Adverse effects of interventions

S Thangaratinam; E Rogozińska; K Jolly; S Glinkowski; W Duda; E Borowiack; T Roseboom; J Tomlinson; J Walczak; R Kunz; BW Mol; A Coomarasamy; KS Khan

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Thangaratinam S, Rogozińska E, Jolly K, et al. Interventions to Reduce or Prevent Obesity in Pregnant Women: A Systematic Review. Southampton (UK): NIHR Journals Library; 2012 Jul. (Health Technology Assessment, No. 16.31.)

4Adverse effects of interventions

Study selection

From a systematic search of the literature to identify the maternal and fetal adverse effects of weight management interventions in pregnancy, 14,832 potentially relevant records were obtained (up to 31 March 2011). A search of the reference lists of the relevant articles led to the identification of 26 further citations. After reviewing the abstracts, the full texts of 180 papers were obtained for detailed assessment. After exclusion of 154 publications, 26 papers were included in the review. Figure 35 provides details of the process of study selection.

Of the included studies, two were RCTs (involving 277 women)¹²⁹^,¹³² and 24 were observational studies (19 cohort studies and five case–control studies, involving 468,581 women).⁶³^,⁶⁴^,⁶⁷^,⁶⁸^,⁷⁰^,⁷³^–⁷⁷^,⁸⁰^,⁸⁵^,⁸⁹^,¹³³^–¹⁴³ The studies evaluated the effect of dietary, physical activity and other lifestyle interventions in pregnancy on maternal and fetal outcomes. Appendices 7 and 10 provide details of the included RCTs and observational studies, respectively, that assessed the adverse effects of outcomes.

Quality of the included studies

Randomised controlled trials

The quality of the two included RCTs¹²⁹^,¹³² is shown in Figure 36. The details regarding sequence generation, allocation concealment and blinding for subjective outcomes were unclear in both studies. A detailed quality assessment of the included RCTs is provided in Appendix 8.

Observational studies

The 24 observational studies included 19 cohort studies and five case–control studies.⁶³^,⁶⁴^,⁶⁷^,⁶⁸^,⁷⁰^,⁷³^–⁷⁷^,⁸⁰^,⁸⁵^,⁸⁹^,¹³³^–¹⁴³ The quality assessment of the cohort and case–control studies is summarised in Appendix 9. The studies, evaluated using NOS, could score a maximum of nine stars, with four stars for selection, two for comparison and three for outcome assessment. In total, 3/19 (15.8%) cohort studies had a low risk of bias and scored seven or more stars; 16/19 (84.2%) had a medium risk of bias and scored between four and six stars.

Results

The adverse outcomes included in the review were defined as those that occurred unintentionally with potential harm to the mother or baby. We also included those outcomes that may have been the direct result of the intervention itself, for example risk of preterm delivery due to strenuous physical exercise.

Randomised clinical trials

The two RCTs¹²⁹^,¹³² were conducted in women already planning to exercise in pregnancy and pregnant athletes. Kulpa et al.¹²⁹ reported on the outcomes of meconium-stained amniotic fluid, uterine atony and chorioamnionitis. Estimated RRs for the above outcomes were 0.62 (95% CI 0.20 to 1.90; p = 0.40), 0.93 (95% CI 0.22 to 3.89; p = 0.92) and 3.69 (95% CI 0.15 to 88.13; p = 0.42) respectively. Bell and Palma¹³² evaluated the effect of vigorous exercise in pregnancy (exercising five or more times per week) on the risk of reduction in birthweight. There was no difference in birthweight between the vigorous exercise group and the control group.

Observational studies

A total of 18 studies⁶⁸^,⁷³^–⁷⁶^,⁸⁰^,⁸⁵^,⁸⁹^,¹³³^–¹³⁹^,¹⁴¹^–¹⁴³ observed the effect of diet on maternal and fetal outcomes. The majority of the included studies produced data on the effects of a severe reduction in caloric intake in extreme conditions such as war or famine (Table 7). The studies on physical activity included women undergoing exercises of various intensities or other recreational physical activity in pregnancy. The rates of congenital abnormalities such as neural tube defects (NTDs) were observed in those following dietary interventions that aimed to significantly reduce weight¹³³ or in those intaking food with a very high- or a very low-glycaemic index.¹⁴³ The risks of coronary artery disease, metabolic syndrome, breast cancer and diabetes were studied in infants born to mothers who were severely diet restricted owing to famine.⁶⁸^,¹³⁵^,¹³⁹

The observational studies on physical activity in pregnancy did not show any significant adverse maternal or fetal outcomes. This was consistently observed for different activities of varying severity.

The detailed clinical characteristics of the included studies for the evaluation of adverse effects are provided in Appendix 10.

Summary

The review of adverse effects identified two RCTs and a relatively large number of observational studies. The data from the observational studies showed a possible association between extremes of diet (exposure to famine) and adverse outcomes; however, there was no evidence to suggest that dietary interventions evaluated in the review or currently offered in clinical practice could be associated with adverse maternal or fetal outcomes. Physical activity in pregnancy and maternal and fetal outcomes were studied in the randomised trials and observational studies. Various forms of physical activity such as structured exercises, running and recreational activities of differing intensities were not associated with adverse maternal and fetal outcomes.

The strength of the review is the systematic search for evidence using a broad search strategy. The inclusion of both randomised and non-randomised data including case series has ensured that the review identifies the evidence for all potential adverse effects of interventions. The review was limited by the RCTs being of poor quality. A large proportion of the evidence from the observational studies was devoted to extremes of diet rather than the components of a balanced healthy diet. There was insufficient evidence on popular diets such as the Atkins diet, the Slimming World diet and ‘high-protein’ diets. The studies on physical activity in pregnancy were mainly concerned with cord abnormalities and abnormal fetal heart rate patterns. The data from RCTs on women undergoing physical activity in pregnancy show no effect on gestational age at delivery or preterm delivery provide reassuring evidence on the safety of these interventions for these outcomes.

Figures

FIGURE 35Flow chart of study identification and selection for the evaluation of adverse maternal and fetal outcomes

FIGURE 36Quality of the included RCTs for the adverse effects review

Tables

TABLE 7Adverse outcomes associated with any diet or physical activity in pregnancy

Outcome	Study	Characteristics of intervention or exposure	Types of intervention	Total N	Intervention or exposure (n/N)	Control (n/N)	OR or HR (95% CI)
NTD	Carmichael 2003¹³³	Diet to lose weight	Diet	1077	29/538	14/539	OR 2.1 (1.1 to 4.1)^a
		Fasting diet			17/538	3/539	OR 5.8 (1.7 to 20.0)^a
		Other special diet			17/538	3/539	OR 1.0 (0.3 to 3.1)^a
		Eating disorder			18/538	11/539	OR 1.7 (0.8 to 3.6)^a
		Any special diet or eating disorder			61/538	31/539	OR 2.1 (1.3 to 3.3)^a
		Binge eating (self-reported dieting behaviour for any time during 3 months before pregnancy or during pregnancy)			36/538	44/539	OR 0.8 (0.5 to 1.3)^a
NTD	Yazdy 2010¹⁴³	Glycaemic index low < 60	Diet	1394	522/698	594/696	OR 2.0 (1.5 to 2.6)^a
		Glycaemic index high ≥ 60			176/698	102/696	OR 1.5 (1.1 to 2.0)^b
		Glycaemic load low < 205			668/698	683/696	OR 2.4 (1.2 to 4.6)^a
		Glycaemic load high ≥ 205			30/698	13/696	OR 1.8 (0.8 to 4.0)^b
		Glycaemic index low < 60		Subgroup BMI ≥ 30 kg/m² (100)	23/36	53/64	OR 2.7 (1.1 to 7.0)^a
		Glycaemic index high ≥ 60			13/36	11/64	OR 2.0 (0.6 to 7.3)^b
		Glycaemic load low < 205			32/36	59/64	OR 1.5 (0.4 to 5.9)^a
		Glycaemic load high ≥205			4/36	5/64	OR 0.9 (0.2 to 4.7)^b
		Glycaemic index low < 60		Subgroup BMI < 30 kg/m² (816)	138/185	540/631	OR 2.0 (1.4 to 3.0)^a
		Glycaemic index high ≥ 60			47/185	91/631	OR 1.7 (1.1 to 2.7)^b
		Glycaemic load low < 205			177/185	623/631	OR 3.8 (1.4 to 10.5)^a
		Glycaemic load high ≥ 205			8/185	8/631	OR 3.3 (1.0 to 10.6)^b
Cord abnormalities	Magann 2002⁷⁷	Exercise: various intensities	Physical activity	750
		Light			15/222	18/217	OR 0.80 (0.39 to 1.63)^a
		Moderate			7/73		OR 1.17 (0.47 to 2.93)^a
		Heavy			9/238		OR 0.43 (0.19 to 0.99)^a
Coronary heart disease (adult)	Roseboom 2000¹³⁹	Diet: famine	Diet	736
		Exposed in late gestation			3/120	6/232	Exposed in late gestation vs not exposed prenatally: OR 0.8 (0.2 to 2.8)
		Exposed in mid-gestation			1/108	8/208	Exposed in mid-gestation: OR 3.0 (0.0 to 2.2)
		Exposed in early gestation			6/68		Exposed early gestation: OR 3.0 (1.1 to 8.0)
	de Rooij 2006¹³⁴	Diet: famine	Diet	694			OR 0.79 (0.42 to 1.49)^a
Metabolic syndrome (adult)	de Rooij 2007⁶⁸	Diet: famine	Diet	783			OR 1.2 (0.9 to 17)
Metabolic syndrome (adult)	de Rooij 2006¹³⁴	Diet: famine	Diet	694			OR 1.09 (0.78 to 1.51)^a
Hypertension (adult)	Lumey 2009⁷⁶	Diet: famine	Diet	638	224/344	168/294	OR 1.40 (1.02 to 1.93)^a
Breast cancer	Painter 2008¹³⁵	Diet: famine	Diet	475			HR (all exposed) 2.6 (0.9 to 7.7)^a
		Exposed in late gestation			3/82	1/126	HR 2.6 (0.9 to 7.7)^b
		Exposed in mid-gestation			3/77	4/144	HR 2.5 (0.8 to 7.4)^b
		Exposed in early gestation			4/46		HR 4.0 (1.1 to 14.5)^b
Cleft lip, cleft palate or both	Vujkovic 2007¹⁴²	Diet: Western vs prudent	Diet	381
		Western (by tertile)
		T1 (127)			58/203	69/178	T1: ref.
							T2: OR 1.3 (0.8 to 2.2)^a
							T3: OR 1.9 (1.2 to 3.1)^a
		T2 (127)			67/203	60/178	T2: OR 1.2 (0.7 to 2.1)^b
		T2 (127)			67/203	60/178	T3: OR 1.7 (1.0 to 3.0)^b
		T3 (127)			78/203	49/178	T2: OR 1.2 (0.8 to 2.1)^b
		T3 (127)			78/203	49/178	T3: OR 1.8 (1.0 to 2.9)^b
		Prudent (by fertile)
		T1 (127)			68/203	59/178	T1: ref.
							T2: OR 0.9 (0.5 to 1.4)^a
							T3: OR 1.1 (0.7 to 1.8)^a
		T2 (127)			64/203	63/178	T2: OR 0.8 (0.5 to 1.4)^b
		T2 (127)			64/203	63/178	T3: OR 1.3 (0.8 to 1.8)^b
		T3 (127)			71/203	56/178	T2: OR 0.7 (0.5 to 1.2)^b
		T3 (127)			71/203	56/178	T3: OR 1.0 (0.6 to 1.7)^b
Antisocial personality disorder	Neugebauer 1999⁸⁰	Diet: famine, western Holland	Diet	76,630
		By trimester
		First, second or third			26/14,310	50/45,007	OR 1.6 (1.02 to 2.6)
							OR 2.0 (1.2 to 3.3)^b
		First and/or second			20/9252		OR 2.0 (1.2 to 3.5)
							OR 2.5 (1.5 to 4.2)^b
		First only			6/2443		OR 2.2 (0.95 to 5.0)
							OR 2.9 (1.2 to 6.7)^b
		First and second only			6/2223		OR 2.4 (1.04 to 5.7)
							OR 3.0 (1.3 to 7.0)^b
		Second only			9/4586		OR 1.8 (0.9 to 3.6)
							OR 2.1 (1.03 to 4.4)^b
		Thirrd only			5/5058		OR 0.9 (0.4 to 2.2)
							OR 1.1 (0.4 to 2.7)^b
		By severity
		Severely exposed			26/14,310	50/45,007	OR 1.9 (1.02 to 2.6)
							OR 2.0 (1.2 to 3.3)^b
		Moderately exposed			10/9615		OR 0.9 (0.6 to 1.9)
							OR 0.7 (0.3 to 1.6)^b
Dyslipidaemia (adult)	Lumey 2009⁷⁶	Diet: famine	Diet	638	96/344	85/294	OR 0.95 (0.61 to 1.34)^a
Obesity (adult)	Ravelli 1976¹³⁶	Diet: famine (by trimester)	Diet	307,700
		Third			51/6200	148/11,200	OR 0.62 (0.45 to 0.85)^a
		Second and third			126/7500	286/17,600	OR 1.03 (0.84 to 1.28)^a
		First and second			119/4300	230/15,900	OR 1.94 (1.55 to 2.43)^a
		First			41/2500	162/10,500	OR 1.06 (0.75 to 1.50)^a
IGT or type 2 diabetes (adult)	Stanner 1997¹⁴¹	Diet: famine	Diet	357
Known diabetes					4/169	7/188	OR 0.63 (0.18 to 2.18)^a
Newly diagnosed diabetes					3/169	5/188	OR 0.66 (0.16 to 2.81)^a
IGT					16/169	16/188	OR 1.12 (0.54 to 2.32)^a
	Ravelli 1998¹³⁷	Diet: famine	Diet	702
		Exposed in late gestation			24/116	33/221	General: OR 1.19 (0.79 to 1.79)^a
		Exposed in mid-gestation			14/100	30/202
		Exposed in early gestation			10/63
Meconium in fluid	Clapp 1990⁶⁴	Physical activity: exercise regularly or at > 50% of their preconceptional level throughout pregnancy	Physical activity	131	12/87	11/44	OR 0.48 (0.19 to1.20)^a
Abnormal heart rate	Clapp 1990⁶⁴	Physical activity: exercise regularly or at > 50% of their preconceptional level throughout pregnancy	Physical activity	131	12/87	11/44	OR 0.48 (0.19 to 1.20)^a
Nuchal cord	Clapp 1990⁶⁴	Physical activity: exercise regularly or at > 50% of their preconceptional level throughout pregnancy	Physical activity	131	23/87	24/44	OR 0.30 (0.14 to 0.64)^a
Threatened abortion	Dale 1982⁶⁷	Physical activity: running	Physical activity	33	1/21	1/11	OR 0.50 (0.03 to 8.85)^a
Chorioamnionitis secondary to prolonged rupture of membranes	Dale 1982⁶⁷	Physical activity: running	Physical activity	33	0/21	1/11	OR 0.16 (0.01 to 4.35)^a
Asphyxia/meconium staining/fetal distress	Dale 1982⁶⁷	Physical activity: running	Physical activity	33	0/21	4/11	OR 0.04 (0.00 to 0.81)
Sepsis	Dale 1982⁶⁷	Physical activity: running	Physical activity	33	0/21	1/11	OR 0.16 (0.01 to 4.35)^a

: HR, hazard ratio; IGT, impaired glucose tolerance.
a: Unadjusted value.
b: Adjusted value.

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