Obstetric Outcomes in Women with Nonalcoholic Fatty Liver Disease

Abstract

Background:

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the Western world and yet there is little research into its impact on pregnancy.

Methods:

A literature review was conducted in the database PubMed, with articles published between 1990 and 2017. The selected studies addressed features specifically attributed to NAFLD and associated obstetric and neonatal outcomes. Nine studies met criteria. Our aim was to consolidate the limited literature and identify trends.

Results:

There was considerable heterogeneity in the diagnostic approach to NAFLD. Data are conflicting as to whether NAFLD increases the risk of gestational diabetes independent of obesity. NAFLD is associated with an elevated risk of extremes of birth weight, both small and large for gestational age. Several studies found a greater impact of NAFLD on maternal morbidity including preeclampsia in women with a body mass index <30kg/m².

Conclusions:

NAFLD appears to be associated with increased obstetric morbidity, particularly among non-obese women. More research is needed to clarify the pathophysiology and optimize safe treatment.

Introduction

Nonalcoholic fatty liver disease (NAFLD) has been recognized as the most common chronic liver disease in the Western world, with a prevalence estimated at 10%–35% in the United States and 20%–30% in unselected European populations.^1,2 NAFLD encompasses a spectrum of fatty liver disease that ranges from simple steatosis to steatosis with inflammation and fibrosis, which can progress to cryptogenic cirrhosis.³ In most cases, fatty liver does not progress to more severe liver disease and only 20%–30% of NAFLD patients have signs of fibrosis and necroinflammation signaling nonalcoholic steatohepatitis (NASH).⁴ However, the clinical course has significant implications for patient mortality and morbidity because once cirrhosis develops, patients are at risk of hepatic decompensation and death from a liver-related cause.^5,6 Moreover, the risk of hepatocellular carcinoma in NAFLD-related cirrhosis appears to be similar to the risk associated with alcohol and hepatitis C infection.⁷ In women of childbearing age, NAFLD prevalence is estimated at 10%.² However, little is known about the fetal impact of this disease. This literature review aims to present and synthesize the available data examining the obstetric and fetal outcomes of women with suspected and established NAFLD.

Noninvasive Diagnosis of NAFLD

While the gold standard diagnostic test for NAFLD is liver biopsy demonstrating fatty liver infiltration, both the morbidity of biopsy and the possibility of missed diagnosis given the nonuniform distribution of fatty change have prompted research into noninvasive modalities.⁸ Researchers have investigated the performance characteristics of both radiographic and serologic proxies for biopsy. The primary laboratory abnormality seen in NAFLD patients is elevated serum aspartate aminotransferase and alanine aminotransferase (ALT) levels, with increased ALT levels corresponding more closely with hepatic fat accumulation.⁹ In 2016, the European Association for the Study of the Liver, Diabetes, and Obesity released Clinical Practice Guidelines that recommended screening every person with suspected metabolic syndrome or type 2 diabetes for NAFLD using at minimum liver function tests (LFTs) alone or, if possible, nested in a validated prediction model such as the Fatty Liver Index (waist circumference, triacylglycerols, and gamma-glutamyl transpeptidase) or the Steatotest^®.¹⁰ However, the utility of abnormal values as a screening test is limited, given that up to 50% of individuals with NAFLD have normal ALT values.^11,12 Epidemiologic work has found a linear relationship between LFTs and risk of metabolic syndrome.¹³ In sum, LFTs may be a reasonable marker, but precise parameters for assessing NAFLD risk are unclear.

As a radiographic alternative to biopsy, the current data best support the use of ultrasound (US) or magnetic resonance imaging (MRI). Ultrasonography is the less expensive and more accessible of the two and has a reported sensitivity of 64% and specificity of 97%, which increases to 89.7% and 100%, respectively, in patients with greater than 30% steatosis.¹⁴ According to the World Gastroenterology Organisation, no imaging modality can accurately identify steatosis if it is present in less than one third of the hepatic parenchyma.¹⁵ To improve on this, many groups have looked into US elastography, MRI, and positron emission tomography and found improved sensitivity and specificity.¹⁶ MRI is generally considered the most accurate technique in diagnosing and quantifying the level of hepatic steatosis, with sensitivity and specificity of 100% and 92.3%, respectively.¹⁷ However, the cost of MRI and elastrography methods makes them thus far untenable as screening modalities.

Pregnancy, Obesity, and Metabolic Syndrome

The impact of the spectrum of metabolic diseases on pregnancy, maternal, and fetal outcomes has been well described. Various studies have identified elevated obstetric risks with maternal obesity, including spontaneous abortion [odds ratio (OR) 1.2; 95% confidence interval (CI) 1.01–1.46], gestational diabetes (GDM) [adjusted odds ratio (aOR) 2.6; 95% CI 2.1–3.4], pre-eclampsia (aOR 1.6; 95% CI 1.1–2.25), gestational hypertension (aOR 2.5; 95% CI 2.1–3.0), and stillbirth [adjusted hazard ratio (HR) 1.4; 95% CI 1.3–1.5].^18
–20 Furthermore, maternal metabolic derangement appears to affect the uterine milieu as fetuses of obese mothers appear to be at an increased risk of birthweight over 4500 g (OR 2.0; 95% CI 1.4–3.0) and growth restriction.^19,21 In addition, offspring of obese women may be at risk of future metabolic syndrome and childhood obesity even after adjusting for confounders such as family socioeconomic status, behavior, activity level, and diet.²²

Independent features of metabolic syndrome also incur maternal morbidity. Maternal hyperlipidemia is associated with an increased risk of pre-eclampsia, infant birthweight over 90%ile for age, and pregnancy-induced hypertension.^23
–25 Diabetes mellitus in pregnancy has well-established adverse obstetric and neonatal outcomes; both pre-existing diabetes and gestational diabetes are associated with an increased risk of pre-eclampsia, neonatal hypoglycemia and hyperbilirubinemia, stillbirth, and fetal overgrowth or macrosomia.^26,27 With excess fetal growth comes an increased risk of shoulder dystocia, a type of obstructed labor. This places the fetus at risk for injury or death and the mother for postpartum hemorrhage and severe perineal damage.²⁸ Pregestational diabetes carries the same risks plus an increased risk for major congenital anomalies of the cardiovascular, skeletal, and central nervous systems, spontaneous abortion, uteroplacental insufficiency, fetal intrauterine growth restriction, and iatrogenic preterm delivery.²⁷

To date, few large-scale studies have reviewed the impact of NAFLD on pregnancy and neonatal outcomes. The risks of liver biopsy for this diagnosis would present unacceptable risks to the developing pregnancy; hence there is scant data on biopsy-proven NAFLD. The variety of noninvasive means of assessing NAFLD in the obstetric literature is summarized in Table 1. This article aims to identify and critically analyze the available research with a broad catchment of NAFLD diagnosis including serology, radiography, mixed indices, and diagnosis codes.

Table 1.

Methods of Nonalcoholic Fatty Liver Disease Assessment in Obstetric Literature

Study, year	Diagnostic modality for hepatic steatosis and/or NAFLD	Obstetric outcome
Diagnostic codes
Hagström et al., 2016³³	Diagnostic coding (ICD-9)	Pre-eclampsia
		Low birthweight (<2500 g)
		Preterm birth (<37 weeks GA and <32 weeks)
		GDM
		Cesarean delivery
Radiographic diagnosis
Ajmera et al., 2016⁴⁶	Noncontrast abdominal CT measuring liver attenuation (LA) in Hounsfield Units (HU)–average of nine measurements on three CT slices of the right lobe of the liver, with NAFLD defined as LA ≤40 HU.	GDM
De Souza et al., 2016⁴¹	Ultrasound of liver in first trimester. Semiquantitative scoring to assess hepatic fat based on presence of the following:	GDM
	Increased echogenicity of liver relative to the right kidney
	Impaired visualization of portal and hepatic veins
Forbes et al., 2011⁶	Ultrasound scan following 8–10 h fast. Detection based on the following:	GDM
	Echogenic parenchyma relative to right kidney
	Posterior attenuation
	Presence of focal fatty sparing
Serologic diagnosis
Mei-Dan³²	Maternal ALT and AST in first and second trimester	Pre-eclampsia
Sridhar et al., 2014⁴⁴	Prepregnancy maternal ALT, AST, and GGT	GDM
Tan et al., 2012⁴⁵	Maternal ALT, GGT, and AST in first and second trimester	GDM
Yarrington et al., 2016⁴³	Maternal ALT in first and second trimester	GDM
Yarrington et al., 2016³⁸	Maternal ALT in first and second trimester	LGA

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GDM, gestational diabetes mellitus; LGA, large for gestational age; NAFLD, nonalcoholic fatty liver disease.

Impact of NAFLD on Pre-eclampsia

Given the association between NAFLD and chronic hypertension, as well as the association of insulin resistance with pre-eclampsia, many studies have explored the relationship between NAFLD and pre-eclampsia. Pre-eclampsia is classically defined as new-onset hypertension after 20 weeks of gestation with either proteinuria or end-organ dysfunction in a woman with no prior history of hypertensive disease.²⁹ Both pre-eclampsia and chronic hypertension carry an increased risk for growth restriction in the fetus.^29
–31 Pre-eclampsia has significant associated maternal morbidities, including seizures, pulmonary edema, stroke, placental abruption, and stillbirth. Pre-eclampsia can also develop superimposed upon pre-existing hypertension. This is diagnosed when a woman with known chronic hypertension develops an acute worsening of blood pressure, new onset proteinuria, or other clinical features of pre-eclampsia. Superimposed pre-eclampsia is significantly more morbid than uncomplicated chronic hypertension, and the incidence of superimposed pre-eclampsia among women with chronic hypertension is four to five times higher than the incidence of pre-eclampsia in nonhypertensive pregnant women.

To date, there have been no studies explicitly examining the relationship between established NAFLD and hypertensive disease in pregnancy, but there are some exploratory and promising data. Mei-Dan found that ALT above 50 IU/mL predicted both mild and severe pre-eclampsia.³² While their findings were highly specific, their low sensitivity (3.3%) limits the applicability of this finding in predictive modeling. Pre-eclampsia was examined as a secondary outcome in a study exploring the association between NAFLD and obstetric outcomes in a large Swedish cohort study by Hagström et al.³³ Using a national registry, the authors identified 110 pregnancies in women with a prior diagnosis of NAFLD by ICD coding. They observed an interaction between NAFLD and body mass index (BMI) in that, in nonobese women, NAFLD was associated with an increased risk for pre-eclampsia (adjusted relative risk [aRR] 6.68; 95% CI 3.61–12.38), whereas affected women with BMI above 30 kg/m² did not incur an increased risk of pre-eclampsia (aRR 1.70; 95% CI 0.87–3.33).

Impact of NAFLD on In Utero Growth and Birthweight

Fetal size is an important factor in perinatal outcomes, especially in the context of known metabolic diseases. Both excessive and inadequate fetal growth are associated with an increased risk for several maternal and newborn complications. Infants may be large for gestational age (LGA) (birthweight ≥90%ile for a given gestational age). These infants are at an increased risk for stillbirth and shoulder dystocia, which have devastating impacts on both maternal and infant morbidity and mortality.³⁴ Sonographically identified growth-restricted fetuses [estimated fetal weight ≤10%ile for gestational age (GA)] have an increased risk for stillbirth, and small for gestational age (SGA) (birthweight ≤10%ile for given GA) newborns are predisposed to hypoglycemia, hyperbilirubinemia, neonatal death, and other respiratory morbidity.³¹ Diabetes is a commonly cited example of a maternal condition that increases the risk for both extremes of birthweight—LGA due to maternal hyperglycemia and excessive fuel delivery to the developing fetus, and SGA due to vasculopathy compromising placental perfusion.²⁷

Small studies have found associations with various maternal metabolic factors and LGA infant birthweight, including maternal triglycerides, free fatty acids, and leptin.^35
–37 The impact of NAFLD on fetal growth and birthweight has only been explored in a handful of studies. Yarrington et al. showed an association of early unexplained elevated ALT levels with LGA birthweight.³⁸ The authors showed that the mean first-trimester ALT among mothers of LGA infants was significantly higher than mothers of non-LGA infants (28 vs. 16 U/L; P = 0.03), and that women with first-trimester ALT above 26 U/L carried a fourfold increased odds of LGA (aOR 4.03; 95% CI 2.84–5.70; P < 0.0001), even when the analysis was restricted to women with a normal glucose screen. In contrast, the aforementioned study by Hagström et al. showed that women with NAFLD had an increased risk of delivering an infant with low birthweight defined as less than 2500 g (aRR 2.40; 95% CI 1.19–4.78), but not an increased risk for SGA birth (aRR 1.28; CI 95% 0.97–3.93).³³ This suggests the prevalence of low birthweight was a consequence of normally grown, but premature infants.

Association of NAFLD and Preterm Delivery

GA has a major impact on clinical outcomes in pregnancy. Preterm birth is defined as birth between 20 weeks and 36 weeks and 6 days of gestation.³⁹ The risk of poor birth outcomes increases with earlier GA. The risks are greatest for infants born before 34 weeks, but all preterm infants are at a higher risk for delivery complications and neonatal death than those born full term.⁴⁰

The aforementioned study by Hagström et al. showed that women with NAFLD had an increased risk for preterm birth less than 37 weeks GA (aRR 2.50; 95% CI 1.38–4.55) and less than 32 weeks GA (aRR 6.92; 95% CI 2.96–16.14) compared to women without NAFLD.³³ However, the authors did not clarify whether this increased risk of preterm birth was related to an increased incidence of spontaneous preterm birth or whether the neonates were delivered prematurely due to maternal complications such as pre-eclampsia.

Impact of NAFLD on Gestational Diabetes Mellitus Development

Gestational diabetes mellitus (GDM) is the onset or recognition of carbohydrate intolerance during pregnancy. For women with no clinical risk factors, screening is recommended at 24–28 weeks gestation by measuring serum glucose after a nonfasting 50 g glucose load.⁴¹ GDM represents a failure to adapt to the metabolic demands of pregnancy and has been shown to confer an increased risk in subsequent diabetes mellitus type 2.⁴² Several studies have investigated the relationship between NAFLD and GDM.

Using the Swedish medical registry, Hagström et al. demonstrated that overall, women with a diagnosis of NAFLD from a prior admission or clinic visit had an increased risk for GDM (aRR 2.78; 95% CI 1.25–6.15) compared to controls.³³ Again, they noted an interaction between NAFLD and BMI. Specifically, nonobese women with NAFLD had an increased risk of GDM compared to controls (aRR 12.50; 95% CI 4.78–32.66), while women with BMI above 30 kg/m² showed no increased risk for GDM (aRR 1.67; 95% CI 0.56–4.97). In another study, De Souza et al. assessed maternal hepatic fat semiquantitatively using ultrasound and found that sonographic evidence of hepatic fat in early pregnancy predicted dysglycemia and GDM in mid-pregnancy.⁴¹ Adjusting for maternal age, ethnicity, BMI, and gestational weight gain, presence of one feature of hepatic fat on ultrasound was associated with twofold odds of developing the composite outcome (aOR 2.0; 95% CI 1.0–4.1) and presence of two features elevated the odds further (aOR 2.9; 95% CI 1.0–18.4).

Yarrington et al. sought to determine the relationship between first-trimester maternal ALT values, as a proxy for NAFLD, with subsequent development of GDM.⁴³ While there was a trend toward higher median ALT values in women who later developed GDM (15 U/L vs. 13 U/L, P = 0.07), there was no statistically significant difference using the 75%ile ALT of 19 U/L as a threshold. However, in a planned post hoc analysis stratifying by maternal BMI, women with prepregnancy BMI less than 30 kg/m² with an early ALT at or above 19 U/L had a fourfold odds of developing GDM (aOR 4.42; 95% CI 1.38–14.16). There was also a linear relationship between log-transformed ALT and GDM among nonobese women (aOR 3.16; 95% CI 1.02–9.75), which was not present in obese women. In contrast, Sridhar et al. examined the correlation of prepregnancy liver enzymes and the incidence of GDM in the next pregnancy. They found that ALT values, assessed on average 7 years before the pregnancy, had no correlation with GDM.⁴⁴ Similarly, Tan et al. assessed liver enzymes in the third trimester simultaneous to the glucose load test and found no association between maternal ALT and GDM diagnosis.⁴⁵ Neither of these studies stratified by BMI category.

Impact of GDM on NAFLD Development

Given the link between type 1 and 2 diabetes mellitus and NAFLD, and the known increased risk of diabetes mellitus incurred by development of GDM, the impact of GDM on the incidence of NAFLD has also been studied. A 25-year longitudinal community-based cohort study, including 1115 women across 4 U.S. cities, found that women with a history of GDM had significantly higher incidence of diabetes (49% vs. 7.6%, P < 0.01) and twofold higher prevalence of radiographic NAFLD (14% vs. 5.8%, P < 0.01) compared to women with no history of GDM.⁴⁶ Similarly, a European group found an increased prevalence of NAFLD, based on ultrasound, serology, and anthropometry, in women with a history of GDM compared with those without previous GDM (38% vs. 17%, P = 0.001).⁶ After adjusting for BMI, the OR of NAFLD in women with previous GDM was more than double that in women with no previous GDM (OR 2.77; 95% CI 1.43–5.37; P = 0.002).

Impact of NAFLD on Mode of Delivery

Cesarean delivery is associated with major complications such as endometritis, wound complications, hemorrhage, and thromboembolic disorders.⁴⁷ In addition, the risk of severe maternal morbidity, including massive hemorrhage requiring hysterectomy, uterine rupture, anesthetic complications, shock, cardiac arrest, or renal failure, is increased threefold with planned cesarean compared to planned vaginal delivery.⁴⁷ This impact is compounded in subsequent cesarean deliveries as the risk for abnormal placentation and iatrogenic preterm delivery increases concurrently.^48
–50

Many of the metabolic conditions associated with NAFLD are themselves associated with an increased risk of cesarean delivery, including diabetes, extremes of fetal growth, and pre-eclampsia. Only one study examined cesarean delivery specifically as a secondary outcome. Hagström et al. found that women with NAFLD had a slightly increased risk for cesarean section (aRR 1.52; 95% CI 1.19–1.94), even after adjusting for confounders, including mother's age, maternal smoking status, and BMI.³³ As the study did not specify the indications for cesarean delivery in these women, it is possible that pre-eclampsia or extremes of fetal weight function as an effect modifier in this finding, such that the association of NAFLD and cesarean in the absence of such complications is unclear.

Conclusion

While the paucity of data examining a nearly ubiquitous feature of metabolic syndrome and its impact on obstetric and neonatal outcomes highlights the need for more research overall, a few themes emerge in the review of the literature. The first is the observation in the works of Hagström and Yarrington that obesity had a differential impact on the association of NAFLD and pregnancy-related outcomes. In both studies, women with a nonobese pre-pregnancy BMI had an elevated risk of gestational diabetes and pre-eclampsia compared to women with obese prepregnancy BMI. This may well be because BMI has such a significant impact on obstetric outcomes, including GDM and pre-eclampsia, that its effect is impossible to tease away from that of NAFLD without very large population cohorts. However, LFTs have been observed to be higher in normal BMI adults with NAFLD compared to obese adults with NAFLD, suggesting that these patients have different physiology or distinct mechanism of steatosis.⁵¹ Basic science research is needed to explore this physiologic phenomenon.

This review also highlights the importance of pursuing treatments for NAFLD that are compatible with pregnancy. Currently available pharmacologic treatments for NAFLD such as vitamin A and thiazolidinediones have known associated fetotoxicities and therefore are not safe to use in pregnancy.⁵² Metformin has limited data for efficacy in NAFLD, but good safety data in pregnancy, and thus may be worth future exploration as an intervention to modulate maternal metabolism.⁵³

Preconception counseling is a key component to healthy pregnancy for any woman with chronic disease. Optimization of concurrent diabetes has been shown to improve outcomes, including rate of congenital malformation, preterm delivery, and perinatal mortality.⁵⁴ As lifestyle changes continue to be the cornerstone of treatment for NAFLD and NASH, prepregnancy weight loss may mitigate the obstetric impact of NAFLD. The impact of preconception optimization of NAFLD has not been studied. Once pregnancy is achieved, there are no data to suggest that women with NAFLD or NASH should gain less than the recommended gestational weight gain. The Institute of Medicine and American Congress of Obstetrics and Gynecology recommend 11–20 lbs of weight gain across pregnancy for women of any obesity class.⁵⁵ While meta-analyses suggests a modest reduction in LGA and possibly pregnancy-related hypertensive disease with weight gain below this recommendation, inadequate weight gain is associated with an increased risk of growth restriction and preterm birth, even among morbidly obese mothers.^56,57 Excessive gestational weight gain is associated with increased rates of gestational diabetes, gestational hypertension, and pre-eclampsia.⁵⁸ Emphasis on optimal gestational weight gain through diet and appropriate exercise should be included in counseling to pregnant women with NAFLD, to avoid compounding the risks of abnormal fetal growth, prematurity, and other morbidities. Of note, in the absence of other known risk factors for stillbirth such as growth restriction or pre-eclampsia, there are no data to support fetal surveillance in women with NAFLD in isolation.

Synthesis of the data presented is limited by the heterogeneity of the diagnostic methods used to assess NAFLD presence and severity. The physiologic severity of NAFLD cannot be compared between studies relying on different methods for diagnosis, including LFTs, ultrasound, or ICD-9 diagnosis. However, the trend toward an increased risk of obstetric morbidity appears to be consistent. In conclusion, NAFLD features appear to be associated with a range of obstetric impact. More research focused on the intersection of the hepatic manifestation of metabolic syndrome, and obstetric and neonatal outcomes may illuminate the pathophysiology and lead to safe and effective interventions in pregnancy.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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