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Child Neuropsychology: A Journal on Normal and Abnormal Development in Childhood and Adolescence Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncny20

Pregnancy complications and neuropsychological outcomes: A review a

Gwendolyn Gerner & Ida Sue Baron

b

a

Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA b

Pediatric Neuropsychology Research, Fairfax Neonatal Associates at Inova Children’s Hospital, Falls Church, VA, USA Published online: 07 May 2014.

To cite this article: Gwendolyn Gerner & Ida Sue Baron (2014): Pregnancy complications and neuropsychological outcomes: A review, Child Neuropsychology: A Journal on Normal and Abnormal Development in Childhood and Adolescence, DOI: 10.1080/09297049.2014.910301 To link to this article: http://dx.doi.org/10.1080/09297049.2014.910301

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Child Neuropsychology, 2014 http://dx.doi.org/10.1080/09297049.2014.910301

Pregnancy complications and neuropsychological outcomes: A review Gwendolyn Gerner1 and Ida Sue Baron2 Downloaded by [New York University] at 10:08 01 October 2014

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Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA 2 Pediatric Neuropsychology Research, Fairfax Neonatal Associates at Inova Children’s Hospital, Falls Church, VA, USA Pregnancy complications elevate risk of associated adverse medical, socioenvironmental, and behavioral outcomes in children. These are likely to have a substantial impact on neuropsychological functioning and mental health across the child’s lifespan. Thus, an understanding of the complex relationships between pregnancy complications and neuropsychological outcomes is critical for both practitioners and researchers. This review summarizes prevalent pregnancy complications and the associated psychological and neuropsychological findings, highlighting methodological challenges that have restricted investigations of these outcomes and identifying opportune areas for future study. Keywords: Pregnancy; Complications; Psychology; Neuropsychology; Outcomes.

Pregnancy complications and subsequent medical, neurodevelopmental, and neuropsychological complications in offspring represent a public health concern in the United States secondary to substantial health care costs, lost earnings of working parents, and provision of therapeutic and special education services for affected children (March of Dimes, 2013). In the United States, prevalent neonatal outcomes following complicated pregnancies include preterm birth (12.3%), low birth weight (8.2%), and infant mortality (6.7%) (March of Dimes, 2010). Intensive care for at-risk mothers and fetuses is crucial and may attenuate neonatal mortality and complications (Lasswell, Barfield, Rochat, & Blackmon, 2010; Samuelson, Buehler, Norris, & Sadek, 2002); however, intensive care is often inaccessible for many who would benefit, along with limited accessibility to High Risk Perinatal units caring for the most at-risk pregnant women and their fetuses. Of further concern, 1 of 24 live births in the United States in 2010 (4.3%) were born to women who received no prenatal care (March of Dimes, 2010). While outcome studies of the long-term effects of pregnancy complications in offspring have been sparse, there is evidence of persistent lifelong medical, neurodevelopmental, and neuropsychological problems. An understanding of pregnancy complications Gwendolyn Gerner’s research was supported by the National Institute of Child Health and Development, 5T32HD007414-18. Address correspondence to Gwendolyn Gerner, Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, 716 N. Broadway, Baltimore, MD 21205, USA. E-mail: [email protected]

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and the associated outcomes is critical for neuropsychologists and other professionals tasked with clinically evaluating these children and young adults. Neuropsychologists are particularly well positioned to conduct research in this area. Therefore, the aim of the present review is to summarize the medical, neurodevelopmental, and neuropsychological outcomes of offspring following fetal exposure to the most prevalent complications of pregnancy.

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METHODS Mesh and Keyword terms and phrases were searched for the concepts of pregnancy complications and prenatal exposure delayed effects and then combined with terms for hypertension, diabetes, infection, nutrition, and obesity. The search was limited to studies written in English. This search from the inception of this database to November 15, 2013, produced 4,763 potential results. Upon review, a total of 91 citations were included in this study. Preclinical and clinical studies were reviewed along with references from key papers. The review was limited to studies written in English. RESULTS Prevalent Pregnancy Complications The most common pregnancy complications associated with early neonatal complications and risk of later neuropsychological problems include hypertensive disorders, diabetes, and infection. Additional influences that tend to mediate and moderate pregnancy complications and subsequent neuropsychological complications in offspring include maternal obesity and inadequate nutrition. Hypertensive Disorders. Hypertensive disorders are an especially prevalent medical complication of pregnancy, occurring in 5–10% of all pregnancies (Cunningham et al., 2010). Hypertensive disorder terminology applies to a range of related conditions, including chronic hypertension, gestational hypertension, preeclampsia, chronic hypertension with superimposed pre-eclampsia, eclampsia, and haemolysis elevated liver enzymes and low platelets (HELLP) syndrome (Cunningham et al., 2010). Hypertensive disorders are the principal etiology for about 16% of maternal deaths in industrialized nations (Khan, Wojdyla, Say, Gülmezoglu, & Van Look, 2006), and frequently a correlate of fetal mortality (Hutcheon, Lisonkova, & Joseph, 2011). Pregnancies complicated by hypertensive disorders are at greater risk of an induced late preterm birth (34 to 36 weeks gestation) and neonatal low birth weight (Himmelman, Himmelman, Niklasson, & Svensson, 1996; Whitehouse, Robinson, Newnham, & Pennell, 2012). Intrauterine growth restriction secondary to placental abnormalities has also been reported (Beauharnais, Roberts, & Wexler, 2012; Gray, O’Callaghan, Harvey, Burke, & Payton, 1999). Neonates born to mothers whose pregnancies were complicated by pre-eclampsia are at an increased risk of neonatal infection (adjusted Odds Ratio [aOR] = 2.3; 95% CI, 1.2–4.3) and intracranial bleeding (aOR = 3.2; 95% CI, 2.1–5.0), even after adjusting for other maternal confounds (Cruz, Gao, & Hibbard, 2011). Neuropsychological and psychological long-term morbidities following pregnancies complicated by hypertensive disorders have been understudied and inconclusive (Table 1).

ICD-9 Codes at Hospital Discharge or on Death Register

ICD-9 codes from Medicaid billing files; Department of Education Classifications; Department of Disabilities and Special Needs Classifications Stanford Binet Intelligence Scales

Tuovinen et al. (2012) Gestational Hypertension

Pre-eclampsia & Eclampsia

Type 1 Diabetes & Gestational Diabetes

Griffith et al. (2011)

Persson & Gentz (1984)

Neuropsychological & Psychological Outcome Measures Child Behavior Checklist Externalizing & Internalizing Problem Indices (T ≥ 70)

Pregnancy Complication

Robinson et al. (2009) Gestational Hypertension

Authors

Children (4–5 years)

Children (3–15 years)

Adults

Children (2–14 years)

Age Group

Table 1 Risk of Neuropsychological and Psychological Problems by Pregnancy Complication.

N = 39 (type I diabetes) N = 17 (gestational diabetes)

N = 1,636

N = 5,970 (3,131 men; 2,839 women)

N = 1644 (8 y) N = 1627 (10 y); N = 1040 (14 y)

N=?

Findings

(Continued )

No increased risk of lower IQ after exposure to Type 1 Diabetes or Gestational Diabetes

Risk of Intellectual Disability after exposure to Preeclampsia: OR = 1.28 (CI: 1.07–1.52, p = .0057)

Risk of Anxiety Disorder after exposure to Gestational Hypertension: RR = 1.39 (CI: 0.99–1.93, p = .05

Risk of Mood Disorder after exposure to Gestational Hypertension: RR = 1.44 (CI: 1.11–1.88, p = .007)

Risk of Any Mental Disorder after exposure to Gestational Hypertension: RR = 1.19 (CI: 1.01–1.41, p = .04)

Age 14 yrs. OR = 2.30 (95% CI, 1.04–5.08, p = .04)

Association between Gestational Hypertension and Externalizing Problems: Age 8 yrs. OR = 2.30 (95% CI, 1.36–3.88, p = .002)

Association between Gestational Hypertension and Internalizing Problems: Age 10 yrs. OR = 1.59 (95% CI, 1.05–2.41, p = .3)

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Gestational Diabetes McArthur Communicative Children Development Inventory-Short (18–72 Form; adapted PPVT; months) Experimental Communication Questionnaire for Teachers Children in any age group falling below 15th percentile on any two measures were classified as having language impairment

Gestational Diabetes ADHD RS-IV; Kiddie Schedule for Children Affective Disorders and (3–6 years) Schizophrenia-Present and Lifetime Version (Kiddie SADSPL); NEPSY; Wechsler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III); Temperament Assessment Batter for Children, Revised (TABC-R); Behavior Assessment System for Children, 2nd edition (BASC-2)

Marks et al. (2012)

N=?

No increased risk of lower IQ following exposure to Type 1 Diabetes after adjusting for maternal age, parity, smoking during pregnancy, sex, and participant age at followup

Findings

N = 212

(Continued )

At 6 years: Exposure to Gestational Diabetes was associated with increased risk of ADHD for children exposed to gestational diabetes and low SES (OR = 14.31; 95% CI 2.14–95.88, p =.006)

At 3–4 years: Exposure to Gestational Diabetes was associated with significantly worse language, visuospatial, and memory performance on the NEPSY; significantly lower Verbal and Full Scale IQ on WPPSI-III; significantly worse inhibition, impulsivity, and persistence on TABC-R

N = 861 (18 months, After Pooling the Samples (Twins and twins only); Singletons) of the association between N = 764 (30 months, Gestational Diabetes and Language twins only); Impairment: N = 955 (30 months, OR = 2.2 (95% CI, 1.4–3.5) twins & singletons); N = 1728 (42 months, twins & singletons); N = 721 (60 months, twins only); N = 833 (72 months; twins only)

Adults N = 158 (18–27 years)

Age Group

Dionne et al. (2008)

Wechsler Adult Intelligence Scale

Neuropsychological & Psychological Outcome Measures

Type 1 Diabetes

Pregnancy Complication

Clausen et al. (2011)

Authors

Table 1 (Continued).

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Chorioamnionitis

Versland et al. (2006)

Wechsler Preschool and Primary Scale of Intelligence, revised edition (WPPSI-R); Wechsler Intelligence Scale for Children, revised editon (WISC-R)

ICD-9 Codes for Cerebral Palsy

Neuropsychological & Psychological Outcome Measures N = 688 cases N = 3068 controls

N=?

Children N = 13 born preterm with (5 years & 11 chorioamnionitis years) exposure N = 117 born preterm without chorioamnionitis exposure

Children (≥ 6 years)

Age Group

Age 11 years: Significant group differences in PIQ (p =.04), but no significant differences in VIQ or FSIQ

Age 5 years: No significant group differences in VIQ, PIQ, or FSIQ

Exposure to perinatal Urinary Tract Infection was associated with Cerebral Palsy by group: No significantly increased risk in full-term neonates (OR = 2.2, 95% 0.9–5.1) Significantly increased risk in preterm neonates (OR = 4.8, 95% CI 1.2–18.3)

Exposure to perinatal chorioamnionitis was associated with Cerebral Palsy by group: No significantly increased risk in full-term neonates (OR = 1.8, 95% CI 0.8–4.4) Significantly increased risk in preterm neonates (OR = 3.6, 95% 1.5–8.4)

Findings

Note. OR = Odds Ration; RR = Risk Ration; FSIQ = Full-Scale Intelligence Quotient; PIQ = Performance Intelligence Quotient; VIQ = Verbal Intelligence Quotient; y = years; N = Study Sample Size.

Bacterial Infections

Pregnancy Complication

Neufeld, Frigon, Graham, and Mueller (2005)

Authors

Table 1 (Continued).

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Some investigators have reported associations with low cognitive ability (Many et al., 2003); however, gestational age at birth, birth weight, sex, and placental insufficiency are factors that may mediate this relationship (Griffith, Mann, & McDermott, 2011; van Wassenaer et al., 2011). One study that controlled for these factors reported associations between hypertensive disorders of pregnancy and reduced performance on a measure of receptive language and a proxy of general cognitive ability (Peabody Picture Vocabulary Test, Revised) in offspring at 10 years of age (Whitehouse et al., 2012). Another study found significant associations between hypertensive pregnancies and intellectual disability when controlling for the above-mentioned factors (Griffith et al., 2011). Increased risk of behavior problems, mood, and anxiety disorders in late childhood and adulthood also has been reported in the offspring of women whose pregnancies were complicated by hypertensive disorder (Robinson et al., 2009; Tuovinen et al., 2012).

Diabetes. Maternal diabetes, whether diagnosed prior to or during pregnancy, has associated pregnancy complications that may result in adverse neuropsychological and psychological sequelae in offspring. Diabetes Mellitus Type 1 and gestational diabetes are both associated with excessive weight gain during pregnancy and an increased risk of preterm birth (35.8% rate of preterm birth in pregnancies complicated by diabetes vs. 7.4% rate of preterm birth in nondiabetic pregnancies), intrauterine growth restriction, and hypoxic-ischemic injury (Hawdon, 2011; McCance, 2011). These complications of diabetes may be related to dysmaturity of the placenta (Beauharnais et al., 2012; Evers, de Valk, & Visser, 2004; Evers, Nikkels, Sikkema, & Visser, 2003). Maternal Type 2 diabetes occurs in approximately 20% of pregnancies and is associated with placental infarcts and comorbid hypertensive disorders (Beauharnais et al., 2012). Type 2 diabetes is also associated with a bimodal distribution of the neonate’s birth weight, either low birth weight ( 4,000 g or above the 90th percentile for gestational age) (Michlin et al., 2000). Some reports indicate an increased risk of stillbirth (OR = 1.40; 95% CI = 1.14–1.71), neural tube defects (OR = 3.5; 95% CI = 1.2–10.3), and congenital heart abnormalities (OR = 2.0; 95% CI = 1.2–3.4) among offspring of women who were obese prior to and during pregnancy (Andreasen, Andersen, & Schantz, 2004; Andreasen et al., 2004; Baeten, Bukusi, & Lambe, 2001; Frøen et al., 2001; Sebire et al., 2001; Watkins, Rasmussen, Honein, Botto, & Moore, 2003). Associations between maternal obesity during pregnancy and neuropsychological and psychological effects in offspring are likely mediated by other pregnancy and delivery complications associated with obesity, such as gestational diabetes and pre-eclampsia. Obstructed labor among obese mothers is one causative factor in fetal and neonatal asphyxia (Hawdon, 2011; Michlin et al., 2000) and subsequent neonatal encephalopathy (Jolly, Sebire, Harris, Regan, & Robinson, 2003). Adverse long-term neuropsychological

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outcomes after severe asphyxia in the perinatal period include intellectual disability, epilepsy, cerebral palsy, sensorineural hearing loss, and cortical visual impairment (American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy and Cerebral Palsy, American College of Obstetric and Gynecologists, & American Academy of Pediatrics, 2003; Robertson & Finer, 1993). After mild-tomoderate perinatal asphyxia, there are reports of memory, attentional, and executive function impairment related to injury to the hippocampus and striatum (de Haan, Mishkin, Baldeweg, & Vargha-Khadem, 2006; de Haan, Wyatt, Roth, Vargha-Khadem, Gadian, & Mishkin, 2006; Lindström, Lagerroos, Gillberg, & Fernell, 2006; Marlow, Rose, Rands, & Draper, 2005). Certain psychiatric disorders also have been reported in individuals with a history of mild-to-moderate perinatal asphyxia, including attention deficit/hyperactivity disorder, autism spectrum disorder, and schizophrenia (de Haan, Wyatt, et al., 2006; DeLong, 1992; Lou, 1996). It remains unclear whether obesity prior to the perinatal period has direct effects on later neuropsychological and psychological functioning in offspring. Any potential direct effects of obesity during pregnancy on neuropsychological and psychological effects in offspring may be better understood within the context of nutrition factors during pregnancy, as discussed below.

Nutritional Factors. The importance of good nutrition during pregnancy is well documented yet difficult to study since researchers necessarily rely on participant selfreport of nutritional intake (e.g., diet diaries) and due to individual differences in synthesis of vitamins and micronutrients. The ethical implications should an investigator manipulate the nutrient intake of pregnant women further complicates study design in this area of research. Therefore, much of the research conducted about nutritional factors and their effects is preclinical. Overall, proper nutritional intake throughout pregnancy is important, and malnutrition during pregnancy increases risk of intrauterine growth restriction and low birth weight (De Prins & Van Assche, 1982; Garofano, Czernichow, & Bréant, 1998; International Dietary Energy Consultancy Group [IDECG], 1997; Mavalankar, Trivedi, & Gray, 1994). More specifically, appropriate levels of vitamins and micronutrients are important for optimal fetal development, including iron, zinc, iodine, and long chain n-3 polyunsaturated fatty acids that are especially important in fetal nervous system development. Micronutrients important for development of neonatal and childhood immune functioning include vitamins A and D, zinc, vitamins B-6, B-12, C, E, and fatty acids, while folic acid may reduce oxidative stress to the placenta and support effective transport of nutrients and oxygen between the mother and fetus (Cetin, Berti, & Calabrese, 2010; McArdle & Ashworth, 1999). Preclinical studies have demonstrated that deprivation of essential nutrients and micronutrients affects brain development and leads to adverse neurobehavioral outcomes (Ranade et al., 2008). For example, deficits in spatial learning were observed in rat pups exposed to global caloric restriction during pregnancy, while reference memory was negatively affected in rat pups exposed to iron deficiency only, and working memory was most negatively impacted by in utero protein deficiency (Ranade et al., 2008). Antenatal and early postnatal iron deprivation in rats delayed maturation of subcortical white matter tracts, compared with controls, and resulted in slower reflexes, slower sensorimotor processing, and impaired recognition memory (Wu et al., 2008).

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Neurochemical changes in the rat hippocampus secondary to iron deprivation during fetal development have also been reported (Carlson, Stead, Neal, Petryk, & Georgieff, 2007; Rao, Tkac, Townsend, Gruetter, & Georgieff, 2003), as have adverse consequences affecting dopaminergic pathway function in the neonatal period and potentially across the lifespan, even after supplementation and normalization of blood iron levels (Beard et al., 2006; Felt et al., 2006). Among primates exposed to iron deficiency during gestation, increased impulsivity, nervousness, and lability of mood have been observed (Golub, Hogrefe, & Germann, 2007; Golub et al., 2006). In humans, low cord blood iron decreases arousal and increases irritability during the neonatal period (Lozoff, Wolf, Urrutia, & Viteri, 1985; Wachs, Pollitt, Cueto, Jacoby, & Creed-Kanashiro, 2005). Neuropsychological and psychological outcomes at age 10 years in children who had decreased cord blood iron compared to controls included worse performance on measures of motor function, selective attention, academic achievement for reading, writing, and math, and there was an increased risk of both internalizing and externalizing behavior problems. These differences remained significant even when controlling for sex, maternal IQ, and socioeconomic status (Lozoff et al., 1985). Other preclinical studies suggest that maternal consumption of saturated fats is an influential dietary factor during pregnancy. Offspring of overweight mice fed high-fat diets had less brain-derived neurotrophic factor (BDNF) in the hippocampus and impaired spatial learning before adulthood (Tozuka et al., 2010). A high-fat diet also increases neuroinflammation and results in slowed spatial learning and anxious behavior across the lifespan (Bilbo & Tsang, 2010). The mechanism by which a high-fat diet leads to neuroinflammation appears to be the activation of inflammatory cytokines in the mother that are then transmitted to the fetus, subsequently affecting the development of melanocortinergic (Grayson et al., 2010; Scarlett et al., 2007), serotonergic (Sullivan et al., 2010), and dopaminergic systems (Naef et al., 2008). Notably, these three systems of neurotransmission are frequently implicated in neuropsychiatric disorders that persist across the lifespan. CONCLUSIONS AND FUTURE DIRECTIONS The most rapid period of neurological development across the human lifespan occurs during the fetal period. Therefore, fetuses are particularly vulnerable to adverse medical, behavioral, and socioenvironmental complications during their gestation. Understanding the types of pregnancy complications that arise and the implications for long-term neuropsychological sequelae in offspring is a critical knowledge base for neuropsychologists, who can be expected to evaluate and treat many of these children and adults. However, to date, there has been sparse empirical investigations of neuropsychological outcomes secondary to the most common pregnancy complications. Those studies conducted highlight extremely complex relationships, often within the context of small sample sizes, making conclusions difficult to interpret. Alternatively, epidemiological studies with large sample sizes highlight associations or risks for developing particular psychiatric conditions within the context of specific pregnancy complications but do not provide a detailed profile of neuropsychological function. Some studies that examined neuropsychological outcomes following pregnancy complications were retrospective and relegated to clinical databases, thus limiting the research variables that can be utilized and ultimately the research questions that can be answered. Finally, research directly examining neuropsychological outcomes secondary to pregnancies complicated

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by obesity, or within the context of nutritional deficiencies, is extremely limited. Examination of the relationship between maternal obesity during pregnancy and outcomes has mostly been restricted to medical outcomes. Research in the area of nutritional variables is extremely difficult given the ethical implications of manipulating dietary factors and extreme variations in the diets of pregnant mothers in naturalistic or observational studies. In the future, carefully designed large-scale longitudinal studies are required in order to systematically investigate neuropsychological outcomes of offspring following specific pregnancy complications. Furthermore, these studies will need to better delineate potential moderating variables, including sex, parental level of education, socioeconomic status, and ethnic background (van Wassenaer et al., 2011), as these likely influence the relationship between any pregnancy complication and its related neuropsychological outcome. Such an approach to examining neuropsychological outcomes of offspring following complicated pregnancies hold the greatest promise to provide the most comprehensive understanding of childhood and adult development subsequent to pregnancy complications and to appreciate the complex interplay between individual vulnerability and effective adaptation across the lifespan. Original manuscript received July 8, 2013 Revised manuscript accepted March 27, 2014 First published online May 9, 2014

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