Preconception environmental factors and placental morphometry in relation to pregnancy
outcome
Salavati, Nastaran
DOI:
10.33612/diss.109922073
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Salavati, N. (2020). Preconception environmental factors and placental morphometry in relation to
pregnancy outcome. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.109922073
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
General
Introduction
GENERAL INTRODUCTION
Fetal size and growth trajectories are important indicators of fetal health and are determined by maternal, placental and fetal factors. Normal fetal growth requires an adequate supply and effective transport of nutrients and oxygen across the placenta, which is dependent on normal placental structure, placental function and adequate maternal supply.
Barker showed with the concept of fetal origins of adult disease, that size at birth is related to the risk of developing diseases in later life 1. In particular, it has been shown
that low birth weight is associated with increased risk of coronary heart disease, diabetes, hypertension and stroke in adulthood 1. The fetal origins of adult disease
concept has been supported by several large birth registries and human cohorts where women and their offspring faced severe malnutrition in the form of famine 2–4.
However, low birth weight is not necessarily a prerequisite for adverse outcome 5,6.
Also those with “normal” birth weight may be at increased risk of adverse pregnancy outcome when they have encountered adverse exposures (e.g. placental insufficiency, inadequate maternal diet and suboptimal maternal health).
For long, the diagnosis of fetal growth restriction (FGR) has mainly been based on birth weight below a reference cut-off, most commonly the 10th percentile (p10),
adjusted for gestational age 7. Birth weight below the p10 indicates that the birth
weight is within the lowest 10% birth weight compared to the reference population. However, this does not necessarily mean that the fetus suffered from FGR, but the fetus is small for gestational age (SGA) and may be healthy. Fetuses who are too small according to the reference chart, may be physiologically small and are grown appropriate according to their individual growth potential (based upon their genetic and epigenetic inheritance at conception, or even transgenerational effects of adverse exposures when their grandmother was pregnant of their mother 8), and
therefore may not be at a high risk from diseases related to FGR. On the other hand, many fetuses with FGR remain unnoticed since they are not necessarily too small in the population based reference chart, but they are too small according to their individual growth potential.
Causes of fetal growth restriction can be divided into maternal (e.g. anemia, malnourishment, (transgenerational) exposure to severe environmental factors), fetal (e.g. infections, maldevelopment) and placental (e.g. poor implantation, morphological abnormalities) factors 9,10.
1
PART 1:
Preconception environmental factors and pregnancy outcome
Although the fetal genetic makeup is complete at conception and regulates growth and organ development, a range of environmental exposures can alter the course of growth and development of the fetus 11. It is becoming more and more apparent that
all non-communicable illnesses are a result of the interaction between genes and environment. In fact, recent evidence confirms that modifiable environmental factors may explain 70-80 percent of illness 12,13. In other words, modifiable determinants
within our environment are in interaction with our genome, and depending on the resilience, it may maintain health or increase disease susceptibility 14. In the
environmental domain it is important to receive determinants that are required for healthy survival and avoid those that are harmful 15. During pregnancy in particular,
it appears that the processes that direct growth and development of the fetus are profoundly sensitive to nutritional requirements and vulnerable to environmental insults. Insufficient intake of required nutrients or adverse exposures during critical phases of development may have serious and life-long consequences 16.
Depending on the stage of organ development impact may be different. To illustrate, periconception intake of folic acid is advised to prevent neural tube defects 17. The
neural tube is developed during the third week of gestation, therefore it is advised to already start taking folic acid supplements when women are trying to conceive until 12 weeks of gestation 18.
Air pollution is one of the environmental factors that has been acknowledged for its adverse influence on fetal development. Several studies have shown an association between exposure to air pollutants and an increased risk of fetal growth restriction
19, low birth weight 19, preterm birth and neonatal mortality 20. There is substantial
evidence that oxidative stress and inflammation are involved in the mechanisms underlying the effects of air pollutants which can contribute to epigenetic changes, including alteration of DNA methylation 21,22. Such epigenetic modifications could
impair normal embryo development and lead to congenital anomalies. Despite the evidence, inconsistencies and uncertainties remain about the effects of specific air pollutants. Accordingly, exposures within the air environment are something to be carefully considered, especially by those who aim to become pregnant. Nutritional requirements during pregnancy, and also prior to pregnancy, are also shown to be associated with fetal growth and development. This association has been established after some important historical events.
In the 1800s, maternal food intake was deliberately limited with the aim to restrict fetal growth and ease deliveries in women who had contracted pelvises. The poor survival rate of those undergrown fetuses led to subsequent studies which identified maternal factors associated with poor fetal growth 23. In 1944-45, after 4 years of
German occupation of the Netherlands, an extreme food shortage occurred in the West Netherlands which persisted for over 5 months during the winter. The, so called, Dutch famine winter provided the unique opportunity to study the effects of a short but severe period of undernutrition during different stages of gestation on the offspring.
Among the group of women exposed to famine during the first trimester of pregnancy, preterm births and stillbirths increased, and also the risk of cardiovascular diseases and obesity later in life was increased among the offspring 24. However, the offspring
of these women had normal birth weight, albeit placental weight was increased in these pregnancies 25. Contrary, those women exposed to famine during mid and late
gestation delivered babies who had lower birth weight than unexposed babies and had an increased risk of impaired glucose tolerance as adults than the offspring of normally fed women 26. Although reduced birth weight is the most easily measured
proxy for intrauterine deprivation, it is not the cause of later adult diseases, as previously mentioned. The fact that placental weight increased in pregnancies of women exposed to famine at the first trimester of pregnancy, while birth weight was within normal ranges, can be interpreted as compensatory mechanism by the placenta for the reduction in maternal nutrient intake. There was possibly no opportunity (e.g. past a window that allows placental size adaptation) to adapt to the relative short period of under nutrition when famine occurred in mid or late gestation, resulting in low birth weights offspring.
There are specific maternal dietary and lifestyle factors that appear to influence fetal growth. Maternal macronutrient intake during pregnancy and its association with birth weight has been subject of several studies. High consumption of fruits, vegetables, low-fat dairy products and lean meats, throughout gestation is associated with a decreased risk of giving birth to a small-for-gestational age (SGA) infant 27,28. On the
other hand, maternal diet characterized by high consumption of red and processed meats and high-fat dairy products increases the risk of giving birth to a SGA infant 27.
Godfrey et al. showed specifically that high carbohydrate intake in early pregnancy was associated with lower birth and placental weight, especially when combined with a low intake of high quality protein (e.g. animal protein) in late pregnancy 29.
1
Largely due to these historical examples, the focus on maternal lifestyle and dietary intake during pregnancy and the association with pregnancy outcome has increased. The formation of most organs (including the placenta) occurs however, when women are not yet aware of being pregnant, between the third and seventh week of gestation, risking several teratogenic effects during this time period 30. In addition, maternal
nutritional status at conception influences pregnancy outcome and long-term health of both women and their offspring, by affecting the way energy is partitioned between maternal and fetal needs. This emphasizes the importance of shifting the focus from during pregnancy only also towards the preconception period. Defining this period has been done previously 31, suggesting that biologically this preconception phase
may start in women around 26 weeks prior to conception when primordial follicles leave their resting state. However, because the most active phase of ovarian follicular development starts around 14 weeks preconception 32, this definition is more often
used 31.
Literature regarding preconception dietary intake and its association with pregnancy is limited. Nevertheless, it has been shown that high pre-pregnancy maternal BMI shows a strong positive association with both neonatal adiposity and large-for-gestational age (LGA) births, and with the risk of preeclampsia 33–38. This probably
reflects the general inflammatory status of the mother and also the condition of the uterine environment 39, and thus highlights the importance of maternal physiology
and body composition, already from preconception onwards 36. Thus, increasing
the knowledge on maternal dietary intake and environmental factors (e.g. exposure to air pollution) during preconception and pregnancy outcome, and consequently improving dietary habits before conception, appears to be an important priority to improve fetal growth and subsequent health outcomes.
PART 2:
Placental development and pregnancy outcome
Placental size, weight and shape are all subject to wide variations 40. Several studies
have described the relationship between placental morphometry and adverse pregnancy outcomes, including fetal growth restriction (FGR). Small placental size
41, decreased placental surface area 42 and small placental volume 43, have been
associated with increased risk of FGR. Smaller surface area and a more oval shape are more common in pregnancies complicated by preeclampsia 43,44. Moreover, low
birth weight to placental weight-ratio (BWPW-ratio) (i.e. grams of the fetus per gram placenta 45), often described as “placental efficiency” 46, has been appointed by a
study as associated with a higher risk of delivering a term small for gestational age (SGA) infant 47.
Besides the fact that several studies have examined the association between placental morphometry and pregnancy outcomes, there is increasing evidence that features of placental gross morphology are linked biologically to the functional capacity of the placenta 48. However, studies investigating this association have mainly
focused on the inter-relationship between antenatal utero-placental Doppler blood flow velocimetry and the post-natal microscopic and ultrastructural characteristics of the placenta and placental bed instead of the gross morphology of the placenta. Nevertheless, it is plausible that utero-placental blood flow may also be related to the gross morphology of the placenta.
Consequently, it is important to increase the understanding of the association between utero-placental blood flow, fetal growth and the gross morphology of the placenta, in relation to pregnancy outcome. Performing studies on morphology of the placenta (after birth) create the opportunity to help finding the neonate who has increased risk of morbidity (e.g. who suffered undetected growth restriction) and should be monitored more closely during postnatal care.
AIMS AND OUTLINE OF THE THESIS
The aim of this thesis was to gain more insight in both the relation between preconception environmental factors (including exposure to air pollution and maternal dietary intake) and in the relation of placental morphometry with pregnancy outcome. Therefore, the following studies have been conducted.
Part 1. Preconception environmental factors and pregnancy outcome.
With the increased understanding of the potential harmful effects of exposure to air pollutants during pregnancy on pregnancy outcome (and more specifically the risk of congenital anomalies), there are increasing numbers of studies focusing on these associations. However, results are inconsistent and most studies have focused only on the association of air pollution with congenital heart defects and orofacial clefts. In chapter 2 we aimed to identify, using an exploratory study design, congenital anomalies that may be sensitive to maternal exposure to specific air pollutants during the periconceptional period.As previously mentioned, literature investigating the link between maternal nutritional status before conception and pregnancy outcome is still scarce. The studies that have investigated the association between preconception dietary intake in relation
1
to pregnancy outcome were either animal studies, limited in value due small sample sizes or focused solely on selected macronutrient intake rather than complete (macro) nutrient composition or dietary intake (e.g. food groups). Therefore, we investigated the association between preconception diet and pregnancy outcomes in a linked birth cohort. In chapter 3 we described the methodology of establishing the Perined-Lifelines linked birth cohort, and included the characteristics of the study population. The aim of chapter 4 was to assess the association between preconception maternal macronutrient intake and birth weight of the offspring, across strata of maternal BMI in the Perined-Lifelines Linked birth cohort. Chapter 5 evaluated the association between preconception food group intake and birth weight of the offspring, in the Perined-Lifelines linked birth cohort.
Part 2. Placenta morphometry and pregnancy outcome.
Placental function can be assessed in vivo by utero-placental Doppler flow velocimetry and fetal growth can be assessed by serial ultrasonic biometry. High resistance pattern of flow in the umbilical artery is widely used as an indicator of placental dysfunction 49. It is known that FGR may be the result of placental
dysfunction, whereby the placenta may exhibit altered nutrient transfer capacity to compensate for suboptimal function. As described previously, diagnostic process of FGR remains difficult. We hypothesized that placental morphometry and BWPW-ratio may be of value in diagnosing FGR. In this part, we aim to increase the understanding of the relation between placental morphometry, and BWPW-ratio (“placental efficiency”), to ultrasound markers of fetal growth restriction and both maternal and neonatal morbidity.
In chapter 6 we investigated the inter-relationships between size and shape of the placenta (assessed following birth), utero-placental Doppler flow velocimetry and the rate of growth of the fetal abdomen measured between 20 and 36 weeks’ gestational age. With this study we aimed to increase the understanding of the (patho-)physiological association between utero-placental Doppler measurements (corresponding to placental function) and the gross morphology of the placenta after birth. Chapter 7 elaborates on the relationship between both a relatively smaller placenta (high birth weight -placenta weight ratio) and a relatively larger placenta (low birth weight-placental weight ratio), with ultrasonic measurements of utero-placental blood flow and neonatal and maternal morbidity. Our hypothesis was that failure of placental development, reflected by high BWPW-ratio, is associated with fetal growth restriction and increased umbilical artery pulsatility index. In chapter 8, a
literature review was presented in which the possible use of placental morphometry in detection of fetal growth restriction has been investigated. Finally, in chapter 9 overall conclusions of the thesis are discussed.
1
REFERENCES
1. Barker, D. J. P. The developmental origins of adult disease. J. Am. Coll. Nutr. 23, 588S–595S (2004).
2. Roseboom, T. J. et al. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol. Cell.
Endocrinol. 185, 93–8 (2001).
3. Stanner, S. A. et al. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. BMJ 315, 1342–1348 (1997).
4. Barker, D. J. P., Osmond, C., Kajantie, E. & Eriksson, J. G. Growth and chronic disease: findings in the Helsinki Birth Cohort. Ann. Hum.
Biol. 36, 445–458 (2009).
5. Valdez, R., Athens, M. A., Thompson, G. H., Bradshaw, B. S. & Stern, M. P. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37, 624–31 (1994).
6. Bhargava, S. K. et al. Relation of Serial Changes in Childhood Body-Mass Index to Impaired Glucose Tolerance in Young Adulthood. N. Engl. J. Med. 350, 865–875 (2004).
7. Beune, I. M., Pels, A., Gordijn, S. J. & Ganzevoort, W. Definitions of fetal growth restriction in existing literature over time. Ultrasound Obstet. Gynecol. (2018). doi:10.1002/uog.19189
8. Painter, R. et al. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.
BJOG An Int. J. Obstet. Gynaecol. 115, 1243–
1249 (2008).
9. Das, U. (‘Shonu’) G. & Sysyn, G. D. Abnormal fetal growth: intrauterine growth retardation, small for gestational age, large for gestational age. Pediatr. Clin. North Am. 51, 639–654 (2004).
10. Maulik, D. Fetal growth restriction: the etiology. Clin. Obstet. Gynecol. 49, 228–35 (2006).
11. Sferruzzi-Perri, A. N., Vaughan, O. R., Forhead, A. J. & Fowden, A. L. Hormonal and nutritional drivers of intrauterine growth. Curr. Opin. Clin.
Nutr. Metab. Care 16, 298–309 (2013).
12. Rappaport, S. M. & Smith, M. T. Environment and Disease Risks. Science (80-. ). 330, 460– 461 (2010).
13. Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016).
14. Genuis, S. J. Our genes are not our destiny: incorporating molecular medicine into clinical practice. J. Eval. Clin. Pract. 14, 94–102 (2008). 15. Genuis, S. J. What’s out there making us sick?
J. Environ. Public Health 2012, 605137 (2012).
16. Genuis, S. J. The chemical erosion of human health: adverse environmental exposure and in-utero pollution - determinants of congenital disorders and chronic disease. J.
Perinat. Med. 34, 185–95 (2006).
17. De-Regil, L. M., Fernández-Gaxiola, A. C., Dowswell, T. & Peña-Rosas, J. P. Effects and safety of periconceptional folate supplementation for preventing birth defects.
Cochrane database Syst. Rev. CD007950
(2010). doi:10.1002/14651858.CD007950.pub2 18. WHO | Periconceptional folic acid
supplementation to prevent neural tube defects. WHO (2019).
19. Pedersen, M. et al. Ambient air pollution and low birthweight: a European cohort study (ESCAPE). Lancet. Respir. Med. 1, 695–704 (2013).
20. Effects of Air Pollution on Children’s Health and
21. Baccarelli, A. & Bollati, V. Epigenetics and environmental chemicals. Curr. Opin. Pediatr.
21, 243–51 (2009).
22. Mazzoli-Rocha, F., Fernandes, S., Einicker-Lamas, M. & Zin, W. A. Roles of oxidative stress in signaling and inflammation induced by particulate matter. Cell Biol. Toxicol. 26, 481–498 (2010).
23. King, J. C. A Summary of Pathways or Mechanisms Linking Preconception Maternal Nutrition with Birth Outcomes. J. Nutr. 146, 1437S–1444S (2016).
24. Susser, M. & Stein, Z. Timing in Prenatal Nutrition: A Reprise of the Dutch Famine Study. Nutr. Rev. 52, 84–94 (2009).
25. Lumey, L. H. Compensatory placental growth after restricted maternal nutrition in early pregnancy. Placenta 19, 105–11 (1998). 26. Painter, R. C., Roseboom, T. J. & Bleker, O. P.
Prenatal exposure to the Dutch famine and disease in later life: An overview. Reprod.
Toxicol. 20, 345–352 (2005).
27. Knudsen, V. K., Orozova-Bekkevold, I. M., Mikkelsen, T. B., Wolff, S. & Olsen, S. F. Major dietary patterns in pregnancy and fetal growth. Eur. J. Clin. Nutr. 62, 463–470 (2008). 28. Grieger, J. & Clifton, V. A Review of the Impact
of Dietary Intakes in Human Pregnancy on Infant Birthweight. Nutrients 7, 153–178 (2014). 29. Godfrey, K., Robinson, S., Barker, D. J.,
Osmond, C. & Cox, V. Maternal nutrition in early and late pregnancy in relation to placental and fetal growth. BMJ 312, 410–4 (1996).
30. Williamson, C. S. Nutrition in pregnancy. Nutr.
Bull. 31, 28–59 (2006).
31. Steegers-Theunissen, R. P. M., Twigt, J., Pestinger, V. & Sinclair, K. D. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum. Reprod.
Update 19, 640–655 (2013).
32. Griffin, J., Emery, B. R., Huang, I., Peterson, C. M. & Carrell, D. T. Comparative analysis of follicle morphology and oocyte diameter in four mammalian species (mouse, hamster, pig, and human). J. Exp. Clin. Assist. Reprod. 3, 2 (2006).
33. Singh, K. A. et al. Birth Weight and Body Composition of Neonates Born to Caucasian Compared With African-American Mothers.
Obstet. Gynecol. 115, 998–1002 (2010).
34. Lewis, R. M. et al. The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition. Ann. Nutr. Metab.
63, 208–215 (2013).
35. Linabery, A. M. et al. Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study. Pediatr. Obes. 8, 159–169 (2013).
36. Pomeroy, E., Wells, J. C. K., Cole, T. J., O’Callaghan, M. & Stock, J. T. Relationships of maternal and paternal anthropometry with neonatal body size, proportions and adiposity in an Australian cohort. Am. J. Phys. Anthropol.
156, 625–636 (2015).
37. Starling, A. P. et al. Associations of maternal BMI and gestational weight gain with neonatal adiposity in the Healthy Start study. Am. J. Clin.
Nutr. 101, 302–309 (2015).
38. Savitri, A. I. et al. Does pre-pregnancy BMI determine blood pressure during pregnancy? A prospective cohort study. BMJ Open 6, e011626 (2016).
39. Lewis, F. I. & McCormick, B. J. J. Revealing the Complexity of Health Determinants in Resource-poor Settings. Am. J. Epidemiol. 176, 1051–1059 (2012).
40. Burton, G. J., Barker, D. J. P., Moffett, A. & Thornburg, K. The Placenta and Human
Developmental Programming. (Cambridge
University Press, 2010). doi:10.1017/ CBO9780511933806
1
41. Proctor, L. K. et al. Placental size and the prediction of severe early-onset intrauterine growth restriction in women with low pregnancy-associated plasma protein-A.
Ultrasound Obstet. Gynecol. 34, 274–82 (2009).
42. Ducray, J. F., Naicker, T. & Moodley, J. Pilot study of comparative placental morphometry in pre-eclamptic and normotensive pregnancies suggests possible maladaptations of the fetal component of the placenta. Eur. J. Obstet. Gynecol. Reprod. Biol.
156, 29–34 (2011).
43. Odibo, A. O. et al. First-trimester serum analytes, biophysical tests and the association with pathological morphometry in the placenta of pregnancies with preeclampsia and fetal growth restriction. Placenta 32, 333–338 (2011).
44. Kajantie, E., Thornburg, K. L., Eriksson, J. G., Osmond, C. & Barker, D. J. P. In preeclampsia, the placenta grows slowly along its minor axis. Int. J. Dev. Biol. 54, 469–73 (2010). 45. Wilson, M. E. & Ford, S. P. Comparative
aspects of placental efficiency. Reprod. Suppl.
58, 223–32 (2001).
46. Fowden, A. L., Sferruzzi-Perri, A. N., Coan, P. M., Constancia, M. & Burton, G. J. Placental efficiency and adaptation: endocrine regulation. J. Physiol. 587, 3459–72 (2009). 47. Luque-Fernandez, M. A. et al. Is the
fetoplacental ratio a differential marker of fetal growth restriction in small for gestational age infants? Eur. J. Epidemiol. 30, 331–41 (2015). 48. Burton, G. J., Fowden, A. L. & Thornburg, K. L.
Placental Origins of Chronic Disease. Physiol.
Rev. 96, 1509–65 (2016).
49. Benirschke, K., Burton, G. (Graham J. . & Baergen, R. N. Pathology of the human
