"There is limited evidence from randomised controlled trials to inform best practice for fetal surveillance regimens when caring for women with pregnancies affected by impaired fetal growth. More studies are needed to evaluate the effects of currently used fetal surveillance regimens in impaired fetal growth."

Haas DM, Morgan AM, Deans SJ, Schubert FP. Ethanol for preventing preterm birth in threatened preterm labor. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes for the fetus, neonate, or infant include:

• Serious infant outcome (defined as death or chronic lung disease (need for supplemental oxygen at 28 days of life or later), grade three or four intraventricular hemorrhage or periventricular leukomalacia, major neurosensory disability (defined as any of: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment (defined as developmental quotient (DQ) or intelligence quotient (IQ) less than two standard deviations below mean))).

"This review is based on evidence from twelve studies, which were mostly low quality. There is no evidence to suggest that ethanol is an effective tocolytic compared to placebo. There is some evidence that ethanol may be better tolerated than other tocolytics (in this case betamimetics), but this result is based on few studies and small sample sizes and therefore, should be interpreted with caution. Ethanol appears to be inferior to betamimetics for preventing preterm birth in threatened preterm labor. Ethanol is generally no longer used in current practice, due to safety concerns for the mother and her baby. There is no need for new studies to evaluate the use of ethanol for preventing preterm birth in threatened preterm labour. However, it would be useful for long‐term follow‐up studies on the babies born to mothers from the existing studies, in order to assess the risk of long‐term neurodevelopmental status."

Heazell AEP, Whitworth M, Duley L, Thornton JG. Use of biochemical tests of placental function for improving pregnancy outcome. Cochrane Database of Systematic Reviews 2015, Issue 11.

Secondary outcomes for the baby include:

• Neurodevelopment in childhood (cerebral palsy, neurodevelopmental delay).

"There is insufficient evidence to support the use of biochemical tests of placental function to reduce perinatal mortality or increase identification of small‐for‐gestational‐age infants. However, we were only able to include data from two studies that measured oestrogens and hPL. The quality of the evidence was low or very low. Two of the trials were performed in the 1970s, on women with a variety of antenatal complications, and this evidence cannot be generalised to women at low‐risk of complications or groups of women with specific pregnancy complications (e.g. fetal growth restriction). Furthermore, outcomes described in the 1970s may not reflect what would be expected at present. For example, neonatal mortality rates have fallen substantially, such that an infant delivered at 28 weeks would have a greater chance of survival were those studies repeated; this may affect the primary outcome of the meta‐analysis. With data from just two studies (740 women), this review is underpowered to detect a difference in the incidence of death of a baby or the frequency of a small‐for‐gestational‐age infant, as these have a background incidence of approximately 0.75% and 10% of pregnancies, respectively. Similarly, this review is underpowered to detect differences between serious or rare adverse events, such as severe neonatal morbidity. Two of the three included studies were quasi‐randomised, with significant risk of bias from group allocation. Additionally, there may be performance bias, as in one of the two studies contributing data, participants receiving standard care did not have venipuncture, so clinicians treating participants could identify which arm of the study they were in. Future studies should consider more robust randomisation methods and concealment of group allocation, and should be adequately powered to detect differences in rare adverse events. The studies identified in this review examined two different analytes: oestrogens and hPL. There are many other placental products that could be employed as surrogates of placental function, including: placental growth factor (PlGF), human chorionic gonadotrophin (hCG), plasma protein A (PAPP‐A), placental protein 13 (PP‐13), pregnancy‐specific glycoproteins, and progesterone metabolites, and further studies should be encouraged to investigate these other placental products. Future randomised controlled trials should test analytes identified as having the best predictive reliability for placental dysfunction leading to small‐for‐gestational‐age infants and perinatal mortality."

Jahanfar S, Jaafar SH. Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes. Cochrane Database of Systematic Reviews 2015, Issue 6.

Secondary outcomes include:

• Cerebral palsy and cognitive impairment.

"There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high‐quality, double‐blinded RCTs to determine whether caffeine has any effect on pregnancy outcome."

Khanprakob T, Laopaiboon M, Lumbiganon P, Sangkomkamhang US. Cyclo‐oxygenase (COX) inhibitors for preventing preterm labour. Cochrane Database of Systematic Reviews 2012, Issue 10.

Secondary neonatal outcomes include:

• Long‐term outcomes, for example developmental delay, cerebral palsy, educational attainment, etc.

"There was very little evidence about using COX‐inhibitors for preventing preterm labour. There are inadequate data to make any recommendation about using COX‐inhibitor in practice to prevent preterm labour. Future research should include follow‐up of the babies to examine the short‐term and long‐term effects of COX inhibitors."

Lalor JG, Fawole B, Alfirevic Z, Devane D. Biophysical profile for fetal assessment in high risk pregnancies. Cochrane Database of Systematic Reviews 2008, Issue 1

Outcomes for the infant include:

• Disability to include non‐ambulant cerebral palsy at or after 12 months of age, sensory impairment (visual, hearing), or both

"At present, there is insufficient evidence from randomised trials to support the use of biophysical profile (BPP) as a test of fetal well‐being in high‐risk pregnancies."

Li W, Tang L, Wu T, Zhang J, Liu GJ, Zhou L. Chinese herbal medicines for treating pre‐eclampsia. Cochrane Database of Systematic Reviews 2006, Issue 2.

Secondary outcomes for the neonate include:

• Measures of long‐term growth and development, such as important impairment and cerebral palsy.

No included trials.

"The efficacy and safety of Chinese herbal medicines for treating pre‐eclampsia remains unclear. There are no randomised controlled trials in this field. High‐quality randomised controlled trials are urgently required."

Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre‐eclampsia or intrauterine growth restriction. Cochrane Database of Systematic Reviews 2006, Issue 3.

Outcomes for the baby include:

• Long‐term follow‐up included measures of neurological and developmental outcome (such as cerebral palsy).

"There is not enough evidence to support the routine use of marine oil, or other prostaglandin precursors, supplements during pregnancy to reduce the risk of pre‐eclampsia, preterm birth, low birthweight, or small‐for‐gestational age."

McNamara HC, Crowther CA, Brown J. Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour. Cochrane Database of Systematic Reviews 2015, Issue 12.

Primary outcomes for the infant or child include:

• Composite serious infant outcome (defined as death or chronic lung disease (oxygen requirement at 28 days of life or later); intraventricular haemorrhage (IVH; grade three or four), or periventricular leuco malacia (PVL); major neurosensory disability (defined as any of legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below the mean)).

Secondary outcomes for the child include:

• Cerebral palsy (mild, moderate, or severe, evaluated separately).

"There are limited data available (three studies, with data from only two studies) comparing different dosing regimens of magnesium sulphate given as single agent tocolytic therapy for the prevention of preterm birth. There is no evidence examining duration of therapy, timing of therapy, and the role for repeat dosing. Downgrading decisions for our primary outcome of fetal, neonatal, and infant death were based on wide confidence intervals (crossing the line of no effect), lack of blinding, and a limited number of studies. No data were available for any of our other important outcomes: birth less than 48 hours after trial entry; composite serious infant outcome; composite serious maternal outcome. The data are limited by volume and the outcomes reported. Only eight of our 45 pre‐specified primary and secondary maternal and infant health outcomes were reported on in the included studies. No long‐term outcomes were reported. Downgrading decisions for the evidence on the risk of respiratory distress were based on wide confidence intervals (crossing the line of no effect), and lack of blinding. There is some evidence from a single study, suggesting a reduction in the length of stay in the neonatal intensive care unit and a reduced risk of respiratory distress syndrome, where a high‐dose regimen of magnesium sulphate has been compared with a low‐dose regimen. However, given that evidence has been drawn from a single study (with a small sample size), these data should be interpreted with caution. Magnesium sulphate has been shown to be of benefit in a wide range of obstetric settings, although it has not been recommended for tocolysis. In clinical settings where health benefits are established, further trials are needed to address the lack of evidence regarding the optimal dose (loading dose and maintenance dose), duration of therapy, timing of therapy, and role for repeat dosing, in terms of efficacy and safety for mothers and their children. Ongoing examination of different regimens with respect to important health outcomes is required."

Meher S, Duley L. Rest during pregnancy for preventing pre‐eclampsia and its complications in women with normal blood pressure. Cochrane Database of Systematic Reviews 2006, Issue 2.

Outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"Daily rest, with or without nutrient supplementation, may reduce the risk of pre‐eclampsia for women with normal blood pressure, although the reported effect may reflect bias, random error, or both, rather than a true effect. There is no information about outcomes such as perinatal mortality and morbidity, maternal morbidity, women's views, adverse effects, and costs. Current evidence is insufficient to support recommending rest or reduced activity to women for preventing pre‐eclampsia and its complications. Whether women rest during pregnancy should therefore be a matter of personal choice."

Meher S, Duley L. Progesterone for preventing pre‐eclampsia and its complications. Cochrane Database of Systematic Reviews 2006, Issue 4.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"There is insufficient evidence for reliable conclusions about the effects of progesterone for preventing pre‐eclampsia and its complications. Therefore, progesterone should not be used for this purpose in clinical practice at present."

Meher S, Duley L. Nitric oxide for preventing pre‐eclampsia and its complications. Cochrane Database of Systematic Reviews 2007, Issue 2.

Outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"There is insufficient evidence to draw reliable conclusions about whether nitric oxide donors and precursors prevent pre‐eclampsia or its complications."

Meher S, Duley L. Garlic for preventing pre‐eclampsia and its complications. Cochrane Database of Systematic Reviews 2006, Issue 3.

Outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"There is insufficient evidence to recommend increased garlic intake for preventing pre‐eclampsia and its complications. Although garlic is associated with odour, other more serious side‐effects have not been reported. Further large randomised trials evaluating the effects of garlic are needed before any recommendations can be made to guide clinical practice."

Meher S, Duley L. Exercise or other physical activity for preventing pre‐eclampsia and its complications. Cochrane Database of Systematic Reviews 2006, Issue 2.

Outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"There is insufficient evidence for reliable conclusions about the effects of exercise on prevention of pre‐eclampsia and its complications."

Naik Gaunekar N, Raman P, Bain E, Crowther CA. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. Cochrane Database of Systematic Reviews 2013, Issue 10.

Primary outcomes include:

• Any neurological disability at paediatric follow‐up (impairment of vision, hearing, intelligence, or cerebral palsy).

"Based on the current available evidence, maintenance treatment with a calcium channel blocker after threatened preterm labour does not prevent preterm birth or improve maternal or infant outcomes."

Nanda K, Cook LA, Gallo MF, Grimes DA. Terbutaline pump maintenance therapy after threatened preterm labor for preventing preterm birth. Cochrane Database of Systematic Reviews 2002, Issue 4.

Outcomes for the infant include:

• Neurological sequelae (general intelligence, hearing, vision, cerebral palsy, and disability).

"Terbutaline pump maintenance therapy has not been shown to decrease the risk of preterm birth by prolonging pregnancy. Furthermore, the lack of information on the safety of the therapy, as well as its substantial expense, argues against its role in the management of arrested preterm labor. Future use should only be in the context of well‐conducted, adequately powered randomized controlled trials."

Neilson JP. Fetal electrocardiogram (ECG) for fetal monitoring during labour. Cochrane Database of Systematic Reviews 2015, Issue 12.

Secondary outcomes for the fetus include:

• Cerebral palsy.

"The modest benefits of fewer fetal scalp samplings during labour (in settings in which this procedure is performed) and fewer instrumental vaginal births have to be considered against the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings. We found little strong evidence that ST‐waveform analysis had an effect on the primary outcome measures in this systematic review. There was a lack of evidence showing that PR‐interval analysis improved any outcomes; and a larger future trial may possibly demonstrate beneficial effects. There is little information about the value of fetal ECG waveform monitoring in preterm fetuses in labour. Information about long‐term development of the babies included in the trials would be valuable."

Nguyen TMN, Crowther CA, Wilkinson D, Bain E. Magnesium sulphate for women at term for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2013, Issue 2.

Primary outcomes for the infant or child include:

• Death or cerebral palsy.

• Cerebral palsy (abnormality of tone with motor dysfunction (as diagnosed at 18 months of age or later)).

Secondary outcomes for the child include:

• Any neurological disabilities (defined as developmental delay or intellectual impairment, blindness (corrected visual acuity worse than 6/60 in the better eye), deafness (hearing loss requiring amplification or worse), cerebral palsy, motor dysfunction). The severity of the disability due to cerebral palsy will be graded into severe, moderate, and mild. Severe disability will include children who are non‐ambulant and are likely to remain so, moderate disability will comprise those children who have substantial limitation of movement, and mild disability will comprise those children walking with little limitation of movement. The neurosensory disabilities imposed by the various sensorineural impairments will be classified as severe, moderate, and mild, as follows: Severe disability will comprise any of severe cerebral palsy, an intelligence quotient (IQ) less than three standard deviations (SD) below the mean, or blindness. Moderate disability will comprise moderate cerebral palsy, deafness, or an IQ from minus three SD to less than two SD below the mean. Mild disability will comprise mild cerebral palsy or an IQ from minus two SD to less than one SD below the mean.

• Major neurological disability (defined as any of: legal blindness, neurosensory deafness requiring hearing aids, moderate or severe cerebral palsy, or moderate or severe developmental delay or intellectual impairment (defined as developmental quotient or IQ less than two SD below the mean)).

"There is currently insufficient evidence to assess the efficacy and safety of magnesium sulphate when administered to women for neuroprotection of the term fetus. As there has been recent evidence for the use of magnesium sulphate for neuroprotection of the preterm fetus, high‐quality randomised controlled trials are needed to determine the safety profile and neurological outcomes for the term fetus. Strategies to reduce maternal side effects during treatment also require evaluation."

Ohlsson A, Shah VS, Stade BC. Vaginal chlorhexidine during labour to prevent early‐onset neonatal group B streptococcal infection. Cochrane Database of Systematic Reviews 2014, Issue 12.

Secondary intellectual impairment outcomes include:

• Long‐term neurological sequelae, which may include cognitive delay, cerebral palsy, cortical blindness, deafness, hydrocephalus, or a combination.

"The quality of the four included trials varied, as did the risk of bias, and the quality of the evidence using GRADE, was very low. Vaginal chlorhexidine was not associated with reductions in any of the primary outcomes of early‐onset GBS disease (sepsis, meningitis, or both), or GBS pneumonia. Vaginal chlorhexidine may reduce GBS colonization of neonates. The intervention was associated with an increased risk of maternal mild adverse effects. The review currently does not support the use of vaginal disinfection with chlorhexidine in labour for preventing early‐onset disease. Results should be interpreted with caution as the methodological quality of the studies was poor. As early‐onset GBS disease is a rare condition, trials with very large sample sizes are needed to assess the effectiveness of vaginal chlorhexidine, to reduce its occurrence. In the era of intrapartum antibiotic prophylaxis, such trials may be difficult to justify, especially in developed countries."

Papatsonis DNM, Flenady V, Liley HG. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database of Systematic Reviews 2013, Issue 10.

Primary outcomes include:

• Perinatal or infant mortality, or any neurological disability at long‐term paediatric follow‐up at two years of age (vision impairment, sensorineural deafness requiring hearing aids, cerebral palsy, or developmental delay or intellectual impairment).

"There is insufficient evidence to support the use of oxytocin receptor antagonists to inhibit preterm birth after a period of threatened or actual preterm labour. Any future trials using oxytocin antagonists or other drugs as maintenance therapy for preventing preterm birth should examine a variety of important infant outcome measures, including reduction of neonatal morbidity and mortality, and long‐term infant follow‐up. Future research should also focus on the pathophysiological pathways that precede preterm labour."

Phipps H, de Vries B, Hyett J, Osborn DA. Prophylactic manual rotation for fetal malposition to reduce operative delivery. Cochrane Database of Systematic Reviews 2014, Issue 12.

Secondary outcomes for the neonate and infant include:

• Severe neurodevelopmental disability in infants (assessed at 12 months of age or older), defined as any one or combination of the following: non‐ambulant cerebral palsy, severe developmental delay assessed using validated tools, auditory and visual impairment.

"Currently, there is insufficient evidence to determine the efficacy of prophylactic manual rotation early in the second stage of labour for prevention of operative delivery. One additional study is ongoing. Further appropriately designed trials are required to determine the efficacy of manual rotation."

Reinebrant HE, Pileggi‐Castro C, Romero CLT, dos Santos RAN, Kumar S, Souza JP, et al. Cyclo‐oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database of Systematic Reviews 2015, Issue 6.

Primary outcomes include:

• Serious infant outcome ‐ death or major sensorineural disability at two years of age (defined as any one or more of the following: legal blindness, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy, or developmental delay or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below the mean)).

"In this review, no clear benefit for COX inhibitors was shown over placebo or any other tocolytic agents. While some benefit was demonstrated in terms of postponement of birth for COX inhibitors over placebo and betamimetics, and also maternal adverse effects over betamimetics and MgSO4, due to the limitations of small numbers, minimal data on safety, lack of longer‐term outcomes, and generally low quality of the studies included in this review, we conclude that there is insufficient evidence on which to base decisions about the role of COX inhibition for women in preterm labour. Further well‐designed tocolytic studies are required to determine short‐ and longer‐term infant benefit of COX inhibitors over placebo and other tocolytics, particularly CCBs and ORAs. Another important focus for future studies is identifying whether COX‐2 inhibitors are superior to non‐selective COX inhibitors. All future studies on tocolytics for women in preterm labour should assess longer‐term effects into early childhood and also costs."

Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxidants for preventing pre‐eclampsia. Cochrane Database of Systematic Reviews 2008, Issue 1.

Secondary outcomes for the child include:

• Disability during childhood (such as cerebral palsy, intellectual disability, hearing disability, and visual impairment).

"Evidence from this review does not support routine antioxidant supplementation during pregnancy to reduce the risk of pre‐eclampsia and other serious complications in pregnancy."

Rumbold A, Ota E, Hori H, Miyazaki C, Crowther CA. Vitamin E supplementation in pregnancy. Cochrane Database of Systematic Reviews 2015, Issue 9.

Secondary outcomes for the neonate include:

• Disability at childhood follow‐up (such as cerebral palsy, intellectual disability, hearing disability, and visual impairment).

"The data do not support routine vitamin E supplementation in combination with other supplements for the prevention of stillbirth, neonatal death, preterm birth, pre‐eclampsia, preterm or term PROM, or poor fetal growth. Further research is required to elucidate the possible role of vitamin E in the prevention of placental abruption. There was no convincing evidence that vitamin E supplementation in combination with other supplements results in other important benefits or harms."

Rumbold A, Ota E, Nagata C, Shahrook S, Crowther CA. Vitamin C supplementation in pregnancy. Cochrane Database of Systematic Reviews 2015, Issue 9.

Secondary outcomes for the child include:

• Disability at childhood follow‐up (such as cerebral palsy, intellectual disability, hearing disability, and visual impairment).

"The data do not support routine vitamin C supplementation alone or in combination with other supplements, for the prevention of fetal or neonatal death, poor fetal growth, preterm birth, or pre‐eclampsia. Further research is required to elucidate the possible role of vitamin C in the prevention of placental abruption and pre‐labour rupture of membranes. There was no convincing evidence that vitamin C supplementation alone or in combination with other supplements results in other important benefits or harms."

Shub A, Walker SP. Planned early delivery versus expectant management for monoamniotic twins. Cochrane Database of Systematic Reviews 2015, Issue 4.

Secondary outcomes for the infant include:

• Cerebral palsy.

No included trials.

"Monoamniotic twins are rare, and there is insufficient randomised controlled evidence on which to draw strong conclusions about the best management. In their absence, we can refer to historical case series and expert consensus. Management plans should take into consideration the availability of high‐quality neonatal care if early delivery is chosen. Women and their families should be involved in the decision‐making about these high‐risk pregnancies. Ongoing, multicentre audits of maternal and perinatal outcomes for monoamniotic twins are needed in order to inform families and clinicians about up‐to‐date perinatal outcomes with contemporary obstetric practice. Research should consider the social and economic implications of planned interventions, as well as the perinatal outcomes."

Spencer L, Bubner T, Bain E, Middleton P. Screening and subsequent management for thyroid dysfunction pre‐pregnancy and during pregnancy for improving maternal and infant health. Cochrane Database of Systematic Reviews 2015, Issue 9.

Primary outcomes for the infant as a child include:

• Neurosensory disability (any of: cerebral palsy, blindness, deafness, developmental delay, intellectual impairment, at latest time reported).

Secondary outcomes for the infant as a child include:

• Cerebral palsy.

"Though universal screening versus no screening for hypothyroidism similarly increased diagnosis and subsequent treatment, no clear difference was seen for the primary outcome: neurosensory disability for the infant as a child (IQ less than 85 at three years); data were lacking for the other primary outcomes: pre‐eclampsia and preterm birth, and for the majority of secondary outcomes, including miscarriage and fetal or neonatal death. For outcomes assessed using the GRADE approach, the evidence was considered to be moderate or high quality, with any downgrading of the evidence based on the presence of wide confidence intervals crossing the line of no effect.

More evidence is needed to assess the benefits or harms of different screening methods for thyroid dysfunction in pregnancy, on maternal, infant and child health outcomes. Future trials should assess impacts on use of health services and costs, and be adequately powered to evaluate the effects on short‐ and long‐term outcomes."

Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P, Ota E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database of Systematic Reviews 2015, Issue 6.

Secondary outcomes for the neonate pre‐specified include:

• Childhood cerebral palsy.

"Antibiotic prophylaxis did not reduce the risk of preterm pre‐labour rupture of membranes or preterm delivery (apart from in the subgroup of women with a previous preterm birth who had bacterial vaginosis). Antibiotic prophylaxis given during the second or third trimester of pregnancy reduced the risk of postpartum endometritis, term pregnancy with pre‐labour rupture of membranes and gonococcal infection when given routinely to all pregnant women. Substantial bias possibly exists in the review's results because of a high rate of loss to follow‐up, and the small numbers of studies included in each of our analyses. There is also insufficient evidence on possible harmful effects on the baby. Therefore, we conclude that there is not enough evidence to support the use of routine antibiotics during pregnancy to prevent infectious adverse effects on pregnancy outcomes."

Turnbull C, Osborn DA. Home visits during pregnancy and after birth for women with an alcohol or drug problem. Cochrane Database of Systematic Reviews 2012, Issue 1.

Outcomes for the infant or child include:

• Disability (cerebral palsy, sensorineural impairment, or significant developmental delay).

"There is insufficient evidence to recommend the routine use of home visits for pregnant or postpartum women with a drug or alcohol problem. Further large, high‐quality trials are needed."

Utama DP, Crowther CA. Transplacental versus direct fetal corticosteroid treatment for accelerating fetal lung maturation where there is a risk of preterm birth. Cochrane Database of Systematic Reviews 2011, Issue 9.

Secondary outcomes for the infant or child include:

• Cerebral palsy (however defined by authors).

No included trials.

"The available clinical studies carried out so far on animals and humans have shown that direct intramuscular injection of corticosteroid into the fetus under ultrasound guidance is feasible, but data on health outcomes are lacking. Therefore, uncertainty persists as to which method could provide better efficacy and safety profile. Randomised controlled trials are required, focusing on the benefits and harms of transplacental versus direct fetal corticosteroid treatment. Until the uncertainties have been answered, it is advisable to stay with the current standard of antenatal transplacental maternally administered corticosteroid treatment."

Vogel JP, Nardin JM, Dowswell T, West HM, Oladapo OT. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database of Systematic Reviews 2014, Issue 7.

Primary outcomes include:

• Short‐term and long‐term serious infant outcome (see definition below), determined by the presence of any of the following: death; chronic lung disease (use of supplemental oxygen therapy at 36 weeks' postmenstrual age, or at 28 days of life, or later); grade three or four intraventricular haemorrhage or periventricular leukomalacia; major sensorineural disability at two years of age, defined as any one or more of the following: severe or profound vision impairment, sensorineural deafness requiring hearing aids, moderate or severe cerebral palsy or developmental delay or intellectual impairment (defined as developmental quotient or intelligence quotient less than two standard deviations below the mean).

"It is unclear whether a combination of tocolytic drugs for preterm labour is more advantageous for women, newborns, or both, due to a lack of large, well‐designed trials including the outcomes of interest. There are no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine), oxytocin receptor antagonists (atosiban), or both. Further trials are needed before specific conclusions on use of combination tocolytic therapy for preterm labour can be made."

Waterfall H, Grivell RM, Dodd JM. Techniques for assisting difficult delivery at caesarean section. Cochrane Database of Systematic Reviews 2016, Issue 1.

Secondary outcomes for the infant include:

• Cerebral palsy.

"There is currently insufficient information available from randomised trials to support or refute the routine or selective use of tocolytic agents or instrument to facilitate infant birth at the time of difficult caesarean section. There is limited evidence that reverse breech extraction may improve maternal and fetal outcomes, though there was no difference in primary outcome of infant birth trauma. Further randomised controlled trials are needed to answer these questions."

Whitworth M, Quenby S. Prophylactic oral betamimetics for preventing preterm labour in singleton pregnancies. Cochrane Database of Systematic Reviews 2008, Issue 1.

Primary outcomes include:

• Death at childhood follow‐up at greater than, or equal to, 12 months of age (corrected for preterm birth), or severe neurodevelopmental disability defined as any one or combination of the following: non‐ambulant cerebral palsy, developmental delay (developmental quotient less than 70, or more than two standard deviations below the mean), severe auditory impairment (sensorineural deafness requiring hearing aids), or visual impairment (legal blindness).

"There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women at high risk of preterm labour with a singleton pregnancy."

Whitworth M, Quenby S, Cockerill RO, Dowswell T. Specialised antenatal clinics for women with a pregnancy at high risk of preterm birth (excluding multiple pregnancy) to improve maternal and infant outcomes. Cochrane Database of Systematic Reviews 2011, Issue 9.

Secondary outcomes for the infant include:

• Disability at childhood follow‐up (including deafness, blindness, neurodisability, or cerebral palsy).

"Specialised antenatal clinics are now an accepted part of care in many settings, and carrying out further randomised trials may not be possible. Any future research in this area should include psychological outcomes, and should focus on which aspects of service provision are preferred by women. Such research could underpin further service development in this area."

Wilkinson D, Shepherd E, Wallace EM. Melatonin for women in pregnancy for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2016, Issue 3.

Primary outcomes for the infant or child include:

• Death or any neurosensory disability (at latest time reported); this combined outcome recognises the potential for competing risks of death or survival with neurological problems.

• Neurosensory disability (any of: cerebral palsy, blindness, deafness, developmental delay or intellectual impairment), at latest time reported.

Secondary outcomes for the infant or child include:

• Cerebral palsy (any, and graded as: severe: including children who are non‐ambulant and are likely to remain so; moderate: including those children who have substantial limitation of movement; mild: including those children walking with little limitation of movement).

• Death or cerebral palsy.

• Major neurosensory disability (defined as any of: moderate or severe cerebral palsy, legal blindness, neurosensory deafness requiring hearing aids, or moderate or severe developmental delay or intellectual impairment).

No included trials.

"As we did not identify any randomised trials for inclusion in this review, we are unable to comment on implications for practice at this stage. Although evidence from animals studies has supported a fetal neuroprotective role for melatonin when administered to the mother during pregnancy, no trials assessing melatonin for fetal neuroprotection in pregnant women have been completed to date. However, there is currently one ongoing randomised controlled trial (with an estimated enrolment target of 60 pregnant women), which examines the dose of melatonin, administered to women at risk of imminent, very preterm birth (less than 28 weeks' gestation), required to reduce brain damage in the white matter of the babies that were born very preterm. Further high‐quality research is needed, and research efforts should be directed towards trials comparing melatonin with either no intervention (no treatment or placebo), or with alternative agents aimed at providing fetal neuroprotection (such as magnesium sulphate for the very preterm infant). Such trials should evaluate maternal and infant short‐ and longer‐term outcomes (including neurosensory disabilities such as cerebral palsy), and consider the costs of care."

Woudstra DM, Chandra S, Hofmeyr GJ, Dowswell T. Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database of Systematic Reviews 2010, Issue 9.

Secondary outcomes for the child include:

• Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay, and cerebral palsy.

"There was no clear evidence of any effect of corticosteroids on substantive clinical outcomes. Those receiving steroids showed significantly greater improvement in platelet counts, which was greater for those receiving dexamethasone than those receiving betamethasone. There is to date, insufficient evidence of benefits in terms of substantive clinical outcomes to support the routine use of steroids for the management of HELLP. The use of corticosteroids may be justified in clinical situations in which increased rate of recovery in platelet count is considered clinically worthwhile."

Yamasmit W, Chaithongwongwatthana S, Tolosa JE, Limpongsanurak S, Pereira L, Lumbiganon P. Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database of Systematic Reviews 2015, Issue 12.

Secondary outcomes for the neonate or infant include:

• Abnormal neurodevelopmental status at more than 12 months corrected age (developmental delay, cerebral palsy, or both).

"There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy."