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Wednesday 27 November 2019

Reproductive Immunology (Things We Don’t Know about Pregnancy Series #7)

Morning sickness aside, I haven’t felt unwell during my pregnancy. Of course, winter is coming and that could all change, but I have prepared myself with influenza and whooping cough inoculations. These vaccines will be inactivated. ‘Live’ vaccines are normally withheld from pregnant women because they could cause unborn babies to become infected, although the risk is low.


So why vaccinate during pregnancy? Not only does vaccinating yourself provide you with a good chance of fighting off a disease if you catch it, it can also incur herd immunity, making it difficult for the most vulnerable members of society to catch a disease, such as, oh, I don’t know, pregnant women and newborn babies, perhaps.

To read more about vaccination, check out our article on the topic.

Babies are vulnerable because their immune systems are starting from scratch: they’re born with just a few antibodies inherited from their mothers before getting their first inoculations and meeting everyday bacteria. Pregnant women are immunosuppressed. This means their ability to fight off disease is lowered during pregnancy.

Flu virus via Wikipedia Commons.

Under normal conditions, the immune system should recognise the growing foetus as a foreign body and attack it, terminating the pregnancy. However, the placenta is believed to be instrumental in conveying ‘immune privilege’ to the foetus. Amongst its many activities, the placenta secretes neurokinin B – the chemical used by parasitic nematodes to avoid detection by the immune system of their host! Scientists think understanding more about the placenta and immune system could reduce miscarriage frequency (~10% of pregnancies).

To read more about the placenta, check out our blog post on the topic.

Food poisoning

Because of immunosuppression, pregnant women are particularly vulnerable to food poisoning.

Whilst food poisoning is very rare in the UK, along with its complications and risks of death, pregnant women are still asked to avoid mould-ripened cheeses, uncooked meats, unwashed greens, and non-British Lion eggs>. This is because of a few nasty food-borne diseases that could have a devastating effect on their unborn baby.

One such disease is listeria. The immune cells that attack and destroy listeria have been seen to infiltrate the placenta, where they make a chemoattractant protein, CXCL9 that draws killer T cell antibodies through that harm the foetus. Scientists think that similar maternal infections could be behind many miscarriages, stillbirths and premature births.

Because of immunosuppression, pregnant women are particularly vulnerable to food poisoning. © Things We Don’t Know

To read more about foods best avoided during pregnancy, or other chemicals that can affect it, check out our blog post on the topic.

Autoimmune disorders

Not only could compromised immune privilege harm the foetus, but so could a defective immune system. This may be triggered by disease-agents such as bacteria or viruses, or could be genetic – scientists are still exploring the causes.

One immune system disorder is anti-phospholipid syndrome (APS), where anti-phospholipid antibodies are produced. These attack the pre-embryo or trophoblast, preventing it from staying implanted, and alter blood flow to the uterus.

Antinuclear antibodies cause an inflammation that make the uterus uninhabitable. Natural killer cells then misinterpret early foetal cells as cancer, destroying them.

Elevated levels of anti-thyroid antibodies don't have a toxic effect, but are indicative of a risk of miscarriage. Scientists think that this is because these antibodies act as markers another problem, known as T-lymphocyte dysfunction.

There is no medical evidence that immunosuppression treatments can prevent miscarriage.

A more common illness is rhesus disease, which only happens when a rhesus negative mother carries a rhesus positive baby after previously coming into contact with rhesus positive blood.

If your red blood cells are coated in an antigen known as rhesus D, you are rhesus positive. If they’re not, you’re rhesus negative. Rhesus state is inherited from the mother or a father, so a rhesus negative mother could carry a rhesus positive foetus if the father is also rhesus positive. In the UK, 85% of people are rhesus positive.

A pregnant rhesus negative woman can come into contact with rhesus positive blood either when the placenta peels away during childbirth, or earlier if maternal and foetal bloods mix, such as after a fall or during a prenatal test. This can make the mother sensitised to rhesus positive blood, which means her immune response to it is amplified next time.

First pregnancies rarely carry rhesus disease complications, but second pregnancies might. When the bloods mix a second time, the mother’s sensitised body launches an immune assault on the new foetus, trying to destroy it. This can lead to jaundice, heart failure, or enlarged organs. The mother won’t feel symptoms though – her body is protecting itself, and only the foetus suffers.

Rhesus disease is normally treated blood transfusion or early delivery.


IVF scientists think that immunological factors might account for 25% of pregnancy failures. However, immunological testing isn’t available on the NHS, which may be because it remains controversial.

Pills by frolicsomepl.
Whilst many people report stories of immunological treatments leading to successful treatments, it’s hard to entangle the effects of these treatments from the benefits of other medical support and interventions offered by ongoing fertility treatment. Underlying mechanisms behind immunological treatments remain obscure. Statistical analyses of 21 antibodies have found no differences in implantation rates, pregnancy rates, or pregnancy outcomes for higher or lower concentrations. Some treatments have been outright refuted, such as leukocyte immunisation therapy, which may be dangerous[2].

Some clinicians think high levels of natural killer cells might be associated with miscarriage, and are treating women who are trying to conceive against them. Natural killer cells occur naturally in the uterus, but may have a different role there to in the blood. They seem to remodel blood vessels through the placenta during pregnancy, and may perform this role instead of fighting off foreign bodies; in fact, some research suggests low numbers of natural killer cells in the uterus may obstruct pregnancy[3]. There’s also no agreed way to get natural killer cell counts. Blood levels and uterine levels are not necessarily linked, and levels in the uterus vary with the menstrual cycle.

Alloimmunity, however, may account for some pregnancy failures: these effects are felt when the female body launches an immunological attack on male tissues – basically killing off his sperm. Alloimmune disease can also strike during pregnancy, when the mother’s immune system accesses the foetus, attacking it and causing anaemia or other blood diseases in the newborn. Scientists are investigating potential mechanisms for alloimmune diseases[4].

In contrast to alloimmune responses against a partner’s sperm, exposure to sperm may sometimes prevent pre-eclampsia, a life-threatening pregnancy complication that sometimes arises in the second half of pregnancy[5]. This may be due to immune modulating factors in the seminal fluid.

Some IVF scientists think that problems conceiving (IVF is ~24% effective) may not be immunological, but due to timing. IVF works by suppressing the natural menstrual cycle, stimulating and gathering eggs, and then reintroducing fertilised eggs. If they are introduced too early or too late, however, the womb may not be ready to receive them, and they will be lost. For most women, this timing is guessed based on averages, but new treatment aims to perform tests and individualise egg reintroduction. A pilot study of 85 women experiencing recurrent IVF failurehad a 33% success rate.

To learn more about timing, we would have to know more about the uterine cycle and endometrium, the inner cell layer of the uterus, which is currently a bit of a black box for medical science!

Menstrual cycle via Wikipedia Commons.

There are many unknowns when it comes to pregnancy, and over the next few months, I’ll be exploring more of them with you. Look out for my next blog post, which will be about exercise.

You can read our full article on the things we don't know about pregnancy here. This article will be updated as we add posts across the coming months.

why don't all references have links?

[1] Ober, C., Karrison, T., Odem, R.R., Barnes, R.B., Branch, D.W., Stephenson, M.D., Baron, B., Walker, M.A., Scott, J.R., and Schreiber, J.R. Mononuclear-cell immunisation in prevention of recurrent miscarriages (a randomised trial).
[2] Lancet. 1999; 354: 365–369; Hill, Joseph A., and Richard T. Scott. Immunologic tests and IVF: Please, enough already. Fertility and sterility 74.3 (2000): 439-442.
[3] Moffett, Ashley, Lesley Regan, and Peter Braude. Natural killer cells, miscarriage, and infertility. BMJ 329.7477 (2004): 1283-1285.
[4] Porter, T. Flint, and James R. Scott. Alloimmune causes of recurrent pregnancy loss. Seminars in reproductive medicine. Vol. 18. No. 04. Copyright© 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+ 1 (212) 584-4662, 2000.
[5] Kenny, Louise C., and Douglas B. Kell. Immunological tolerance, pregnancy, and preeclampsia: the roles of semen microbes and the father. Frontiers in medicine 4 (2018): 239..

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