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What are treatable foetal conditions during pregnancy?

What are treatable foetal conditions during pregnancy?


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What are different foetal conditions during pregnancy that could be treated with appropriate prenatal genetic testing?

I only know that pregnant women are encouraged to take certain supplements to make sure certain conditions won't develop in the foetus, and which are apparently also the case for deficiencies in human growth hormone, but I imagine there must be other specific cases that are treatable for specific conditions diagnosed to only a small number of cases?


Your question probably expresses a subtle confusion about the prenatal diagnostics and genetic testing.

So, genetic testing is one of the diagnostic methods in prenatal diagnostics (among with the other methods, see the list) which is used to diagnose genetic disorders of the foetus, whereas the disorders that are diagnosed on this stage are mostly genetic anomalies with dramatic impact on the feotus development, for example chromosome aberrations (like Down or Turner Syndromes). Should these conditions be diagnosed, the woman is given a choice to interrupt the pregnancy prematurely.

Less dramatic conditions (like sickle-cell disease) can be diagnosed at this time too, but are not treated before the birth.

The genetic disorders that are amenable to the dietary or medical treatment (like phenylketonuria or congenital hypothyroidism) are usually diagnosed in the newborn screening tests (newborn heel prickle test), because these screening is more precise and less dangerous compared to the pre-born diagnostics.


Welcome to the Living World

45 to 50 million MTPs are performed in a year all over the world (i.e. 1/5th of total number of conceived pregnancies).

MTP helps to decrease the population.

Many countries have not legalised MTP due to emotional, ethical, religious and social issues.

Government of India legalised MTP in 1971 with some strict conditions to check illegal female foeticides.

  • To avoid unwanted pregnancies due to casual intercourse or failure of the contraceptive used during coitus or rapes.
  • It is essential in cases where continuation of pregnancy could be harmful to the mother or to the foetus or both.

Problems related with MTP

  • Majority of the MTPs are performed illegally.
  • Misuse of amniocentesis test for foetal sex determination. If the foetus is female, it is followed by MTP. Such practices are dangerous for the young mother and foetus.

Government of India enacted The Medical Termination of Pregnancy (Amendment) Act, 2017 to reduce illegal abortion and consequent maternal mortality and morbidity.

According to this Act, a pregnancy may be terminated within the first 12 weeks on the opinion of a registered medical practitioner. If the pregnancy is between 12 - 24 weeks, two registered medical practitioners must be of the opinion.

SEXUALLY TRANSMITTED DISEASES (STDs)

E.g. Gonorrhoea, syphilis, genital herpes, chlamydiasis, genital warts, trichomoniasis, hepatitis-B & HIV leading to AIDS.

  • By sharing of injection needles, surgical instruments etc.
  • By transfusion of blood.
  • From infected mother to foetus.

Early symptoms: Itching, fluid discharge, slight pain, swellings, etc. in the genital region.

Absence or less significant early symptoms and the social stigma deter the infected persons to consult a doctor. This leads to pelvic inflammatory diseases (PID), infertility, ectopic pregnancies, abortions, still births, cancer of the reproductive tract etc.

All persons are vulnerable to STDs. These are very high among persons in the age group of 15-24 years.


How Common Is Diabetes During Pregnancy?

In the United States, about 1% to 2% of pregnant women have type 1 or type 2 diabetes and about 6% to 9% of pregnant women develop gestational diabetes. Diabetes during pregnancy has increased in recent years. Recent studies found that from 2000 to 2010, the percentage of pregnant women with gestational diabetes increased 56% and the percentage of women with type 1 or type 2 diabetes before pregnancy increased 37%.

Diabetes in pregnancy varies by race and ethnicity. Asian and Hispanic women have higher rates of gestational diabetes and black and Hispanic women have higher rates of type 1 or type 2 diabetes during pregnancy.


Gestational Diabetes

Gestational diabetes occurs when a woman who didn't have diabetes before pregnancy develops the condition during pregnancy.

Normally, the body digests parts of your food into a sugar called glucose. Glucose is your body's main source of energy. After digestion, the glucose moves into your blood to give your body energy.

To get the glucose out of your blood and into the cells of your body, your pancreas makes a hormone called insulin. In gestational diabetes, hormonal changes from pregnancy cause the body to either not make enough insulin, or not use it normally. Instead, the glucose builds up in your blood, causing diabetes, otherwise known as high blood sugar.

Managing gestational diabetes, by following a treatment plan outlined by a health care provider, is the best way to reduce or prevent problems associated with high blood sugar during pregnancy. If not controlled, it can lead to high blood pressure from preeclampsia and having a large infant, which increases the risk for cesarean delivery. 4


Progesterone and the immunology of pregnancy ☆

The foetal–placental unit is a semi-allograft and the immunological recognition of pregnancy, together with the subsequent response of the maternal immune system, is necessary for a successful pregnancy. This recognition of pregnancy results in an upregulation of progesterone receptors on activated lymphocytes amongst placental cells and decidual CD56+ cells. In the presence of sufficient progesterone, these cells synthesise progesterone induced blocking factor (PIBF), a mediator that exerts substantial anti-abortive activities. PIBF affects B cells and induces an increased production of asymmetric, non-cytotoxic antibodies. It also alters the profile of cytokine secretion by activated lymphocytes resulting in an increase in the production of non-inflammatory, non-cytotoxic interleukins (IL) (e.g. IL-3, IL-4 and IL-10) and a reduction in the production of inflammatory, cytotoxic cytokines (e.g. interferon (IFN)-δ, tumour necrosis factor (TNF)-α and IL-2). PIBF also inhibits the cytotoxity of natural killer (NK) cells by blocking their degranulation and perforin release, as well as inhibiting IFN-δ, TNF-α and IL-2-mediated transformation of NK cells into detrimental lymphokine activated killer (LAK) cells.


3. Micronutrients

During pregnancy, micronutrient requirements increase more than those of macronutrients, and inadequate intakes (and, thus, a low nutritional quality of the diet) can have significant consequences for both the mother and the developing fetus. In particular, there is evidence to support the physiologic role played by selected minerals and vitamins [12,32].

3.1. Iron

Involved in numerous enzymatic processes, iron (the foremost constituent of hemoglobin, myoglobin and various enzymes) plays essential roles in the transfer of oxygen to tissues. Iron deficiency causes anemia, a very common condition worldwide, affecting 22% of women of childbearing age in Europe and as much as 50% in developing countries [33]. In addition, iron deficiency is frequent in children between 6 and 36 months of age [34].

Meat and fish, but also legumes and green leafy vegetables are the main dietary sources of iron. In Italy, most dietary iron is found in a non-heme form, the absorption of which is closely linked to the overall composition of the diet and the individual nutritional status. For example, phytates and polyphenols are able to inhibit the absorption of non-heme iron, which is favored by ascorbic acid or by the consumption of meat and fish. In general, the human body is able to absorb 2%�% of non-heme versus about 25% of heme iron [7].

During pregnancy, iron requirement progressively increases until the third month, in parallel with the accumulation in fetal tissues. The transfer from the maternal compartment to the fetus is regulated by a complex mechanism of transport that include: release from maternal liver—in which it is stored as ferritin—into circulation as Fe 2+ , uptake by the placenta, transfer to the fetus (by a specific protein), oxidation to Fe 3+ , storage (as ferritin) or transport into the fetal circulation (still bound to transferrin) [35].

Inadequate intakes during pregnancy associated with the increase of iron demand makes pregnant mothers at even greater risk of iron deficiency, that may affect growth and development of the fetus and increase the risk of preterm delivery, low birth weight and post-partum hemorrhages [36,37]. Moreover, according to some recent studies, inadequate iron intakes during pregnancy are associated with increased cardiovascular risk for the offspring in adulthood [38].

In fact, iron supplementation in pregnancy is often recommended to improve pregnancy and birth outcomes [35,37,39]. On the other hand, an excessively high iron intake may expose women to oxidative stress, lipid peroxidation, impaired glucose metabolism, and gestational hypertension [40]. International recommendations in terms of intake levels range from the 27 mg per day for all pregnant women as advised by the Center for Disease Control and Prevention and the WHO to the 30� mg as advised by the Italian RDA ( Table 2 ).

Table 2

Different recommended intakes for iron in pregnancy and breastfeeding. Modified from [41].

Country/InstitutionPregnancy (mg/day)Breastfeeding (mg/day)
Italy [6]2711
Germany-Austria-Switzerland3020
Nordic Countries-15
WHO/FAO 1 -10� 2
France3010
Institute of Medicine279
Scientific Committee on Food-10
The Netherlands11-15-19 3 20

1 Supplementation recommended to all pregnant women 2 According to bioavailability 3 In the 1 st , 2 nd and 3 rd trimester respectively.

The immediate postpartum period is characterized by maternal susceptibility to anemia because of blood loss at delivery even in industrialized countries, where almost 50% of women require iron supplementation. However, the amount of iron secreted in milk is quite small and the WHO and FAO indications support a reduced supply of iron during breastfeeding to compensate for amenorrhea. Eleven mg per day should therefore be recommended and increased to 18 mg/day after the resumption of menstruation.

3.2. Iodine

Iodine is a major component of thyroid hormones and is essential for their functions, namely growth, formation and development of organs and tissues, in addition to the metabolism of glucose, proteins, lipids, calcium and phosphorus, and thermogenesis. Iodine is mostly found in organic form in the body, bound to thyroglobulin. The inadequate availability of iodine causes deficiency of circulating thyroid hormones, increase of pituitary thyroid stimulating hormone (TSH) and the consequent hypertrophy of the thyroid gland (goiter) [42].

Fish and shellfish are the main food sources of iodine, receiving it from the algae they eat, that absorb the mineral from marine water. However, due to water evaporation and rain, iodine is also absorbed by the soil and, consequently, enters into water, fruits, vegetables, and—in relevant concentrations—in milk, eggs and then meat (to a variable extent).

The average daily intake of iodine in the general population is less than that indicated by WHO, at the European level, where iodine deficiency affects mainly the child population [43], and all over the Italian territory (85� µg/day vs. 150 µg/day) [44].

In pregnancy, iodine deficiency can increase the risk of spontaneous abortion, perinatal mortality, birth defects and neurological disorders [45], and is considered by the WHO as the most important preventable cause of brain damage.

In the general population, iodine deficiency can be prevented by supplementing the diet with adequate amounts of this mineral, for example by using iodized salt.

During pregnancy, when iodine is necessary also for the production of fetal thyroid hormones (as the fetal thyroid begins to function only around the twelfth week of gestation), women need to increase iodine intake by about 50% [46,47].

Moreover, even in conditions of only mild or moderate iodine nutritional deficiency, the fetus and the newborn (especially preterm born) have a much higher risk of developing hypothyroidism compared to all other age groups (National Observatory for the Monitoring of Iodoprophylaxis in Italy). The most critical period goes from the second trimester of pregnancy to the third year of extrauterine life. Adequate supplementation with iodine, from pre-conception and until the end of the first trimester of pregnancy, reduces—up to 73%—the incidence of cretinism in the areas of highest deficiency risk [48]. The estimated amount that would avoid deficiency is 200 µg/day (compared to 150 µg/day for adults) according to the EFSA, or 250 µg/day according to the WHO/UNICEF joint document [49]. Two hundred µg/day are recommended also during lactation, to ensure a milk content of about 100� µg/100 mL.

3.3. Calcium

As the most abundant mineral in the human body, 99% located in the skeleton and in the teeth, calcium is critical to reach the peak bone mass in the first decades of life, to maintain bone mass in adulthood, and to slow the physiological age related reduction of bone mineral density.

Calcium deficiency may be worsened by genetic and hormonal factors along with insufficient physical activity. Calcium metabolism also requires vitamin D, the lack of which can also be due to calcium deficiency: in both cases, the result is a reduced mineralization of the bone matrix. Inadequate levels of calcium in children can result in rickets [50].

The main sources of calcium are milk and derivatives (about 50%), followed by cereals and vegetables (11% each) [51]. The bioavailability of calcium from these foods is different, being highest for milk and derivatives and for mineral water. Conversely, bioavailability from fiber- and phytate-rich vegetables is quite low. The efficiency of calcium absorption from food affects calcium concentrations in the body, which remains constant from adolescence to adulthood and decreases in post-menopausal women, by 2% every 10 years [50].

The EPIC (European Prospective Investigation into Cancer and Nutrition) study has shown a wide variability in calcium levels among the different European populations, with the lowest values in Italian women [52]. According to the results of the Italian survey INRAN-SCAI 2005-06, calcium intake in the Italian population corresponds to 76% of the recommendations [53].

Calcium is essential for fetal development. The requirement increases during pregnancy (from 50 mg/day at the halfway point, up to 330 mg/day at the end) and lactation, due to the mobilization from the maternal skeleton, the greater efficiency of intestinal absorption and the increased renal retention [54]. High birth weight, reduced risk of preterm delivery, and better blood pressure control are also associated with an adequate calcium intake during pregnancy. The transport of calcium from the maternal compartment to the fetus takes place through active transporters in the epithelial layer of the placenta. From the 20th week of pregnancy, calcium levels in the fetal circulation are higher than those detectable in the maternal plasma.

The recommendations for calcium intake are different in different countries, also for pregnant and breastfeeding women. The Italian RDA indicate PRI values of 1.2 g/day in the gestational period, while the WHO recommends 1.5𠄲.0 g/day from the 20th week until the end of pregnancy, especially for women at risk of gestational hypertension.

It has been proposed that a low-dose supplementation with calcium during pregnancy reduces the risk of developing both gestational hypertension and pre-eclampsia [55]. However, excessively high levels correlate with increased risk of developing HELLP (Haemolysis, Elevated Liver enzymes and Low Platelets) syndrome.

The daily amount of calcium secreted in breastmilk is quite variable (150 to 300 mg/day), mainly depending on the mobilization from bones and the reduced urinary secretion. Calcium stores in maternal bones are restored after weaning and the recovery of ovarian function [56].

Some studies have shown that calcium secretion in milk is substantially independent of its dietary intake and of supplementation. Therefore, the recommended intake during lactation is not different from that of the healthy adult female population (1.0 g/day). However, women with dietary calcium intakes lower than 300 mg/day and adolescents, with high basal requirements (1.2 g/day according to the RDA) are at risk of deficiency also during lactation.

3.4. Vitamin D

The term vitamin D comprises the two main molecular species that share vitamin activity: cholecalciferol (vitamin D3, derived from cholesterol and synthesized by the animal organisms) and ergocalciferol (vitamin D2, derived from ergosterol, found in vegetables).

The circulating levels of vitamin D are only partly affected by the dietary intakes. In fact, only the first of the two hydroxylation processes occurring in vitamin D metabolism (e.g., that responsible for the production of 25-hydroxy-vitamin D) is modulated by the dietary contribution to some extent (the increase of circulating levels is not proportional to the amount ingested). The hydroxylation into 1,25-hydroxy-vitamin D in the proximal renal tubules is closely regulated by feedback mechanisms and primarily depends on the requirement for calcium and phosphorus [57].

The endogenous synthesis of vitamin D requires exposure to ultraviolet radiation with a wavelength between 290 and 315 nm, and is influenced by several factors, related to both the individual’s characteristics (such as sex and phenotype, weight), and environmental factors (the degree of physical activity, latitude, season, time of exposure to sunlight, pollution, use of sunscreens and supplements). With aging, the synthesis of vitamin D in the epidermis layer becomes less efficient also, diseases associated with intestinal malabsorption, such as celiac disease, Crohn’s disease, cystic fibrosis, ulcerative colitis, liver and kidney disorders and some pharmacological treatments, may contribute to the development of vitamin D deficiency [57].

Vitamin D deficiency is common in Italy too [52], in the geriatric population and during winter. Higher intakes may be required for obese subjects, due to the high depots of the vitamin in adipose tissue [58].

High amounts of vitamin D are contained in cod liver oil. Fish (especially fatty fish such as herring and salmon) are also major food sources, while pork liver, eggs, butter, high fat cheeses provide smaller amounts, but relevant to the total intake.

In the first stage of pregnancy, vitamin D (mainly Vitamin D3, the predominant form in the maternal blood) is involved in the regulation of cytokine metabolism and in the modulation of the immune system, thereby contributing to the embryo implantation and regulating the secretion of several hormones.

Vitamin D deficiency in mothers and breastfed infants was observed several decades ago in some Nordic countries, especially in winter, because of the lack of natural light [59]. However, vitamin D deficiency is very common during pregnancy even in countries with sunny climates and is associated with an increased risk of developing pre-eclampsia and gestational diabetes mellitus. The season of birth, ethnicity, and maternal prophylaxis during pregnancy affect the vitamin D status of infants. Low birth weight, impaired skeletal development, and respiratory infections and allergic diseases in the early years of life are often associated with inadequate contribution of vitamin D from the mother’s diet.

According to a recent systematic review, maternal supplementation during pregnancy reduces the risk of pre-eclampsia as well as preterm delivery and low birth weight [60].

Despite the lack of consensus on adequate intakes among different countries ( Table 3 ), supplementation with vitamin D is recommended for all pregnant women at a dose of 600 IU/day (15 µg/day) [57].

Table 3

Recommended intakes for vitamin D in adult and elderly population, and in pregnant and breastfeeding women, in some European countries. Modified from [57].

CountriesAdult (μg/die)Elderly (μg/die)Pregnancy (μg/die)Breastfeeding (μg/die)
Austria20202020
Belgium10�152020
France551010
Germany20202020
Ireland0�101010
Italy 15201515
Spain15201515
Switzerland20202020
Turkey1010
The Netherland 10201010
Scandinavian Countries10201010
UK101010

In women at risk for vitamin D deficiency, the recommendations should be reach 1000� IU/day. Prophylaxis with vitamin D should be planned from the beginning and throughout the pregnancy, as underlined also in the recent consensus document from the Italian pediatric societies [61].

Given the influence of sunlight exposure on vitamin D metabolism, attention to ethnic groups with hyper-pigmented skin or with little exposure to sunlight should be paid also during lactation. Moreover, the habitual dietary intake of vitamin D may be limited in specific conditions of higher requirements and in areas and/or countries with little availability of food sources [62]. Breastmilk, in fact, contains amounts of vitamin D (㲀 IU/L) that are insufficient for deficit prevention in the first year of life [63]. An intake of 15 µg/day (600 IU/day), e.g., in women of childbearing age, is therefore needed to meet the requirement for vitamin D during breastfeeding, as highlighted in the aforementioned consensus document. These levels can be increased up to 1000� IU/day for the whole breastfeeding period in presence of risk factors for deficiency.

3.5. Folic Acid

Folates play a crucial role in many metabolic reactions such as the biosynthesis of DNA and RNA, methylation of homocysteine to methionine, and amino acid metabolism. In fact, metabolically active forms of folates act as transport co-enzymes facilitating the transfer of carbon units from one compound to another. They are therefore essential for health: inadequate dietary levels can give rise to anemia, leucopenia, and thrombocytopenia [64]

Folates are mostly found in green leafy vegetables, fruits (such as oranges), cereals and offal. Their bioavailability from foods depends on the presence of anti-nutrients, which can reduce their absorption.

The requirement for folates undergoes a progressive increase throughout the periconceptional period, in association with the use for the development of cells and fetal tissues [65]. Maternal supplementation with folic acid is widely recommended to all women of childbearing age, especially to reduce the risk of neural tube defects [66,67]. According to recent studies, folic acid supplementation during pregnancy should also reduce the risk of congenital heart disease and support proper development of the placenta [68].

The RDA during pregnancy increases by 50% for pregnant as compared with non-pregnant women of childbearing age (600 µg/day vs. 400 µg/day). Ideally, supplementation should begin two months before conceiving and even reach 800 µg/day [69]. The use of folic acid-based supplements is considered as safe [65]. The benefits of higher amounts are unclear.

The folate concentrations in breastmilk increase progressively from colostrum to mature milk, reaching much higher levels than those measured in maternal plasma. The absence of a correlation between maternal status and breastmilk content suggests an active role of the mammary glands in the transport and regulation of folate secretion, only marginally influenced by dietary intakes [70].

Intakes of folates by the breastfeeding mother should be increased by 25%, up to 500 µg/day [71].


What are treatable foetal conditions during pregnancy? - Biology

Abstract

Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult organism, except notably among certain eusocial species (mostly haplodiploid insects).

In humans, infertility may describe a woman who is unable to conceive as well as being unable to carry a pregnancy to full term. There are many biological and other causes of infertility, including some that medical intervention can treat. Infertility rates have increased by 4% since the 1980s, mostly from problems with fecundity due to an increase in age. About 40% of the issues involved with infertility are due to the man, another 40% due to the woman, and 20% result from complications with both partners.

Women who are fertile experience a natural period of fertility before and during ovulation, and they are naturally infertile during the rest of the menstrual cycle. Fertility awareness methods are used to discern when these changes occur by tracking changes incervical mucus or basal body temperature

Infertility is &ldquoa disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (and there is no other reason, such as breastfeeding or postpartum amenorrhea). Primary infertility is infertility in a couple who have never had a child. Secondary infertility is failure to conceive following a previous pregnancy. Infertility may be caused by infection in the man or woman, but often there is no obvious underlying cause.

One definition of infertility that is frequently used in the United States by doctors who specialize in infertility, to consider a couple eligible for treatment is:

&bull a woman under 35 has not conceived after 12 months of contraceptive-free intercourse. Twelve months is the lower reference limit for Time to Pregnancy (TTP) by the World Health Organization.

&bull a woman over 35 has not conceived after 6 months of contraceptive-free sexual intercourse

Theory

Researchers commonly base demographic studies on infertility prevalence on a five-year period. Practical measurement problems, however, exist for any definition, because it is difficult to measure continuous exposure to the risk of pregnancy over a period of years.

Primary vs. secondary infertility

Primary infertility is defined as the absence of a live birth for women who desire a child and have been in a union for at least five years, during which they have not used any contraceptives. The World Health Organization also adds that 'women whose pregnancy spontaneously miscarries, or whose pregnancy results in a still born child, without ever having had a live birth would present with primarily infertility

Secondary infertility is defined as the absence of a live birth for women who desire a child and have been in a union for at least five years since their last live birth, during which they did not use any contraceptives.

Thus the distinguishing feature is whether or not the couple have ever had a pregnancy which led to a live birth.

Effects

Psychological impact

The consequences of infertility are manifold and can include societal repercussions and personal suffering. Advances in assisted reproductive technologies, such as IVF, can offer hope to many couples where treatment is available, although barriers exist in terms of medical coverage and affordability. The medicalization of infertility has unwittingly led to a disregard for the emotional responses that couples experience, which include distress, loss of control, stigmatization, and a disruption in the developmental trajectory of adulthood.

Infertility may have profound psychological effects. Partners may become more anxious to conceive, increasing sexual dysfunction Marital discord often develops in infertile couples, especially when they are under pressure to make medical decisions. Women trying to conceive often have clinical depression rates similar to women who have heart disease or cancer. Even couples undertaking IVF face considerable stress.

The emotional losses created by infertility include the denial of motherhood as a rite of passage the loss of one&rsquos anticipated and imagined life feeling a loss of control over one&rsquos life doubting one&rsquos womanhood changed and sometimes lost friendships and, for many, the loss of one&rsquos religious environment as a support system.

Emotional stress and marital difficulties are greater in couples where the infertility lies with the man.

Social impact

In many cultures, inability to conceive bears a stigma. In closed social groups, a degree of rejection (or a sense of being rejected by the couple) may cause considerable anxiety and disappointment. Some respond by actively avoiding the issue altogether middle-class men are the most likely to respond in this way.

In an effort to end the shame and secrecy of infertility, Redbook in October 2011 launched a video campaign, The Truth About Trying, to start an open conversation about infertility, which strikes one in eight women in the United States. In a survey of couples having difficulty conceiving, conducted by the pharmaceutical company Merck, 61 percent of respondents hid their infertility from family and friends. Nearly half didn't even tell their mothers. The message of those speaking out: It's not always easy to get pregnant, and there's no shame in that.

There are legal ramifications as well. Infertility has begun to gain more exposure to legal domains. An estimated 4 million workers in the U.S. used the Family and Medical Leave Act (FMLA) in 2004 to care for a child, parent or spouse, or because of their own personal illness. Many treatments for infertility, including diagnostic tests, surgery and therapy for depression, can qualify one for FMLA leave. It has been suggested that infertility be classified as a form of disability.

Causes

Sexually transmitted disease

Infections with the following sexually transmitted pathogens have a negative effect on fertility: Chlamydia trachomatis, Neisseria gonorrhoeae, and Syphilis. There is a consistent association of Mycoplasma genitalium infection and female reproductive tract syndromes. M. genitalium infection is associated with increased risk of infertility.

Genetic

A Robertsonian translocation in either partner may cause recurrent spontaneous abortions or complete infertility.

Other causes

Factors that can cause male as well as female infertility are:

&bull DNA damage

&bull DNA damage reduces fertility in female ovocytes, as caused by smoking,other xenobiotic DNA damaging agents (such as radiation or chemotherapy)or accumulation of the oxidative DNA damage 8-hydroxy-deoxyguanosine

&bull DNA damage reduces fertility in male sperm, as caused by oxidative DNA damage,smoking,other xenobiotic DNA damaging agents (such as drugs or chemotherapy)or other DNA damaging agents including reactive oxygen species, fever or high testicular temperature

&bull General factors

&bull Diabetes mellitus, thyroid disorders,undiagnosed and untreated coeliac disease adrenal disease

&bull The presence of anti-thyroid antibodies is associated with an increased risk of unexplained subfertility with an odds ratio of 1.5 and 95% confidence interval of 1.1&ndash2.0
&bull Environmental factors

&bull Toxins such as glues, volatile organic solvents or silicones, physical agents, chemical dusts, and pesticides Tobacco smokers are 60% more likely to be infertile than non-smokers.

German scientists have reported that a virus called Adeno-associated virus might have a role in male infertility, though it is otherwise not harmful. Other diseases such aschlamydia, and gonorrhea can also cause infertility, due to internal scarring (fallopian tube obstruction).

Females

The following causes of infertility may only be found in females. For a woman to conceive, certain things have to happen: intercourse must take place around the time when an egg is released from her ovary the system that produces eggs has to be working at optimum levels and her hormones must be balanced.

For women, problems with fertilisation arise mainly from either structural problems in the Fallopian tube or uterus or problems releasing eggs. Infertility may be caused by blockage of the Fallopian tube due to malformations, infections such as Chlamydia and/or scar tissue. For example, endometriosis can cause infertility with the growth of endometrial tissue in the Fallopian tubes and/or around the ovaries. Endometriosis is usually more common in women in their mid-twenties and older, especially when postponed childbirth has taken place.

Another major cause of infertility in women may be the inability to ovulate. Malformation of the eggs themselves may complicate conception. For example, polycystic ovarian syndrome is when the eggs only partially developed within the ovary and there is an excess of male hormones. Some women are infertile because their ovaries do not mature and release eggs. In this case synthetic FSH by injection or Clomid (Clomiphene citrate) via a pill can be given to stimulate follicles to mature in the ovaries.
Other factors that can affect a woman's chances of conceiving include being overweight or underweight, or her age as female fertility declines after the age of 30.

Sometimes it can be a combination of factors, and sometimes a clear cause is never established.

Common causes of infertility of females include:

&bull Ovulation problems (e.g. polycystic ovarian syndrome, PCOS, the leading reason why women present to fertility clinics due to anovulatory infertility)

&bull pelvic inflammatory disease caused by infections like tuberculosis

The main cause of male infertility is low semen quality. In men who have the necessary reproductive organs to procreate, infertility can be caused by low sperm count due to endocrine problems, drugs, radiation, or infection. There may be testicular malformations, hormone imbalance, or blockage of the man's duct system. Although many of these can be treated through surgery or hormonal substitutions, some may be indefinite. Infertility associated with viable, but immotile sperm may be caused by primary ciliary dyskinesia

Combined infertility

In some cases, both the man and woman may be infertile or sub-fertile, and the couple's infertility arises from the combination of these conditions. In other cases, the cause is suspected to be immunological or genetic it may be that each partner is independently fertile but the couple cannot conceive together without assistance.

Unexplained infertility

In the US, up to 20% of infertile couples have unexplained infertility.In these cases abnormalities are likely to be present but not detected by current methods. Possible problems could be that the egg is not released at the optimum time for fertilization, which it may not enter the fallopian tube, sperm may not be able to reach the egg, fertilization may fail to occur, transport of the zygote may be disturbed, or implantation fails. It is increasingly recognized that egg quality is of critical importance and women of advanced maternal age have eggs of reduced capacity for normal and successful fertilization. Also, polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.

Treatment

Treatment depends on the cause of infertility, but may include counseling, fertility treatments, which include in vitro fertilization. According to ESHRE recommendations, couples with an estimated live birth rate of 40% or higher per year are encouraged to continue aiming for a spontaneous pregnancy. Treatment methods for infertility may be grouped as medical or complementary and alternative treatments. Some methods may be used in concert with other methods. Drugs used for both women and men includeclomiphene citrate, human menopausal gonadotropin (hMG), follicle-stimulating hormone (FSH), human chorionic gonadotropin (hCG), gonadotropin-releasing hormone (GnRH)analogues, aromatase inhibitors, and metformin

Medical treatments

Medical treatment of infertility generally involves the use of fertility medication, medical device, surgery, or a combination of the following. If the sperm are of good quality and the mechanics of the woman's reproductive structures are good (patent fallopian tubes, no adhesions or scarring), a course of ovarian stimulating medication maybe used. The physician or WHNP may also suggest using a conception cap cervical cap, which the patient uses at home by placing the sperm inside the cap and putting the conception device on the cervix, or intrauterine insemination (IUI), in which the doctor or WHNP introduces sperm into the uterus during ovulation, via a catheter. In these methods, fertilization occurs inside the body.

If conservative medical treatments fail to achieve a full term pregnancy, the physician or WHNP may suggest the patient undergo in vitro fertilization (IVF). IVF and related techniques (ICSI, ZIFT, and GIFT) are called assisted reproductive technology (ART) techniques.

ART techniques generally start with stimulating the ovaries to increase egg production. After stimulation, the physician surgically extracts one or more eggs from the ovary, and unites them with sperm in a laboratory setting, with the intent of producing one or more embryos. Fertilization takes place outside the body, and the fertilized egg is reinserted into the woman's reproductive tract, in a procedure called embryo transfer

Other medical techniques are e.g. tuboplasty, assisted hatching, and Preimplantation genetic diagnosis.

Effects on the Population

Perhaps except for infertility in science fiction, films and other fiction depicting emotional struggles of assisted reproductive technology have had an upswing first in the latter part of the 2000s decade, although the techniques have been available for decades. Yet, the number of people that can relate to it by personal experience in one way or another is ever growing, and the variety of trials and struggles is huge.

Pixar's Up contains a depiction of infertility in an extended life montage that lasts the first few minutes of the film.

There are several ethical issues associated with infertility and its treatment.

&bull High-cost treatments are out of financial reach for some couples.

&bull Debate over whether health insurance companies (e.g. in the US) should be required to cover infertility treatment.

&bull Allocation of medical resources that could be used elsewhere

&bull The legal status of embryos fertilized in vitro and not transferred in vivo. (See also Beginning of pregnancy controversy).

&bull Pro-life opposition to the destruction of embryos not transferred in vivo.

&bull IVF and other fertility treatments have resulted in an increase in multiple births, provoking ethical analysis because of the link between multiple pregnancies, premature birth, and a host of health problems.

&bull Religious leaders' opinions on fertility treatments for example, the Roman Catholic Church views infertility as a calling to adopt or to use natural treatments (medication, surgery, and/or cycle charting) and members must reject assisted reproductive technologies.

&bull Infertility caused by DNA defects on the Y chromosome is passed on from father to son. If natural selection is the primary error correction mechanism that prevents random mutations on the Y chromosome, then fertility treatments for men with abnormal sperm (in particular ICSI) only defer the underlying problem to the next male generation.

Many countries have special frameworks for dealing with the ethical and social issues around fertility treatment.

&bull One of the best known is the HFEA &ndash The UK's regulator for fertility treatment and embryo research. This was set up on 1 August 1991 following a detailed commission of enquiry led by Mary Warnock in the 1980s

&bull A similar model to the HFEA has been adopted by the rest of the countries in the European Union. Each country has its own body or bodies responsible for the inspection and licencing of fertility treatment under the EU Tissues and Cells directive

&bull Regulatory bodies are also found in Canada and in the state of Victoria in Australia

CONCLUSIONS

Infertility is often not seen (by the West) as being an issue outside industrialized countries.This is because of assumptions about overpopulation problems and hyper fertility in developing countries, and a perceived need for them to decrease their populations and birth rates. The lack of health care and high rates of life-threatening illness (such as HIV/AIDS) in developing countries, such as those in Africa, are supporting reasons for the inadequate supply of fertility treatment options.Fertility treatments, even simple ones such as treatment for STIs that cause infertility, are therefore not usually made available to individuals in these countries.
Despite this, infertility has profound effects on individuals in developing countries, as the production of children is often highly socially valued and is vital for social security and health networks as well as for family income generation. Infertility in these societies often leads to social stigmatization and abandonment by spouses.Infertility is, in fact, common in sub-Saharan Africa. Unlike in the West, secondary infertility is more common than primary infertility, being most often the result of untreated STIs or complications from pregnancy/birth.

Due to the assumptions surrounding issues of hyper-fertility in developing countries, ethical controversy surrounds the idea of whether or not access to assisted reproductive technologies should comprise a critical aspect of reproductive health or at least, whether or not the distribution and access of such technologies should be subject to greater equity. However, as highlighted by Inhorn the overarching conceptualisation of infertility, to a great extent, disguises important distinctions that can be made within a local context, both demographically and epidemiological and moreover, that these factors are highly significant in the ethics of reproduction.

An important factor, argues Inhorn, is the positioning of men within the paradigm of reproductive health, whereby because rates of general infertility mask differences between male and female infertility, men remain a largely invisible facet within the theorisation and discourse surrounding infertility, as well as the related treatments and biotechnologies. This is particularly significant given that male infertility accounts for more than half of all cases of infertility and moreover, it is evident that the attitudes and behaviours of men have profound implications for the reproductive health of both individuals and couples. For example, Inhorn notes that when couples in Egypt are faced with seemingly intractable infertility problems - due to a range of family and societal pressures that centre around the place of children in constituting the gender identity of men and women - it is often the women who is forced to seek continued treatment this continues to occur, even in known instances of male infertility and that the constant seeking of treatment frequently becomes iatrogenic for the women.

Inhorn states that infertility often leads to &ldquomarital demise, physical violence, emotional abuse, social exclusion, community exile, ineffective and iatrogenic therapies, poverty, old age insecurity, increased risk of HIV/AIDS, and death&rdquoSignificantly, Inhorn demonstrates that this phenomenon cannot simply be explained by a lack of knowledge, rather it occurs in a complex interaction between the centrality of children in the male gender identity as a symbol of maturity and the relative lack of power of women in Egyptian society, whereby they effectively become scapegoats for a culturally accepted narrative as a site of blame for the lack of childlessness. It should be emphasised that this is not simply an issue of &ldquowomen oppressed by men&rdquo but rather, that men and women both share the burden of this narrative, but in different, unequal and highly complex ways.

Therefore, while the notion that reproductive health is a &lsquowomen&rsquos issue&rsquo, may have powerful social currency, especially within popular discourse and indigenous systems of meaning, the reality of infertility suggests that medical and health paradigms have a significant part to play in challenging the validity of this entrenched belief . Moreover, the effectiveness of any therapeutic intervention, medical or otherwise will be contingent on such outcomes and has an important part to play in the alleviation of gendered suffering, especially the burden imposed on women, who continue to suffer disproportionately from the effects of infertility.

High costs may also be a factor and research by the Genk Institute for Fertility Technology, in Belgium, claimed a much lower cost methodology (about 90% reduction) with similar efficacy, which may be suitable for some fertility treatment. At the 1994 United Nations International Conference on Population and Development (ICPD) in Cairo, the prevention and treatment of infertility was accepted into the program of action for reproductive healthcare. Infertility has shown to have a greater affect on developing nations than on birth rates or population control, but also on a social level as well.

Reproduction is a large aspect of life for many cultures within developing nations, and infertility can lead to social and familial problems such as rejection or abandonment as well as personal psychological issues. Currently, fertility treatment options and programs are only available through private health sectors in developing nations and little-to-no treatment is available through public health sectors. The fertility treatment options offered through the private sectors are often costly or not easily accessible. Additionally, counseling is considered an essential aspect of fertility treatment, and due to lack of education and resources such forms of therapy remain scarce as well. While quality fertility care is not readily available in developing nations (such as sub-Saharan African countries), a standard procedure of care could be easily implemented for a low cost as a basic intervention. The lack of fertility treatment is problematic, and high birth and population rates are every reason to implement treatment options rather than reject them.

Reference

 Biological Science: Third Edition By, N. P. O. Green (Author), G. W. Stout (Author), D. J. Taylor (Author), R. Soper (Editor)


Hormones During Pregnancy

Many hormone levels are affected in the body during pregnancy. Several hormones play major roles during pregnancy. These are:

Human chorionic gonadotropin hormone (hCG). This hormone is only made during pregnancy. It is made almost exclusively in the placenta. HCG hormone levels found in the mother's blood and urine rise a lot during the first trimester. They may play a part in the nausea and vomiting often linked to pregnancy.

Human placental lactogen (hPL). This hormone is also known as human chorionic somatomammotropin. It is made by the placenta. It gives nutrition to the fetus. It also stimulates milk glands in the breasts for breastfeeding.

Estrogen. This group of hormones helps develop the female sexual traits. It is normally formed in the ovaries. It is also made by the placenta during pregnancy to help maintain a healthy pregnancy.

Progesterone. This hormone is made by the ovaries and by the placenta during pregnancy. It stimulates the thickening of the uterine lining for implantation of a fertilized egg.


The maternal immune system during pregnancy and its influence on fetal development

1 Department of Obstetrics, Gynecology and Women's Health, New Jersey Medical School, Rutgers University, Newark, 2 Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, 3 Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers University, Newark, 4 Graduate School of Biomedical Sciences, Rutgers University, Newark, NJ, USA

Abstract: The maternal immune system plays a critical role in the establishment, maintenance, and completion of a healthy pregnancy. However, the specific mechanisms utilized to achieve these goals are not well understood. Various cells and molecules of the immune system are key players in the development and function of the placenta and the fetus. Effector cells of the immune system act to promote and yet limit placental development. The T helper 1 (Th1)/T helper 2 (Th2) immune shift during pregnancy is well established. A fine balance between proinflammatory and anti-inflammatory influences is required. We herein review the evidence regarding maternal tolerance of fetal tissues and the underlying cell-mediated immune and humoral (hormones and cytokines) mechanisms. We also note the many unanswered questions in our understanding of these mechanisms. In addition, we summarize the clinical manifestations of an altered maternal immune system during pregnancy related to susceptibility to common viral, bacterial, and parasitic infections, as well as to autoimmune diseases.

Keywords: maternal&ndashfetal interface, immune system, fetal tolerance, lymphocyte subsets, decidua, pregnancy

The relationship between mother and fetus has fascinated immunologists for decades. Survival of the semiallogeneic fetus was used by Billingham et al 1 in 1953 as an example of immune tolerance to the fetus by the maternal immune system. Numerous hypotheses related to placental protection of the fetus, including expression (or lack of expression) of histocompatibility antigens on fetal tissues, maternal immune tolerance to fetal antigens, and inhibition and/or regulation of maternal antifetal immune responses have been put forth to explain the survival of the “immunogenic” fetus. Yet, the mechanisms still remain to be totally clarified.

Part of the difficulty in studying these mechanisms is due to the variation among species in which such investigations are conducted. Mice are used for many of these investigations because of their short gestational time, relatively lower cost, well-defined genetics (including mutant, transgenic, and knockout strains), and availability of a wide spectrum of antibodies and reagents to perform immunologic and molecular studies. However, differences in the reproductive system in general, and the feto–materno–placental unit in particular, as well as differences in the development and function of immune elements, often preclude direct extension of results observed in mice to humans. In contrast, studies designed to investigate such questions in humans are unethical, and studies incorporating nonhuman primates for these investigations raise similar moral issues and are also prohibitively expensive.

Therefore, our review is not designed to address all the unanswered questions surrounding the significance of the maternal immune system during pregnancy and its influence on fetal development. Rather, our goals are to identify the gaps in the knowledge and understanding about the topic from the published literature about various species and to acknowledge contexts wherein differences preclude a direct comparison with humans. Notwithstanding these differences however, investigations conducted in other species, such as rodents, do serve to identify possible strategies to address some of these unanswered questions.

Additionally, we take an interdisciplinary approach as coauthors who bring clinical and basic science perspectives and expertise in reproductive and immunological disciplines. Thus, we address topics related to definition of the maternal–fetal interface, as well as the significance of maternal immune responses in regulating key early events during both pregnancy (eg, implantation, angiogenesis, and vascular remodeling) and in development of the fetal immune system. We then review current understanding about maternal tolerance of fetal tissues and the underlying cellular and humoral immune mechanisms. Finally, we examine clinical manifestations of an altered maternal immune system during pregnancy related to susceptibility to certain viral, bacterial, and parasitic infections, as well as to autoimmune disorders.

Description and definition of the maternal–fetal interface

In women, invasion by the trophoblast is extensive, encompassing the endometrium as well as the inner third of the myometrium. 2 To accommodate this, a pronounced remodeling process must occur, involving multiple cellular compartments of the uterus in preparation for implantation and establishment and support of pregnancy. This process, decidualization, occurs in humans on a cyclic basis beginning in the midluteal phase of the menstrual cycle, independently of pregnancy. In contrast, in rodents and most other species, decidualization requires the presence of a blastocyst. The term maternal decidua thus refers to the uterine mucosal layer (endometrium) after it has undergone decidualization, the requisite and complex differentiation process involving the multiple cellular compartments of the endometrium in preparation for embryo implantation.

The parenchymal cellular compartments of the maternal decidua include the glandular epithelial compartment, the luminal epithelial compartment, the endothelium of the spiral arteries, and the decidualized stromal cells, all of which undergo dramatic transformation in preparation for pregnancy. The glandular epithelium acquires increased secretory activity under the influence of maternal progesterone. 3 Dramatic remodeling of spiral arteries occurs during decidualization, discussed in greater detail later in this review. The endometrial stromal fibroblasts that undergo dramatic morphologic and biochemical differentiation in preparation for implantation and support of pregnancy become known as decidual cells, or decidualized stromal cells. Decidualized stromal cells no longer have the characteristic spindle shape of the endometrial stromal fibroblast and, instead, have acquired an epithelioid phenotype, characterized by progressive cell enlargement, rounding of the nucleus, and expansion of the rough endoplasmic reticulum and Golgi complex, all consistent with the transformation into a secretory cell. 3 Major secretory products of decidualized stromal cells include prolactin and insulin-like growth-factor-binding protein-1, the hallmark proteins widely used as phenotypic markers of decidualization. 4 These cells also secrete a number of cytokines and growth factors (eg, interleukin [IL]-11, epidermal growth factor [EGF], heparin-binding EGF-like growth factor), which further regulate the process of decidualization in an autocrine and/or paracrine manner. 5

In addition to the parenchymal cellular compartments making up the maternal decidua, various populations of immune cells exist in the human endometrium throughout the menstrual cycle. In early pregnancy, leukocytes are abundant, comprising 30%󈞔% of all human decidual stromal compartment cells. 6 The basalis layer of the human endometrium contains lymphoid aggregates composed of T-cells and a small number of B-cells. In the functionalis layer of the proliferative phase, few uterine natural killer (uNK) cells, T-cells, and macrophages are scattered throughout the stromal compartment. 7 Although the numbers of T-cells and macrophages remain largely unchanged throughout the luteal phase and during the process of decidualization, 7 there is a dramatic increase in the number of uNK cells postovulation, playing a critical role in preparation of the endometrium for pregnancy. With regard to decidual immune cell populations during early pregnancy, studies using flow cytometry and immunostaining of human tissues demonstrate that the majority of first-trimester human decidual leukocytes are uNK cells (ㅾ%), followed by macrophages (ㅌ%). 8 T-cells make up approximately 10%󈞀% of decidual leukocytes, and dendritic cells (DCs) and B-cells are rare. 8 As in humans, uNK cells are the predominant leukocyte population in the decidua of the rhesus macaque and the mouse, but studies to determine relative numbers of other leukocyte populations in murine decidua are lacking. The functions of each immune cell type at the maternal–fetal interface are discussed in more detail in this review, with a particular focus on uNK cells.

Fetal: placenta, fetal membranes (amnion and chorion)

Structurally, the interface between the uterine mucosa and the extraembryonic tissues is commonly referred to as the maternal–fetal interface. This is represented in Figure 1, which depicts the maternal immune cells and the fetal trophoblast. 9

Figure 1 Schematic depiction of the human maternal–fetal interface including maternal immune cells such as uterine natural killer (uNK) cells, macrophages, (the predominant immune cell types) and T helper (Th) cells, T-cytotoxic (Tc) cells, dendritic cells, as well as invading trophoblast cells.
Notes: Copyright © 2009 by SAGE Publications. Modified from: Weiss G, Goldsmith LT, Taylor RN, Bellet D, Taylor HS. Inflammation in reproductive disorders. Reproductive Sciences. 200916(2):216� by permission of SAGE Publications. 9

Extraembryonic cells in direct contact with maternal cells are the trophoblast cells, derived from the trophectoderm layer surrounding the blastocyst. In women, invasion by the trophoblast into maternal spiral arteries substantially increases uterine blood flow, puts maternal blood in direct contact with fetal trophoblast cells, and ensures sufficient delivery of maternal nutrients and oxygen to the placenta. 10 However, the maternal and fetal circulations do not mix. After attachment of the blastocyst to the endometrial luminal epithelium, trophoblast cells invade the decidua as depicted in Figure 1. The trophoblast, composed of an inner cell layer (cytotrophoblast) and outer cell layer (syncytiotrophoblast), does not give rise to the fetus itself, but rather to the placenta and fetal membranes (amnion and chorion). As the blastocyst and surrounding trophoblast invade the decidua, one pole of the blastocyst remains oriented toward the endometrial lumen, and the other remains buried in the decidua, which will develop into the anchoring cytotrophoblasts and villous trophoblasts, contributing to formation of the placenta, chorion, and amnion. Of note are the species differences in the degree of invasion by trophoblast cells, which have been documented in detail elsewhere. 11 In distinct contrast to the process in women, trophoblast invasion is minimal in rodents. 11,12

Significance of maternal immune responses during pregnancy

Immune cell subtypes and their functional significance

Immune cells accumulating in the human endometrium at the time of decidualization play critical and diverse roles at the maternal–fetal interface, including functions in implantation, placental development, and immunity against infectious diseases. Of all decidual leukocyte populations, the most abundant are the phenotypically unique uNK cells. These cells dramatically increase in number in the human endometrium 3𔃃 days postovulation, accounting for 25%󈞔% of endometrial leukocytes prior to implantation and accounting for ㅾ% of decidual leukocytes in the first trimester. 7,8 It is critical to note that uNK cells are both phenotypically and functionally distinct from peripheral NK cells. Phenotypically, they are identified by expression of the NK cell marker CD56, expressed at high concentrations (CD56 bright ), but they lack expression of CD16, found on most peripheral NK cells (CD56 dim CD16 + ). 7 In terms of function, peripheral CD56 dim CD16 + NK cells are highly cytotoxic, mediating both natural and antibody-dependent killing, whereas uNK cells are only weakly cytotoxic and do not normally kill trophoblast cells. 13 In addition, uNK cells are a potent source of immunoregulatory cytokines, 14 matrix metalloproteinases (MMPs), 15 and angiogenic factors. 16 These various factors mediate extracellular matrix remodeling, trophoblast invasion, and angiogenesis, which are key processes in placentation and establishment of early pregnancy at the maternal-fetal interface. 17

In addition to uNK cells, decidual macrophages are relatively abundant, comprising ㅌ% of the human decidual leukocyte population in the first trimester. 8 In normal pregnancy, most of the macrophages at the maternal–fetal interface are of the M2 (immunomodulatory) phenotype. 18 Present in decidua prior to the presence of extravillous trophoblast, 19 macrophages play a role in early spiral artery remodeling by producing factors associated with tissue remodeling (MMP-9) and angiogenesis (vascular endothelial growth factor [VEGF]). 18 Apoptosis is an important event during spiral artery remodeling and trophoblast invasion, and decidual macrophages phagocytose apoptotic cells in remodeled vascular wall and apoptotic trophoblast cells, thereby preventing the release of proinflammatory substances from the apoptotic cells into the decidua. 20 First-trimester decidual macrophages may also be responsible for inhibition of human uNK cell–mediated lysis of invasive cytotrophoblast, mediated by decidual secretion of transforming growth factor-beta-1 (TGF-۵), as demonstrated in human in vitro studies. 21 In distinct contrast to human uNK cells, which peak in number at 20 weeks gestation and are nearly absent in the decidua at term, 12 decidual macrophages are present throughout pregnancy, but the precise role of decidual macrophages at the end of pregnancy remains unknown. 18

T-cells are also fairly abundant in human decidua, comprising ㅂ%󈞀% of the human decidual leukocyte population, 22,23 of which 30%󈞙% are CD4 + T-cells and 45%󈞷% are CD8 + T-cells. 23 The main function of T-cells in the decidua, particularly of CD4 + T-regulatory (Treg) cells, is generally thought to be the promotion of tolerance to the fetus 24 (discussed in detail later in this review). However, because a variety of different T-cell subsets are present, the complex interactions of T-cells in the decidua have not been completely defined. 25 Human in vitro studies of CD8 + T-cells isolated from first-trimester decidua demonstrate that these cells exhibit cytotoxic activity as well as cytokine production (predominantly interferon-gamma [IFN-γ] and IL-8). 26 Since decidual CD8 + T-cell supernatants increase the in vitro invasive capacity of extravillous trophoblast cells, secreted products of CD8 + T-cells may play a role in regulation of trophoblast invasion, but precise mediators have not yet been identified. 26

DCs, which are antigen-presenting cells that play a critical role in regulation of the adaptive immune response, make up a very small portion of human decidual leukocytes. However, no single specific marker for DCs exists and their phenotypic definition is therefore controversial, thereby limiting the existing studies of decidual DCs. 27 Using lineage-negative and human leukocyte antigen-DR-positive (HLA-DR + ) status as a combination marker for DCs, Gardner and Moffett 28 demonstrated that decidual DCs comprised ӭ% of first-trimester human decidual leukocytes. Due to the rarity of this cell population, functional studies of human decidual DCs are scarce. Human in vitro studies have demonstrated that decidual DCs, isolated from early-pregnancy decidua, are more likely than peripheral DCs to prime naïve CD4+ T-cells into a Th2 phenotype, suggesting a potential role for decidual DCs in averting Th1-mediated rejection of the fetus. 29 Decidual DCs also appear to regulate uNK cell function, since coculture of decidual DCs with uNK cells stimulated uNK cell proliferation and activation. 30 In vivo functional studies of decidual DCs exist only in mice and are more definitive. Decidual DC–depleted mice exhibit severely impaired implantation, impaired decidual proliferation and differentiation, impaired angiogenesis, impaired differentiation of uNK cells, and resorption of embryos. 31,32 Therefore, at least in mice, decidual DCs play an important role in decidualization and establishment and maintenance of early pregnancy.

Mechanisms by which immune cells (focus: uNK cells) regulate key early events in establishment of pregnancy: implantation, angiogenesis, and vascular remodeling

uNK cells regulate trophoblast invasion

Studies performed by Hanna et al 33 provided strong evidence that human uNK cells play a role in regulation of trophoblast invasion. These investigators demonstrated that uNK cells isolated from first-trimester human decidua express the chemokines IL-8 and IFN-inducible protein (IP)-10, and that purified human invasive trophoblasts express the chemokine receptors for these ligands: CXCR1 (IL-8 receptor) and CXCR3 (IP-10 receptor). The ability of uNK cells, but not peripheral blood NK cells, to induce trophoblast migration in an in vitro trophoblast migration assay was significantly reduced in the presence of neutralizing antibodies to IL-8 and IP-10. These investigators subsequently performed in vivo studies in which NK cell subsets embedded in Matrigel were injected into the subcutaneous tissues of nude mice, and human trophoblast cells were injected around the Matrigel plug. These in vivo experiments further demonstrated that uterine, but not peripheral, NK cells promoted trophoblast invasion, and that migration of trophoblast cells into the Matrigel plug was significantly reduced in the presence of IL-8- and IP-10-neutralizing antibodies. Overall, these studies demonstrated the ability of uNK cells to positively regulate invasion of trophoblast, mediated by the uNK-derived cytokines IL-8 and IP-10. 33 However, trophoblast invasiveness into maternal decidua must be tightly regulated. The balance of factors involved in regulation of invasion is not yet precisely determined. Excessive invasion predisposes to placenta accreta, a potentially life-threatening obstetrical condition in which the placenta attaches abnormally to the uterine myometrium. 34 Interestingly, human uNK cells also have the ability to inhibit trophoblast invasion, as demonstrated by Lash et al 35 using in vitro Matrigel invasion assays. These investigators demonstrated that human uNK cells isolated from early human pregnancy decidua are a source of IFN-γ, which inhibits trophoblast invasion by increasing apoptosis of extravillous trophoblast cells and decreasing trophoblast secretion of MMP-2. 35 Thus, the fine balance required to avoid either underinvasion or overinvasion of trophoblast in early human pregnancy is regulated, at least in part, by the various cytokines derived from human uNK cells present in decidua.

Role of uNK cells in angiogenesis and vascular remodeling in early pregnancy

In humans, extensive vascular remodeling must occur to allow for placentation and establishment of early pregnancy, as well as to support the demands of a growing fetus. The decidual spiral arteries must be transformed into larger-diameter vessels with low resistance and high flow, capable of transporting nutrients and oxygen to the fetus. 22 In addition, the endothelium of these vessels is replaced by extravillous trophoblast cells that have migrated from the placenta, allowing for diversion of blood flow into the space surrounding the placental villous tree and thereby permitting nutrient and gas exchange between mother and fetus. 36 Not only is adequate vascular remodeling critical for the establishment of a normal pregnancy, but abnormalities in these early events are associated with later complications of pregnancy such as preeclampsia and intrauterine growth restriction, which can have a major impact on fetal and neonatal health. 34

A critical role for uNK cells in vascular remodeling has been demonstrated in both murine in vivo and human in vitro studies. However, it is important to note significant differences among species in terms of strategies to increase blood flow to the site of maternal–placental exchange. In humans, extensive invasion and destruction of preexisting arteries by trophoblast occurs. In nonhuman primates such as rhesus macaques, trophoblastic invasion and modification of uterine arteries occurs, but unlike in humans, invasion of decidual stroma by trophoblast in the rhesus monkey occurs only to a minimal extent. 12 In mice, the extent to which the trophoblast invades both the decidual stroma and uterine arteries is even more limited. 12 Rodent models thus have limited value in advancing our understanding of mechanisms of vascular remodeling that facilitate human pregnancy. Nevertheless, there are in vivo studies performed in mice that cannot be performed in humans, and the availability of nonhuman primates for such in vivo studies in early pregnancy is limited. Therefore, much of the existing data on uNK cell functions in vascular remodeling are derived from murine studies.

Multiple murine in vivo studies demonstrate that uNK cells play a critical role in the remodeling of endometrial spiral arteries both prior to and during pregnancy. The earliest studies demonstrating a critical role for uNK cells in vascular remodeling in pregnancy were those conducted by Guimond et al, 37 who demonstrated several reproductive abnormalities in the Tg䛎 mouse strain, which is deficient in NK cells. Multiple vascular abnormalities associated with implantation sites, including thickening of the media and adventitia, endothelial damage, reduction in placental size, and onset of fetal loss at Day 10 of gestation, were demonstrated in NK-cell-deficient mice. Subsequent studies from the same laboratory 38 demonstrated that bone marrow transplantation from severe combined immunodeficient mice (which lack T- and B- lymphocytes but not NK cells) to NK-cell-deficient mice led to restoration of the uNK cell population in recipients, reduced anomalies in decidual blood vessels, increased placental size, and restored fetal viability. Overall, these studies provide strong support for a critical role of murine uNK cells in decidualization, placentation, and the appropriate vascularization of implantation sites.

The role of murine uNK cells in vascular remodeling and decidualization appears to be mediated via IFN-γ, since transgenic mice that lack IFN-γ or its receptor fail to initiate modification of decidual arteries and exhibit necrosis of decidual cells, and treatment of NK-deficient mice with recombinant IFN-γ rescues decidual morphology and initiates decidual vessel modification. 39,40 However, whether human uNK cells regulate decidual vascular remodeling via IFN-γ is yet to be definitively determined. The data regarding IFN-γ expression by human uNK cells are conflicting, likely due to differences in methodology between studies and the status of cytokine stimulation of the uNK cells being studied. Evidence for production of IFN-γ in unstimulated human uNK cells is limited, but after exposure to stimulatory cytokines such as IL-2, IL-12, or IL-15, human uNK cells isolated from first-trimester decidua exhibit significantly increased IFN-γ secretion. 41,42 In addition, because IFN-γ is rapidly secreted once produced, and expression of IFN-γ mRNA and protein by human uNK cells rapidly decreases after 24󈞜 hours in culture, 35 conflicting data regarding IFN-γ expression by human uNK cells may be attributable to length of time in culture before measurement. In a nonhuman primate model of early pregnancy, the major population of CD56 bright uNK cells isolated from early-pregnancy rhesus monkey decidua is not a source of IFN-γ. 43 Therefore, while compelling evidence exists to support the role of IFN-γ in decidual vascular remodeling in rodents, whether uNK cell-derived IFN-γ plays an equally important role in vascular remodeling in humans and in nonhuman primates remains unclear.

Rather, the finding that human uNK cells isolated from first-trimester decidua are a potent source of the angiogenic factors angiopoietin (Ang)1, Ang2, VEGF, and PLGF 16,33 supports an important role for these cells in the vascular remodeling required for successful human pregnancy. Functional studies by Hanna et al 33 demonstrated that human uNK cells isolated from first-trimester decidua are potent secretors of angiogenic factors such as VEGF and placental growth factor (PLGF). Supernatants derived from human uterine (but not peripheral) NK cells promoted in vitro angiogenesis, as demonstrated by an increased ability of human umbilical vascular endothelial cells to form network-like structures, a process inhibited in the presence of VEGF- and PLGF-neutralizing proteins. In addition, these investigators 33 demonstrated the in vivo ability of human uNK cells to promote angiogenesis and growth of human trophoblast choriocarcinoma (JEG-3) tumor cells when injected subcutaneously into nude mice. In vivo angiogenic properties of uNK cells were inhibited in the presence of a VEGF- and PLGF-neutralizing protein. These studies provide strong evidence that the angiogenic properties of human uNK cells are mediated, at least in part, by their secretion of VEGF and PLGF.

Influence of maternal immune response on development of the fetal immune system

Compelling clinical data demonstrate that children of mothers exposed to certain infectious organisms during pregnancy have significantly higher frequencies of neurological disorders, 44󈞡 including schizophrenia and autism spectrum disorders. In such scenarios, the etiology of these disorders has been linked to activation of the maternal inflammatory/immune responses (reviewed by Jonakait 54 and Patterson 55 ). Rodent studies in which the maternal immune system is activated during pregnancy replicate these clinical findings and provide validated mouse models of these disorders. 46,47,51,56󈞮 Thus, maternal immune stimulation during pregnancy acts as an environmental risk factor that affects development of the brain and the immune system in the offspring.

The underlying mechanisms of these phenomena have been studied primarily in prenatal rodent models, in which pregnant dams are injected with either infectious pathogens or synthetic agents that mimic viral or bacterial infections (namely, lipopolysaccharides and polyinosinic:polycytidylic acid [poly(I:C)]). Offspring of such immunostimulated pregnant dams exhibit immune dysregulation and behavioral abnormalities, as well as chemical and structural anomalies of the brain, which are similar to those seen in individuals with schizophrenia and autism spectrum disorders. 63,67󈞴

There is a transient increase of cytokines (IL-1, IL-6, IL-12, tumor necrosis factor-alpha [TNF-α], granulocyte-macrophage colony stimulating factor) in the blood and amniotic fluid of immunostimulated pregnant dams, 73,74 which appears to influence development of the fetal immune system, a concept known as “fetal programming”. 75󈞻 Mandal et al 73,74,80 have also shown that offspring of immunostimulated pregnant dams exhibit accelerated development and heightened responsiveness of Th1, Th17, and cytotoxic effector T-cell subsets, indicating a proinflammatory phenotype in these offspring.

We hypothesized that in utero exposure of the fetus to cytokines elicited by maternal immune stimulation acts as a “first hit” to influence fetal programming of the immune system, which persists postnatally and into adulthood. Such alterations of normal fetal programming results in development of a “proinflammatory” phenotype, and upon subsequent postnatal exposure to an immune stimulus (ie, second hit), the offspring of the immunostimulated pregnant dams exhibit exacerbated responses in comparison to offspring of phosphate-buffered saline (PBS)-injected dams. Such a scenario is also consistent with the “multiple hit” concept of mental disorders. 81,82 In the context of neurodevelopmental disorders, this would mean that abnormalities of behavior and immune dysregulation observed in some affected children could reflect such altered fetal programming that is manifested postnatally upon encounter with a second hit (eg, infection) to their immune system. We tested this hypothesis in adult offspring of immunostimulated pregnant dams using well-documented in vivo experimental models that involve activation of the innate and/or adaptive immune systems. In each of these models, the adult offspring of immunostimulated dams mounted a more robust inflammatory response than adult offspring of control dams injected with PBS. 73,83 Thus, offspring from immunostimulated dams exhibit behavioral anomalies reminiscent of those seen in individuals with some neurodevelopmental disorders, such as schizophrenia and autism. In addition to their behavioral abnormalities, our studies show that as a result of in utero exposure to products of maternal immune stimulation, these adult offspring also exhibit a “proinflammatory” phenotype that confers a vulnerability to develop immune-mediated pathology after birth and into adulthood. 73,74,80

In this regard, the results obtained from our investigations in mouse models have provided the scientific rationale for an ongoing translational research project to determine whether similar molecular pathogenic mechanisms are involved in a cohort of autistic children who also exhibit diagnostic evidence of immune dysregulation. 84 Using DNA obtained from the Autism Genetic Resource Exchange database, we initiated a study to determine whether polymorphisms in selected maternal cytokine genes occurred more frequently in mothers of these autistic children. Our results show that mothers of autistic children in this cohort have significantly higher frequencies of proinflammatory cytokine gene polymorphisms, thereby conferring the genetic capability to respond more vigorously to immune stimulation by producing the types and amounts of cytokines that promote inflammatory reactions. Moreover, analysis of preliminary data from the offspring indicates that the autistic children of these mothers inherit the maternal genotype. Thus, results obtained from our investigation of the experimental prenatal mouse model of maternal immune stimulation during pregnancy 73 appear to have biological relevance to humans.

Billingham et al 1 in 1953 were the first to propose the concept of immune tolerance during pregnancy. They hypothesized that the semiallogeneic fetus is able to survive due to regulation of the immunologic interactions between mother and fetus. Such regulation can be caused by a lack of fetal antigen expression and/or functional suppression of maternal immune response. 1

HLAs that are expressed in the fetal membranes are tolerogenic rather than immunogenic, 85 and expression of major histocompatibility complex (MHC) proteins at the maternal–fetal interface is tightly regulated during pregnancy. 86 The MHC class I genes are subdivided into classes Ia and Ib. The MHC class Ia is further subdivided into HLA-A, B, and C and class Ib is subdivided into HLA-E, F, and G. HLA class II (HLA-D) genes are not translated in human trophoblast cells. 87 Human trophoblast cells express one MHC class Ia (HLA-C) and all MHC class Ib molecules. In human placenta, fetal trophoblast cells do not express MHC class Ia (HLA-A and B) molecules that are responsible for the rejection of allografts in humans. 88,89 Interactions between HLA-C and decidual NK cells may also cause infiltration of trophoblast into maternal tissue. Pregnancies with mismatched fetal HLA-C exhibit a greater number of activated T-cells and functional Tregs in decidual tissues compared to HLA-C-matched pregnancies. 90 This suggests that in uncomplicated pregnancies, decidual T-cells recognize fetal HLA-C at the maternal–fetal interface but are prevented from inducing a destructive immune response. 91

Regarding pregnancy, one of the most important questions is how the fetal–placental unit escapes maternal rejection. Although there is a continuous interaction between the fetus and maternal cells throughout pregnancy, the fetus acts as a privileged site that is protected from immune rejection. 91 Expression of MHC molecules on trophoblast cells is repressed in most of the species as a strategy to avoid recognition and destruction by the maternal immune cells. 92 Peripheral blood lymphocytes from pregnant mares demonstrate reduced capacity to develop into effector cytotoxic T lymphocytes. 93 This reduction in T-cell-mediated alloreactivity returns to normal after termination of pregnancy and is not observed in nonpregnant mares. In addition, extracts from Day 80 placentas from mares have been shown to inhibit proliferation of maternal lymphocytes, and coculture of trophoblast cells with maternal lymphocytes caused reduction in proliferation and cytokine production. 94

Cell-mediated immunity: mechanisms promoting maternal–fetal tolerance

The Th1–Th2 shift in pregnancy

Pregnancy is a complex immunological state, wherein the mother must tolerate the “foreign” fetus, and thus requires a degree of immunosuppression. On the other hand, the mother must maintain sufficient immune function to fight off infection. One mechanism that plays a role in maintenance of successful pregnancy is a switch from the Th1 cytokine profile to the Th2 profile. This switch is more prominent at the maternal–fetal interface. Th2 cells accumulate in decidua, and uterine DCs can drive naïve T-cells to become Th2 cells. 95,96 Therefore, the switch to a Th2 phenotype is due to both migration of Th2 cells and induction of Th2 cells at the maternal–fetal interface, but there is little change in the systemic immune system. 96 The hypothesis of Th2 predominance and downregulation of Th1 response during pregnancy was proposed by Wegmann et al, 97 which is supported by both murine and human studies. In mice, the proinflammatory cytokines IFN-γ and TNF-α, or stimulation of toll-like receptors, induce miscarriage, which can be reversed by inhibitors of Th1 cytokines or by administration of anti-inflammatory IL-10 (Th2 cytokine). 98 However, IFN-γ also plays an important role in vascular remodeling in early murine pregnancy. Therefore, Th1-type immunity appears to be controlled to avoid overstimulation during pregnancy. Progesterone, estradiol, prostaglandin D2 (PGD2), and leukemic inhibitory factor generated during pregnancy promote the Th2 profile and are, in part, responsible for the Th2 bias associated with normal pregnancy. 96 However, transgenic Th2 cytokine single-knockout mice such as IL-4 −/− , IL-10 −/󔽫 and mice with single, double, triple, and quadruple gene deletions of IL-4, IL-5, IL-9, and IL-13 have normal pregnancies, suggesting that a predominant Th2-type immunity might not be essential for successful pregnancy. 100

An increase of Th2 cytokines IL-4, IL-10, and monocyte-colony stimulating factor in the peripheral blood and the maternal–fetal interface is associated with successful pregnancy. Trophoblast, decidua, and amnion contribute to the Th2 cytokine-biased environment by production of IL-13, IL-10, IL-4, and IL-6. 101� Human placental cytotrophoblasts have been shown to produce the immunosuppressive cytokine IL-10. 101 In addition, macrophages and Tregs present within decidua during pregnancy also produce IL-10 and are involved in maintenance of immune tolerance toward allogeneic fetal antigens. 91 The placenta also produces PGD2, which can act as a chemoattractant for Th2 cells to the maternal–fetal interface via the Th2 receptor CRTH2 (a chemoattractant receptor-homologous molecule expressed on Th2 cells). Women suffering recurrent pregnancy loss have reduced expression of CRTH2+ cells than women undergoing elective termination of pregnancy. 104 Anti-inflammatory cytokines IL-4 and IL-10 inhibit Th1 cells and macrophages, which in turn prevent fetal allograft rejection. In addition, these cytokines also inhibit TNF-α, cyclooxygenase-2 (COX-2), and prostaglandin E2 in amnion-derived cells, which prevent the onset of labor. 24,105�

Labor is often associated with a proinflammatory state with reversal back to Th1 rather than Th2. Studies indicate increases in Th1 proinflammatory cytokines and reduction in Th2 cytokines in women who are in active labor. Fetal membranes, myometrium, amnion, amniotic fluid, and decidua produce proinflammatory cytokines IL-1² and TNF-α at term and can induce nuclear factor kappa B. This transcription factor regulates the expression of labor-associated genes such as COX-2, IL-8, and MMP-9 and triggers a cascade of labor-inducing events. Despite the proinflammatory nature of Th1 cytokines, they are essential for successful pregnancy, contributing to timely labor. 108�

Role of Tregs in pregnancy

CD4+CD25+ Tregs are a subpopulation of T-cells responsible for the maintenance of immunological self-tolerance by suppressing self-reactive lymphocytes in a cell contact-dependent manner by production of TGF-² and IL-10. 111,112 Tregs express transcription factor forkhead box transcription factor (FoxP3), which acts as a major regulator in their development and function. 113 There are two main Treg subsets: naturally occurring or thymic Tregs (tTregs) and induced or extrathymic/peripheral Tregs (pTregs). tTregs are CD4+CD25+Foxp3+ and express cytotoxic T lymphocyte-associated antigen 4. pTregs develop from naïve T-cells after exposure to antigens in the periphery and exposure to either IL-10 or TGF-² and can be either Foxp3- or Foxp3+. 114,115 Owing to their immunosuppressive function, Tregs also play a key role during pregnancy by maintaining maternal–fetal tolerance.

Several studies have confirmed an increase in Tregs during pregnancy in blood, lymph nodes, and thymus, followed by decrease from midgestation onward until they reach nonpregnant levels at term or shortly thereafter. They play a critical role in embryo implantation and in the maintenance of the maternal immune tolerance against semiallogeneic fetal antigens. 116,117 Evidence suggests that Tregs during pregnancy are specific to paternal alloantigens, which protects the fetus from rejection by the mother’s immune system. 118 Expansion of Tregs in decidua from normal pregnant women suppresses maternal Th1/Th17 activity on the semiallogeneic fetus. 119

Murine experiments have shown increased levels of Tregs in both syngeneic and allogeneic matings, suggesting alloantigen-independent Treg expansion. 120 Treg expansion appears to be regulated by estradiol. This is supported by in vitro studies, which show that physiological levels of estradiol not only expand Tregs but also stimulate conversion of CD4+CD25- T-cells into CD4+CD25+ T-cells. 121 On the other hand, Zhao et al 122 observed no increase in Tregs in ovariectomized mice. Moreover, they detected higher number of Tregs in pregnant mice from allogeneic versus syngeneic matings, suggesting an involvement of paternal antigens in Treg expansion. 122 Recently, Robertson et al 123 showed that seminal fluid can drive Treg expansion. Therefore, both antigen-dependent and antigen-independent mechanisms are likely to be involved in Treg expansion.

Tregs express various chemokine receptors whose ligands are expressed at the maternal–fetal interface, which might contribute to chemokine-mediated migration of Tregs to the decidua. 120 Furthermore, other immune cells produce large amounts of CCL17, CCL4, and CCL1, 124� which might attract Tregs specifically expressing CCR4 and CCR8. 127,128 Besides chemokine-mediated migration of Tregs, integrins, similar to CD62L, seem to play an important role in Treg migration, as neutralizing CD62L-specific antibody blocks expansion of Tregs in draining lymph nodes and results in allograft rejection. Schumacher et al 129 have shown the importance of human chorionic gonadotropin as one of the main attractants of Tregs to the maternal–fetal interface.

Aluvihare et al 117 first noted that Tregs increased in all lymphoid organs in allogeneic matings of C57BL/6 female mice with CBA males. They also adoptively transferred lymphocytes from BALB/c females, either allopregnant from C57BL/6 males or synpregnant from BALB/c males, into T-cell-deficient BALB/c females, which were then mated with C57BL/6 males. Pregnancy proceeded normally when whole lymphocyte populations were transferred. In contrast, lymphocytes depleted of Tregs resulted in fetal resorptions, and there was a massive infiltration of T-cells into the implantation sites. 117 Zenclussen 130 and Zenclussen et al 131 have shown complete prevention of abortion in the CBA × DBA/2J model of naturally occurring spontaneous abortions by transferring Tregs from alloimmunized mice, and they also reported that no abortions occurred in the CBA × BALB/c and CBA × CBA control matings. Finally, Chen et al 116 demonstrated that stimulation of Tregs, either directly by low dose of IL-2 or indirectly by Fms-related tyrosine kinase 3 ligand, led to normal pregnancy rates in CBA × DBA/2J abortion-prone mice. The results of these experiments all demonstrate that in allogenic matings, Tregs are necessary for prevention of a maternal immune response against the fetus.

Clinical manifestations of an altered immune system in pregnancy

The notion of pregnancy as an altered state of immune suppression is well documented. 132� Pregnancy is a time period that poses a risk of increased susceptibility to infectious diseases, and the maternal immune system is solely responsible for defending against infectious microorganisms and protecting the fetus because both the fetal and the placental responses are limited. 132,136 The Th1/Th2 immune shifts in pregnancy are well established and have provided a platform to further study the immune system. 136 This has led to refining our understanding about the immune system and the development of a new paradigm regarding pregnancy and immune function. This newer theory proposes that the immune system during pregnancy is a functional and active system, wherein not only a maternal immune response exists but also a fetal–placental immune response, which in combination is powerful in defending both the mother and the fetus. 133,136 With this notion, the immune system is not suppressed, but rather in a modulated state, and therefore, this explains why pregnant women have differential responses to various pathogens. 133 During this altered response, signals are generated in the placenta, which modulate the maternal immune system to behave uniquely to different microorganisms. 133 Although these old and new paradigms surrounding the immunology of pregnancy differ, it is clear that the immune system’s goal in pregnancy is to ensure that a pregnancy progresses successfully, while still providing protection for both mother and fetus from external pathogens.

Endocrine regulation of immune cells

Hormone concentrations vary with the initiation of pregnancy, and there are specific fluctuations in hormone levels throughout each trimester of pregnancy. In general, pregnancy hormones are thought to suppress maternal alloresponses, while promoting pathways of tolerance. 137 Hormonal shifts are thought to reduce the number of DCs and monocytes, decrease macrophage activity, while blocking NK cells, T-cells, and B-cells. 137 Each of the major pregnancy-associated hormones is thought to directly and indirectly affect the function of the major immune cells and thus impacts the immune milieu during pregnancy. These alterations are discussed in Table 1.

Table 1 Endocrine regulation of immune cells and immune function
Abbreviations: CD, cluster of differentiation IL, interleukin IFN, interferon LH/CG, luteinizing hormone/chorionic gonadotropin TGF, transforming growth factor Th, T helper cell TNF, tumor necrosis factor Treg, T-regulatory cell uNK, uterine natural killer , decreased , increased.

Evidence of altered immune function in pregnancy: effects of infectious organisms on pregnancy

The alterations in the immune system during pregnancy are well established, and subsequently, these changes result in increased susceptibility to certain viral, bacterial, and parasitic infections. 132 This increased susceptibility is believed to result from the suppression of cell-mediated immunity, as pregnancy promotes a shift away from the Th1 to the Th2 immune environment. 132,134 Additionally, infection with certain pathogens has been documented to result in severe symptoms in pregnant patients because of these immune changes. 133,138 However, it is important to note that, in certain infectious diseases among gravid patients, the morbidity and mortality vary between developed and nondeveloped countries. For example, pregnant women with varicella in the US or Canada fare better than those diagnosed in underdeveloped countries, where resources are limited. 139 Thus, some bias may result when evaluating the severity of disease states in pregnant women depending on geographical distribution.

Table 2 summarizes the more commonly recognized and studied pathogens related to pregnancy. As seen in Table 2, infectious diseases during pregnancy are associated with not only maternal risks but fetal risks as well. These fetal effects result from infections that cross the placenta, which can cause miscarriage, congenital anomalies, or even fetal death. 133 As a result, the American Congress of Obstetricians and Gynecologists and the US Centers for Disease Control and Prevention recommend that all women be vaccinated for influenza and tetanus, diphtheria, and pertussis (Tdap) during pregnancy. 140� Both these vaccines appear to be safe when administered during pregnancy, with few maternal and fetal adverse events. 142,143 In contrast, live vaccines, such as measles–mumps–rubella (MMR) and varicella, are not recommended during pregnancy due to the theoretical risks to the fetus. 141,142

Table 2 Common infectious organisms in pregnancy
Abbreviations: CD, cluster of differentiation DC, dendritic cell GA, gestational age G-CSF, granulocyte-colony stimulating factor IAV, influenza A virus H1N1, influenza A virus subtype H1N1 IFN, interferon IL, interleukin IUGR, intrauterine growth restriction IVS, intervillous space MCP-1, monocyte chemotactic protein-1 PRR, pattern recognition receptor Th, T helper cell TNF, tumor necrosis factor Treg, T-regulatory cell uNK, uterine natural killer , decreased , increased.

The risk of infection during pregnancy is a serious matter, not only for concerns of maternal well-being but also the potential fetal risks, which may have long-term consequences. Animal studies have elucidated that the placenta may trigger fetal inflammatory response syndrome (FIRS), which is the diagnosis of a placental infection without the growth of an organism, from the microbiology standpoint. 133,136 FIRS is serious and results in increased circulating levels of cytokines, such as IL-1, IL-6, IL-8, and TNF-α. 133 These inflammatory shifts have been demonstrated to increase the risk of fetal abnormalities, such as ventriculomegaly or hemorrhages. Furthermore, human studies have demonstrated an association between FIRS and the development of autism, schizophrenia, neurosensorial deficits, and psychosis. 133,136 These observations further validate the experimental mouse models described earlier in which immunostimulation induces high levels of proinflammatory cytokines in blood and amniotic fluid of pregnant dams, which are likely involved in the etiology of neurodevelopmental disorders exhibited in their offspring. 63,72󈞶 In contrast, bacterial infections that reach the decidua trigger a proinflammatory response that leads to the development of intrauterine infections. 144 This is through the activation of pattern recognition receptors (PRRs) and increased secretion of cytokines, such as IL-1 and TNF-α. 145 Combined, these contribute to poor pregnancy outcomes, disruption in fetal development, or preterm births with resultant low-birth-weight infants. 146,147 Thus, it is important to recognize that pregnancy can cause increased disease susceptibility, which not only affects maternal morbidity but contributes to detrimental long-term fetal and neonatal outcomes.

Evidence of altered immune function in pregnancy: effects of pregnancy on autoimmune disease

As discussed, pregnancy confers a shift from Th1- to Th2-mediated immunity, and this shift affects disease status in women with known autoimmune diseases. In general, the hormonal milieu induced by pregnancy shifts the cytokine profile away from cell-mediated immunity (Th1 type of immunity) and, therefore, improves inflammatory-type autoimmune diseases. 132 In contrast, autoimmune diseases that are humorally (or antibody) mediated are exacerbated, as pregnancy favors increased Th2-related activities, as well as a Th2 cytokine profile. 132,148 For details, please view Table 3.

Table 3 Autoimmune disease in pregnancy
Abbreviations: Abs, antibodies CD, cluster of differentiation E2, estradiol IUGR, intrauterine growth restriction Th, T helper cell Treg, T-regulatory cell TSH-R, thyroid stimulating hormone-receptor.

Conclusion and future outlook

Pregnancy in women is a dynamic state, with different mechanisms used during different trimesters to enable and ensure successful establishment, maintenance, and timely termination of the pregnancy. Mechanisms operative in early pregnancy to establish the pregnancy may differ from those needed to maintain the pregnancy and from those required to ensure successful and timely labor and delivery. Recent data challenge the notion that pregnancy is simply an immunosuppressed state protecting the allogeneic fetus from attack by the maternal immune system. The evidence suggests that rather, pregnancy may be a state of upregulated innate immune response and decreased cell-mediated response. Unique decidual lymphoid cell populations actively contribute to placental development and to tolerance of the fetus. Although substantial progress in the understanding of the function of immune cells during pregnancy, especially early pregnancy, has been achieved, many unanswered questions regarding regulation of their proliferation and function by endocrine and other factors still remain. The published results from human studies and animal models clearly indicate that a fine balance between proinflammatory and anti-inflammatory influences is critical for successful pregnancy. Thus, the future challenge for translational research in reproductive immunology will be to define more completely those factors that favor optimal immunological environments that promote fetal health and development at specific stages of pregnancy, so that evidence-based regulatory therapeutic strategies can then be designed.

The authors thank Yingting Zhang for her assistance with the manuscript. Mili Mandal is currently affiliated with Oncology, R&D, GlaxoSmithKline, Collegeville, PA, US.

The authors report no conflicts of interest in this work.

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Diagnosis - Congenital Heart Defects

Some congenital heart defects are diagnosed during pregnancy or soon after birth. Others may not be diagnosed until adulthood. Your or your child’s doctor will perform a physical exam and order diagnostic tests and procedures based on what he or she finds in the physical exam.

During a physical exam, your doctor will do the following:

  • Listen to your or your child’s heart and lungs with a stethoscope.
  • Look at your baby’s general appearance. Some children with certain heart defects also have genetic syndromes that make them look a certain way.
  • Look for signs of a heart defect, such as shortness of breath, rapid breathing, delayed growth, signs of heart failure, or cyanosis.

To diagnose a congenital heart defect, your doctor may have you or your baby undergo some of the following tests and procedures:


Watch the video: Rådgivning til gravide medarbejdere på arbejdspladsen fra Conopor - Gravid på Arbejdet (September 2022).


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