The evolutionary biology of morning sickness disease defense

The evolutionary biology of morning sickness: disease, defense, or outcome of maternal-fetal conflict?

Diseases, defenses, and byproducts: “Morning sickness” (1) What is ‘morning sickness’? (2) Hypotheses for the causes of morning sickness EVALUATION OF THREE ALTERNATIVES (a) Protection of fetus and mother from food-borne infections and toxins (b) Maternal/fetal conflict & screening of embryo quality (c) Stimulation of placental growth via alterations to maternal physiology

(1) What is ‘morning sickness’? (a) Not just morning, and not a ‘sickness’ per se; also called “nausea and vomiting of pregnancy” (NVP), or ‘emesis gravidarum’ (b) Affects over 80% of women worldwide, severity is a continuum (c) Affects healthy pregnant females, who have healthy babies (d) Most common in first trimester (e) Causes reduced food intake, more-selective choice of food; also may involve food cravings (f) Proximate cause is unknown, quelled by thalidomide (g) In severe cases (about 1%) of females, called hyperemesis gravidarum, involves fluid and weight loss, severe enough for hospital admission, can be life-threatening

Nausea and vomiting in pregnancy also has negative impacts on woman, family relationships, and working abilities; -Anxiety and worry about effects on fetus -Cited as reason for elective abortions, smaller family size -47% of working women with NVP feel job efficiency is reduced, -35% lose work time (mean loss of 62 working hours per woman), and -25% lose time from housework (mean loss of 32 hours per woman). WHY COMMON AND PERSISTENT, GIVEN NEGATIVE ASPECTS?

HYPOTHESIS (a): 1. 2. 3. 4. Protection of fetus and mother from food-borne infections and toxins (Sherman and Flaxman 2002, and earlier studies) NVP is an adaptation of mothers and fetuses to expel foods that contain dietary toxins (such as plant secondary compounds) or infectious agents, and to avoid eating such foods in the first place Adaptive functions of such expulsion and avoidance: (i) help prevent miscarriage and birth defects (ii) also help protect the mother, given that the maternal cell-mediated immune system is depressed in pregnancy

The mother and embryo protection hypothesis High nausea and vomiting Avoid bad foods Reduced rate of miscarriage and birth defects

Testing the mother and embryo protection hypothesis: six predictions Sensitive Fetal organ Percent with NVP (1) NVP should peak when embryo is most susceptible to dietary toxins and infection, and when mother’s immune system is most depressed Post-menstrual week of pregnancy

(2) Avoided foods should contain plant toxins or pathogenic microbes, but craved food should not

(3) Aversions to potentially harmful foods should peak in the first trimester when organogenesis is most sensitive to disruptions

Percentage of pregnancies with miscarriage (4) Presence and magnitude of NVP should be positively associated with favorable outcomes of pregnancy Study State no association with low birth weight, birth defects, prematurity

More data on why it is good to have NVP

(5) Expression of NVP should depend on diet and should occur least often among women who are seldom exposed to dangerous food -> test for local adaptation with comparative method Flaxman and Sherman 2002

(6) Alleviating NVP should leave embryo more vulnerable to harmful substances Meta-analysis of 24 studies by Seto et al. (1997): Women who took anti-emetic drugs (antihistamines) were slightly and significantly less likely to bear children with birth defects But consider: (a) women might have developed aversions before taking anti-emetics, or (b) stronger symptoms may have caused anti-emetic use and positive outcomes, or (c) positive outcomes may have been due to antihistamine use

Some questions about the mother and fetus protection hypothesis High nausea and vomiting Avoid bad foods (1) Might there be a Reduced rate of miscarriage and common cause of NVP birth defects and better outcomes? (2) What about the physiological mechanism? Who controls it? (3) Why not just develop Pike (1997): women in food aversions without NVP? Kenya with NVP more than (4) Are societies studied representative twice as likely to lose fetus, baby; likely due to nutritional deficits of human evolutionary history? (5) Are aversions and cravings specifically adaptive to pregnancy (eg, what about chemotherapy nausea)? (1) (6) Where is the evidence for infectious-disease, (2) teratogenic effects of putatively-harmful foods?

HYPOTHESIS (b): Screening of embryo quality

HYPOTHESIS b: Screening of embryo quality High production of h. CG by healthy embryo, fetus, due to selection on fetus to maintain pregnancy in situation of maternal-fetal conflict - ‘test’ of embryo metabolic abilities, to produce large amounts of a protein High NVP Good outcome, low miscarriage rate (BYPRODUCT****)

Basis, rationale for embryo quality hypothesis (1) Maternal-fetal conflict is predicted by inclusive fitness theory (2) A potential conflict is expected over maintenance of pregnancy: ->fetus selected for phenotypes (and underlying alleles) that maintain pregnancy, ->mother is selected to (a) abort any fetus in poor circumstances, (b) screen fetuses for quality (lack of genetically-based defects) Especially strong potential conflicts in humans, which have enormous levels of parental investment; costs associated with infanticide are much larger than early miscarriage costs

Parent-offspring conflict is due to higher relatedness to self/own offspring than to sib/nieces, nephews r = 1/2 r = 1/4

Mom maximizes her inclusive fitness at a lower level of maternal investment than the level that maximizes inclusive fitness for any one offspring Selection for alleles in mom ‘for’ adaptations that constrain investment Selection for alleles in offspring ‘for’ adaptations to take more from mom, to the point that negative effects on other sibs are not too great Mom Kid MAIN STAGES OF CONFLICT: (1) Survival of conceptus (2) Growth in the womb (3) Survival at birth (4) Investment in childhood (5) Inheritance as adult Strategies (variation) available?

Manifestations of maternal-fetal conflict Spontaneous abortion - Should mom maintain the pregnancy? Depends on the quality of the fetus and state of the mother. These hinge on cost/benefit issues in relation to possible future pregnancies. POSSIBILITIES (1) Mother and baby BOTH want pregnancy maintained (2) Baby wants pregnancy maintained, mother does not CONFLICT (3) NEITHER wants pregnancy maintained (embryo selected to abort self) What is a conceptus to do? SHOUT that they are here and take over the system that maintains pregnancy as rapidly as possible

h. CG bypasses pathway and stimulates the corpus luteum to produce progesterone and by the 8 th week of pregnancy, anterior pituitary luteinizing hormone produces enough P to sustain pregnancy on its own. chorionic gonadotropin placenta progesterone corpus luteum progesterone uterus How might this ‘subversion system’ have evolved? ?

Scenario for evolution of subversion by h. CG (1) Mother alone maintains early pregnancy via LH, regulated to maximize her inclusive fitness (2) Embryo is selected to also produce LH, released into mother’s bloodstream, to help maintain the pregnancy (3) Mothers selected for reduced LH production, to abort less-vigorous fetuses -> ‘arms race’ ensues (4) Series of gene duplications involving gene for LH, evolution of h. CG gene via positive selection (1) (baby evolves subversion, mom evolves ability to abort (2) subnormal embryos) The gene for one of the two h. CG subunits (CGbeta subunit, CGbeta) arose by duplication from the luteinizing hormone beta subunit gene (LHbeta)

Positive selection on chorionic gonadotropin gene

Other evidence salient to the embryo quality hypothesis (1) There is a close association between the timing of h. CG production and the timing of nausea and vomiting

How h. CG from baby apparently makes mum pregnancy sick Proximate mechanism

Other evidence salient to the embryo quality hypothesis (2) Low h. CG production is associated with early pregnancy loss (3) High h. CG production is often associated with hyperemesis gravidarum (4) Higher h. CG production with female fetus, and higher levels of nausea and vomiting with female fetus - WHY? (5) Higher h. CG production with twins, and higher levels of nausea and vomiting with twins (6) Evidence that most early miscarriages are due to intrinsic genetic causes, mainly chromosomal defects (aneuploidies), not diet (clinicians use h. CG production as a measure of embryo health!) (7) Embryos with trisomy 21 produce exceptionally-high levels of h. CG, and mothers have high nausea, vomiting

Other evidence salient to the embryo quality hypothesis Is h. CG subject to genomic imprinting? (Haig 1993) Humans: are two kinds of triploid fetus Diandric - large fetus, large placenta, high h. CG in mom Digynic - small fetus small placenta, low h. CG in mom -> due to paternal expression of h. CG? h. CG is also in genomic region with imprinted genes Horses have independently evolved a CG and show paternal expression of the gene

Evolution of genomic imprinting in placental mammals under multiple paternity and high maternal investment: Paternal gene Relatedness of paternal gene in offspring, to siblings, goes from 0. 5 to 0 as we go from monogamy to polygamy Maternal gene Relatedness of maternal gene in offspring, to siblings, is always 0. 5 Paternally-expressed genes are expected to be more ‘selfish’, with regard to mother-offspring interactions

Evidence against the embryo quality hypothesis? (1) Absence of nausea and vomiting in some pregnancies, and apparently some societies -> many factors other than embryo quality are involved (2) Apparent absence of nausea and vomiting in other species of mammals, which are subject to maternal-fetal conflicts? -> only a few species (horses, humans) have evolved the mechanism, chorionic gonadotropins

HYPOTHESIS b (reviewed): Screening of embryo quality High production of h. CG by healthy embryo, fetus, due to selection on fetus to maintain pregnancy in situation of maternal-fetal conflict High NVP Good outcome, low miscarriage rate (BYPRODUCT, usually only a nuisance to females)

HYPOTHESIS (c): Stimulation of placental growth

Pregnancy sickness and stimulation of placental growth: rational and evidence Nausea and vomiting Reduced food intake in first trimester Placental development stimulated (1) Dutch hunger winter - First trimester undernutrition associated with higher placental weights (2) Epidemiologic studies - increased food intake in first trimester results in infants with smaller placental and birth weights (nutrient partitioning is favoring the mom) (3) Animal husbandry - well nourished sheep, mate them, move them to poor pasture -> best outcomes of pregnancies

Pregnancy sickness and stimulation of placental growth: mechanism? -> Reduced nutrient intake in early pregnancy lowers maternal levels of anabolic hormones, insulin, and IGF-1. -> This helps to ensure ‘sufficient’ nutrient delivery to placenta -> Fetal growth is regulated by IGF-2 during this period! (IGF-2 is imprinted and paternally-expressed, as you recall). It is regulated by IGF-1 in 2 nd, 3 rd trimesters. -> Placenta also secretes leptin into mother’s blood in first trimester, which suppresses appetite

Pregnancy sickness and stimulation of placental growth: how and where is selection working here? Benefit to both? But fetus is altering the mother’s physiology Benefit to fetus? : fetus makes mother ill to gain increased share of maternal resources

CAN THE THREE HYPOTHESES FOR MORNING SICKNESS BE RECONCILED? 1. (a) Toxin/pathogen: NVP is adaptive to mom 2. and fetus, as a mechanism to avoid bad foods (b) Embryo quality/maternal-fetal conflict: NVP is a non-adaptive byproduct of maternal-fetal conflict (c) Placental growth: NVP is adaptive for mom and fetus, as a mechanism to reduce food intake in first trimester Functional design Comparative method Measurement of selection

NEED DIFFERENTIATING PREDICTIONS of the three hypotheses NEED TO KNOW THE MECHANISMS in more detail (functional design of physiology, genetics) Imprinting? Proximate, Ultimate causes NEED TO KNOW WHO BENEFITS in what situations, in traditional societies

EVALUATING, RECONCILING THE HYPOTHESES Fetus, placenta secrete h. CG -> helps maintain pregnancy and reduces maternal food intake (via nausea), which stimulates placental growth? ? Might protection from toxins, pathogens be a byproduct of this system? ? Might variation in aversion to different foods be a non-adaptive byproduct of general nausea? ?