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Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes
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Higher maternal BMI is also predictive of greater hepatic lipid and fat content in infants, as measured by magnetic resonance imaging in early neonatal life.
Our data highlight the impact of this national epidemic on reproductive-aged women in particular, with NAFLD rates in pregnancy tripling since 2007.
JNL of Hepatology - June 9 2020
Highlights
• The prevalence of non-alcoholic fatty liver disease (NAFLD) has nearly tripled over the past decade.
• Maternal and perinatal complications are more common in mothers with NAFLD than in those with other liver diseases.
• NAFLD in pregnancy is independently associated with adverse maternal and perinatal outcomes.
• Women with NAFLD warrant pre-conception counseling, and may benefit from high-risk obstetrics management during pregnancy.
Background & Aims
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising in young adults, with potential implications for reproductive-aged women. Whether NAFLD during pregnancy confers more serious risks for maternal or perinatal health is unclear.
Methods
Using weighted discharge data from the US national inpatient sample, we evaluated temporal trends of NAFLD in pregnancies after 20 weeks gestation, and compared outcomes to pregnancies with other chronic liver diseases (CLDs) or no CLD. Study outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (pre-eclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. NAFLD prevalence was estimated by calendar year and temporal trends tested by linear regression. Outcomes were analyzed by logistic regression adjusted for age, race, multiple gestation, and pre-pregnancy diabetes, obesity, dyslipidemia and hypertension.
Results
Among 18,574,225 pregnancies, 5,640 had NAFLD and 115,210 had other, non-NAFLD CLD. Pregnancies with NAFLD nearly tripled from 10.5/100,000 pregnancies in 2007 to 28.9/100,000 in 2015 (p <0.001). Compared to the other groups, patients with NAFLD during pregnancy more frequently experienced gestational diabetes (7-8% vs. 23%), hypertensive complications (4% vs. 16%), postpartum hemorrhage (3-5% vs. 6%), and preterm birth (5-7% vs. 9%), all p values ≤0.01. On adjusted analysis, compared to no CLD, NAFLD was associated with hypertensive complications, preterm birth, postpartum hemorrhage and possibly maternal (but not fetal) death.
Conclusion
The prevalence of NAFLD in pregnancy has nearly tripled in the last decade and is independently associated with hypertensive complications, postpartum hemorrhage and preterm birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counseling and pregnancy care.
Lay summary
The prevalence of non-alcoholic fatty liver disease (NAFLD) in pregnancy has almost tripled over the past 10 years. Having NAFLD during pregnancy increases risks for both the mother and the baby, including hypertensive complications of pregnancy, bleeding after delivery, and preterm birth. Thus, pre-conception counseling is warranted with consideration of high-risk obstetric management among women with NAFLD in pregnancy.
In summary, we identified a near tripling of NAFLD prevalence in pregnancies over the past 10 years. While pregnancies with NAFLD were more likely to have co-existing metabolic disease, NAFLD was associated with adverse maternal and perinatal outcomes independent of metabolic comorbidities. These data support a critical need to recognize the public health implications of NAFLD in reproductive-aged women, and ensure that women with NAFLD receive adequate pre-conception counseling, including efforts to optimize metabolic health. Moreover, pregnant women with NAFLD may warrant management by high-risk obstetrics, with the goal of improving outcomes in this growing population of mothers and infants.
• In this large nationally representative US database, we identified a more than tripling of NAFLD prevalence in pregnancies over the past 10 years.
• Pregnant women with NAFLD had significantly higher odds of serious maternal and perinatal complications, highlighting the importance of this emerging “high-risk pregnancy” group.
• Recent US data show a 5-fold rise in NAFLD incidence over the past 20 years, with the largest rise in adults under the age of 40 years. 2
• The most striking finding from this study was the more than 3-fold higher risk of hypertensive complications, including pre-eclampsia, eclampsia, or HELLP in pregnancies affected by NAFLD.
• The mechanisms by which NAFLD may promote adverse maternal and perinatal events are not well defined..... Insulin resistance in the setting of NAFLD is associated with hepatic production of inflammatory mediators such as tumor necrosis factor-alpha and interleukin -1β. 19 Insulin resistance outside of pregnancy interacts with the renin-angiotensin-aldosterone system, contributing to systemic hypertension.
• In addition to more immediate peripartum risks, NAFLD in pregnant mothers may adversely affect the long-term health of their children. Parental history of NAFLD is associated with risk of NAFLD in children although whether having NAFLD during pregnancy influences this risk is unknown. Other forms of metabolic disease during pregnancy do appear to contribute to childhood NAFLD, including baseline and trajectory of weight gain in pregnancy.
Higher maternal BMI is also predictive of greater hepatic lipid and fat content in infants, as measured by magnetic resonance imaging in early neonatal life.
• At the time of pediatric NAFLD diagnosis, between 25-50% of children have been shown to have NASH, up to 25% of whom have advanced fibrosis.
• Thus, the rising rates of NAFLD in pregnancy may have much farther reaching implications for liver disease in youth.
Our data highlight the impact of this national epidemic on reproductive-aged women in particular, with NAFLD rates in pregnancy tripling since 2007.
All metabolic comorbidities, as well as cesarean deliveries, were more common in pregnancies affected by NAFLD. Moreover, after adjusting for metabolic risk factors, NAFLD remained associated with hypertensive complications, postpartum hemorrhage and preterm birth. NAFLD increased the odds of maternal mortality, though maternal death was overall quite rare, thus findings must be interpreted with caution. Overall these data do support the need for increased awareness of the risks of NAFLD in pregnant women and their need for linkage with high-risk obstetric care.
In the 5 most recent years of data (2012-2016), there were 18,574,225 eligible pregnancies for evaluating the association of NAFLD with maternal and perinatal outcomes; 5,640 with NAFLD (0.1% with cirrhosis), 115,210 with other CLD (0.7% with cirrhosis), and 18,453,375 with no CLD.
The mean age of women in the NAFLD, other CLD, and no CLD groups were 31, 30, and 29 years, respectively (Table 1). Notable racial/ethnic differences included a higher proportion of Hispanics with NAFLD and higher proportion of Asian-Pacific Islanders with other CLD. Pre-existing metabolic comorbidities were more common in pregnancies with NAFLD including diabetes, obesity, dyslipidemia, and hypertension (all p values <0.001) (Table 1). Most notably, obesity was present in nearly 40% of pregnancies with NAFLD (vs. 6-7% in other groups), pre-pregnancy hypertension was thrice as common with NAFLD (15.5% vs. <5% in other groups), and dyslipidemia present in 7.4% of the NAFLD group compared to <0.5% of the other pregnancy groups. A slightly higher proportion of pregnancies with NAFLD had multiple gestation (3% vs. 1.8%, p values <0.001).
Maternal complications in pregnancies with NAFLD vs. non-NAFLD CLD and no CLD
Gestational DM, gestational hypertension, hypertensive complications (pre-eclampsia, eclampsia, and/or HELLP), cesarean section, and postpartum hemorrhage were significantly more common in pregnancies with NAFLD, compared to pregnancies with other CLD or no CLD (p values <0.001) (Table 2). GDM was present in 23% of NAFLD pregnancies vs. 7-8% in the other 2 groups. Hypertensive complications occurred in 16% of NAFLD pregnancies vs. 4% for the other groups; 52% of NAFLD pregnancies resulted in cesarean section, compared to 33% and 36% in the other CLD and no CLD groups, respectively (p values <0.001). Maternal mortality was also more common in the NAFLD group than the no CLD group (0.1% vs. 0.005%, p <0.001).
After adjusting for age, race, multiple gestation and all pre-existing metabolic disease codes (Table 3), NAFLD was associated with higher odds of hypertensive complications and postpartum hemorrhage compared to no CLD (adjusted odds ratio [AOR] 3.1; 95% CI 2.6-3.8; p <0.001 and AOR 1.7; 95% CI 1.3-2.1; p <0.001, respectively). NAFLD also conferred higher odds of maternal mortality (AOR 17.9; 95% CI 2.1-149; p = 0.01), although this estimate reflects only 5 deaths in the NAFLD group. Compared to pregnancies with other CLD, NAFLD was also associated with 3-fold higher odds of hypertensive complications (AOR 3.1; 95% CI 2.5-3.8; p <0.001). The odds of postpartum hemorrhage and maternal death were similar between NAFLD and other CLD groups (Table 3).
Perinatal complications in pregnancies with NAFLD vs. non-NAFLD CLD and no CLD
Preterm birth was more common with NAFLD compared to other CLD and no CLD groups (9% vs. 7% and 5%, respectively), as was LGA (5% vs. <3% in other groups), p values <0.001 (Table 2). Conversely, FGR was less common in pregnancies with NAFLD at 1.3% vs. 3.6% in the other CLD group (p <0.001), and 2.0% in the no CLD group (p = 0.10) (Table 2). On multivariate analysis, adjusting for age, race, multiple gestation and all pre-existing metabolic diseases, NAFLD was associated with higher odds of preterm birth compared to CLD (AOR 1.6; 95% CI 1.3-2.0; p <0.001) (Table 3). Compared to other CLD in pregnancy, NAFLD was associated with a lower odds of FGR (AOR 0.4; 95% CI 0.2-0.7; p <0.001), and conversely a higher odds of having LGA infants (AOR 1.8; 95% CI 1.4-2.5; p <0.001). No differences in fetal growth or size were observed on adjusted analyses comparing pregnancies with NAFLD vs. no CLD (Table 3).
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