Motherisk Int J 2020;1:3
Asher Ornoy and Matitiyahu Berkovitch MD
Hebrew University and Tel Aviv University
Does hyperemesis gravidarum pause (HG) neurodevelopmental risk to the fetus?
Recent studies have suggested that in HG the baby is at an increased risk for developmental delay and neurobehavioral risks, such as ADHD. These are supported by famine studies as well as by the biology of nutritional deficiencies in pregnancy
Nausea and vomiting of pregnancy (NVP) affects an estimated 80% of pregnant women and is characterized by different degrees of severity of symptoms starting typically at 5-6 weeks of gestation, and in most cases resolves by the end of the first trimester, although it may continue up to term in the minority of cases . Repeated studies have documented that the mild and moderate forms of NVP are associated with favorable fetal outcomes when compared to women who do dot experience NVP: Lower rates of miscarriage, prematurity, stillbirth and of a variety of malformations  have been documented, when compared to women not experiencing NVP. Moreover, NVP has been shown to confer higher cognitive achievements in the offspring after controlling for different confounders . Although the etiology of this protective effect is unknown, it has been postulated that a favorable hormonal milieu is the underlying cause .
Hyperemesis gravidarum (HG) defines the severe end of NVP. Characterized by severe and prolonged nausea and repeated vomiting, HG leads to dehydration , electrolyte imbalance and very often to hospitalization for rehydration and correction of electrolyte and nutritional imbalances . HG affects an estimated 1-2% of NVP cases, and can persist into the second and third trimesters of pregnancy . HG tends to reoccur at high percentages among the same women, and it clusters in families.
HG has been shown to adversely affect the health and well-being of the women, who are suffering from weight loss, nutritional deficiencies, fatigue, frustration, resentment and depression. These women report major effects on their quality of life: depression, inability to take care of themselves, their children and family, inability to work and to socialize [5-6]. These symptoms sometime lead women to consider termination of HG-affected pregnancies , or to avoid a subsequent pregnancy after experiencing HG.
While most women recover from HG favorably, there is evidence of apparent increased fetal risk for adverse pregnancy outcomes such as small for gestational age, low birth weight, preterm delivery and low 5-min Apgar score [8-10].
However, till recently, the potential impact of HG on fetal brain development, and hence on the long term development of the child, have not been addressed.
Recent Developmental Studies:
In recent years several studies have pointed out that women with severe NVP- HG, have increased risk for developmental delay in their offspring:
In the first study, child long-term neurodevelopment after maternal hospitalization for severe NVP was sought .
Out of a cohort of 219 mother-child pairs, 22 women were hospitalized for severe NVP. Children of hospitalized mothers achieved significantly lower scores on verbal (107.2 vs. 112.7, p=0.04), performance (105.6 vs. 112.3, p=0.03) and full scale IQ (108.7 vs. 114.2, p=0.05). Duration of hospitalization, maternal depression, and maternal IQ were significant predictors of these outcomes. Daily intake of delayed preparation of doxylamine- pyridoxine was not associated with any adverse outcomes. This study suggested that in women with insufficiently managed severe NVP or HG, there is an apparent increased fetal risk for adverse neurodevelopment.
These findings may be consistent with HG being associated with smaller head circumference (12).
In a second study, neurodevelopmental outcome of 312 children born to 203 mothers with HG were compared to 169 children conceived by 89 women with no HG . Children exposed to HG had an odds ratio of 3.8(95% CI 1.56-11.55) for attention deficit hyperactivity disorder, OR of 4.02 (95%CI 1.36-17.24) for learning difficulties, and 2.5(95% CI 1.43- 31.83) for speech or language impairment. Only early onset of HG symptoms (prior to 5 weeks gestation) was associated with neurodevelopmental delay. Similar to the first study , the authors concurred that common antiemetic treatments have not been associated with developmental delay, whereas early symptoms may play a role.
The Biological Basis of Adverse Fetal Neuronal Effects of Malnutrition- Starvation
HG involves prolonged periods of malnutrition and starvation. HG-induced gestational malnutrition is characterized by severe shortage of numerous nutritional elements needed for optimal fetal brain development :
Caloric restriction has been associated with restricted maturation of myelin, whereas lack of optimal protein intake reduces synaptogenesis. Shortage in vitamin B12 my lead to various degrees of brain atroph , while B1 deficiency has been associated with hippocampal hypoplasia. Restricted maternal choline intake leads to acetylcholine and phosphatidylcholine shortage. Lack of folic acid causes neural tube defects and vitamin C shortage is affecting adversely hippocampal neurogenesis. Iodine deficiency causes impaired cognition, while lack of copper alters dopamine synthesis. Restricted maternal iron intake reduces central myelination, whereas shortage in dietary zinc reduces hippocampal neurotransmission .
Fetal Effects of HG- Learning from Famine Victims:
From October 1944 to May 1945, the German army blockaded food supplies to the Netherlands, subjecting the western Netherlands first to moderate (official food rations, 4200-6300 kJ/d) then to severe (<4200 kJ/d) nutritional deficiency. The northern and southern regions of the Netherlands were subjected to moderate nutritional deficiency only. The authors detected cognitive deficits mostly among fetuses exposed during the first 10 weeks of pregnancy, as compared to their unexposed controls [cognitive functioning index 4.36 (95% CI 8.04-0.67) points lower]. Within-sibling-pair analyses gave consistent results.. These results mirror- image those of Fejzo et al. from 2015 , showing the potentially powerful impact of first trimester exposure to starvation.
The most detailed famine effects on offspring cognition was examined among 2446 villagers born between 1958 and 1963 after in utero exposure to China's 1959-61 famine . The authors found that the cohort who had experienced full-term prenatal and partial-term postnatal exposures to famine had lower scores on the Telephone Interview of Cognitive Status (TICS), a test of drawing pentagons, and general cognition at age 50 years compared with the post famie unexposed cohort. The Chinese cohort concurs with the Dutch studies in showing that severe nutritional deprivation during prenatal life has a long lasting impact on cognitive performance.
The Dutch famine has been used to study also other aspects of fetal brain development. Dutch men exposed prenatally to severe maternal nutritional deficiency during the first and/or second trimesters of pregnancy exhibited increased risk for antisocial personality disorder (ASPD) . In contrast, third-trimester exposure to severe nutritional deficiency and prenatal exposure to moderate nutritional deficiency were not associated with risk for ASPD .
In a Dutch study of 116 males exposed in utero to famine, exposure in early gestation was associated with smaller intracranial and total brain volume in males, but not in females.. These findings are consistent with the psychological testing showing that prenatal undernutrition permanently affect brain size .
Because NVP occurs in 80% of women, and 1-2% of them experience HG, an estimated 1% of unborn babies are exposed to HG. Hence, a cognitive decrease of 5-7 points IQ would translate into huge economic loss, in addition to the effects on child performance. We need much more preventative and therapeutic interventions to ensure that the mother and her unborn childare not starving during this experience, as maternal starvation leads to long term adverse effects on fetal brain development.
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