The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 54

68. How does mast cell disease affect pregnancy?

One of the things mast cells normally do in the body is regulate the female reproductive cycle. Mast cells in the endometrium, the uterine lining that is shed during menstruation, become activated and release mediators in the days before and during menstruation. Many of the symptoms of premenstrual syndrome (PMS) occur because of mast cell degranulation. These symptoms include things like cramps and bloating.

Because mast cells are involved in controlling the reproductive cycle, they are responsive to the effects of hormones like estrogen and progesterone. In particular, estrogen can directly cause mast cell degranulation.

In some allergic conditions like asthma, patients often have flares right before or during their menstrual period. This is often the case with mast cell patients as well. The change in hormones, the built in mast cell activation, and the bleeding, can all cause mast cell symptoms.

A study on the effects of the pregnancy on mastocytosis found that there was a lot of variability in what patients experienced. 33% of women had symptom improvement during pregnancy. In these women, their symptoms mostly improved beginning in the first trimester and continued throughout their pregnancy. 45% of patients had no change in symptoms during pregnancy. The remainder had worsened symptoms.

Mastocytosis did not seem to affect the outcome of pregnancy compared to the normal population. Premedication was recommended at the start of labor. Many women safely received anesthesia. In women who reacted, 2/3 had not premedicated. Induction of labor with medication was well tolerated. Both vaginal delivery and Caesarean section was performed safely on women with mastocytosis. The frequency of Caesarean section, miscarriage, prematurity and low birth weight were similar to the general population.

In some instances, severe allergic reactions and anaphylaxis can induce early labor, so patients should be aware of this risk.  Histamine can trigger uterine contractions.

An important thing to consider is that mast cell patients may have to change or stop some of their medications while pregnancy to avoid effects upon the fetus. In particular, the use of epinephrine is discouraged in pregnancy because it causes uterine contractions. Mast cell patients should have an alternative plan for anaphylaxis that excludes epinephrine where possible. Any mast cell patient who is pregnant or considering becoming pregnant should have detailed discussions with their providers about it.

For more detailed reading, please visit the following posts:
Pregnancy in mastocytosis
Effects of estrogen and progesterone and the role of mast cells in pregnancy

Effects of estrogen and progesterone and the role of mast cells in pregnancy

The term estrogen generally refers to estrogen estradiol (E2.)  This steroid hormone is induced when gonadotropin releasing hormone (GnRH) is released in the hypothalamus and acts on the pituitary gland.  This in term releases follicle stimulating hormone (FSH) which acts on the follicle, resulting in the release of estrogen.  Secretion of GnRH is stimulated by a protein called kisspeptin. High levels of estrogen or progesterone inhibit the secretion of kisspeptin.  Hormone levels are regulated in this way. 

Estrogen is mostly produced by the ovaries and placenta, but is made in smaller amounts by the liver, adrenal glands, breasts and fat cells.  E2 promotes secondary female sex characteristics, increases metabolism, increases fat stores, stimulates endometrial and uterine growth, promotes vaginal lubrication, thickens the vaginal wall, maintains integrity of blood vessels and skin, reduces bone resorption and increases bone formation.  It also promotes effective coagulation by increasing platelet adhesion.  E2 increases HDL cholesterol and triglycerides while decreasing LDL and fat deposition.  It balances salt and water retention, increases cortisol levels, reduces bowel motility, and increases the amount of cholesterol found in bile.  It also promotes wound healing and has anti-inflammatory properties.

With progesterone, E2 promotes and maintains the uterine lining, as well as increasing the amount of oxytocin released during pregnancy.  Estrogen surge induces the secretion of luteinizing hormone, triggering ovulation. 
Progesterone (P4) also regulates salt and water balance, prepares the uterus for implantation, affects vaginal tissue and cervical mucus to prevent sperm from entering the uterus during pregnancy, suppresses menstruation, decreases maternal immune response to pregnancy, decreases contractility of uterine smooth muscle and inhibits lactation during pregnancy.  With prolactin, progesterone prepares breast tissue for milk production after childbirth.  Drop in progesterone levels during pregnancy is thought to be a key step in induction of labor.  Progesterone also has a variety of other regulatory effects, though the exact nature of these functions is not entirely clear.
Progesterone receptors on cells can be increased by the action of estrogen.  Furthermore, the activity of progesterone is amplified by the presence of estrogen.
The importance of mast cells in reproductive biology has been known for over sixty years.  Mast cells express receptors for both estrogen and progesterone.  These hormones together attract mast cells from the peripheral tissues to the uterus.  Furthermore, they induce the maturation of mast cells and directly cause degranulation in a dose dependent manner.  Together, they induce more degranulation than individually.
During pregnancy, embryo-derived histamine releasing factor induces secretion of histamine by uterine mast cells.  Histamine is also secreted by endothelial and decidual cells.  Mast cells have a protective role in ensuring successful embryo implantation.  Mast cells also positively influence the growth of blood vessels and participate in tissue remodeling so that the pregnancy can be sustained through placental growth and adequate blood supply. Degranulation increases uterine contractility through histamine and serotonin action.  Allergic activation causes significant contractions. 
In placentas from intrauterine growth retardation, mast cell concentrations are significantly decreased.  When mast cell numbers are diminished, the cells formed following implantation are at different stages, and are smaller and delayed.  Pregnancies with this feature generally do not survive.
In some cases, severe allergic reactions are thought to be responsible for preterm labor.  Additionally, degranulation in pre-eclampsic patients caused increased vascular resistance, likely from vasoconstriction by histamine.  Asthmatic pregnant women are known to be at a higher risk of pre-eclampsia.  People with other mast cell diseases should likewise by monitored for this condition.
Estrogen and progesterone levels can be correlated to symptoms in asthma.  Postmenopausal women taking hormone replacement therapy have a higher risk of new onset asthma.  30-40% women have asthma with more symptoms during the premenstrual period when estrogen and progesterone concentrations are dynamic.  Many women with mast cell disease likewise report more degranulation when menstruating.  Mast cell density in non-uterine tissues is much higher in pregnant woman, likely due to the higher hormone concentrations. 
A paper released in 2013 referenced a 2001 study by Metcalfe and Akin that found that women with SM were more likely to have preterm labor and delivery.  However, a 2011 study in Spain found that only 3/45 (6.7%) women delivered prematurely.  The rate of preterm birth in the general Spanish population is 7.4%.  It is unclear whether this change was due to increasing understanding of SM and more effective treatment, or due to the changes in diagnostic criteria between these studies.
The presence of mast cells is crucial for healthy pregnancy.  However, excessive activation can cause contractions and increased symptoms for pre-eclampsia patients.  The most recent study demonstrates that overwhelmingly, women with SM deliver healthy babies at the appropriate time.

 

References:
Woidacki, K., Jensen, F., Metz, Zenclussen, A. (2013). Mast cells as novel mediators of reproductive processes. Front. Immunol. 10.
Woidacki, K., Popovic, M., Metz, M., Schumacher, A., Linzke, N., Teles, A., et al. (2013). Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis.4, e462.
Metcalfe, D. D., and Akin, C. (2001). Mastocytosis: molecular mechanisms and clinical disease heterogeneity. Leuk. Res. 25, 577–582.
Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S et al. (2010). Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One 2010; 5: e14409.
Matito, A., et al.  (2011.) Clinical impact of pregnancy in mastocytosis: A study of the Spanish network on mastocytosis (REMA) in 45 cases.  Int Arch Allergy Immunol; 156: 104-111.

Pregnancy in mastocytosis

Mast cells are involved in regulating the female reproductive cycle.  There are direct correlations between the contraction of uterine wall and serum histamine during pregnancy, as well as correlations to other mast cell mediators.  Mast cell activation and degranulation in the endometrium occurs immediately before and during menses.  Many allergic conditions, including asthma and angioedema, are exascerbated during menses, which is thought to be due to mast cell activation.

Throughout pregnancy, sex hormone levels change.  Sex hormones, such as estrogen, can directly influence mast cell activation and degranulation.  Mastocytosis patients often discontinue antihistamine and antimediator medications during pregnancy due to safety concerns.  In 2011, a study was published examining the effect of pregnancy on mastocytosis patients and of mastocytosis on pregnancy and delivery.
During pregnancy, 45% had itching; 40% had flushing; 24% had GI symptoms; and 9% had anaphylaxis.  22% of patients reported worsening symptoms throughout the pregnancy.  2% felt their symptoms were more frequent, while 18% developed new symptoms, and 2% had both new and more frequent symptoms.  New symptoms generally appeared in the first trimester, occasionally in the third.  Worsening of symptoms occurred in 3/6 women with CM and 7/35 with ISM with skin involvement.  One woman developed skin lesions during the third trimester and was diagnosed with ISM via bone marrow biopsy after delivery.
33% of women reported their symptoms had improved during pregnancy.  15% had complete resolution of symptoms, 15% had at least one symptom disappear and 3% had at least one symptom disappear but others worsen.  All resolutions occurred during the first trimester and lasted throughout the pregnancy with the exception of one patient.  In patients who had idiopathic anaphylaxis before pregnancy, 50% of them had no anaphylaxis while pregnant.  In those women who did have anaphylaxis during pregnancy, it was resolved without the use of epinephrine and did not cause early labor or complications.
Complete resolution of symptoms occurred in a patient with well differentiated SM (WDSM), ½ patients with ISM and no skin involvement, 9% of patients with ISM with skin involvement and 17% of patients with CM.  Partial resolution occurred in ½ patients with ISM and no skin involvement, 11% of patients with ISM with skin involvement and 17% of patients with CM.  In 6% of patients with ISM with skin involvement, at least one symptom disappeared while others worsened. 
45% had no change in symptoms during pregnancy (19/35 ISM with skin involvement patients, 1/6 CM patients.)  One patient experienced significant improvement of skin lesions in the first trimester. 
For women who worsened during pregnancy, mast cell symptoms continued to be worse after delivery for 50% of them.  Symptom resolution observed during pregnancy continued after delivery for 4/7 cases that had complete resolution and 3/6 cases that had partial resolution.  Complete resolution of symptoms occurred in two patients that had partial resolution during pregnancy.  There were five cases of worsening skin lesions after delivery. 
78% of infants were delivered vaginally and 22% by Caesarean.  Nine deliveries were induced with oxytocin (8/9) or dinoprostone (1).  In 38% of cases, the patient took mast cell pre-meds at the onset of labor.  Anesthesia was used in 82% of cases, including epidural (32 cases), local (3) and general (2.)  11% of patients had mast cell attacks during or immediately after labor.  Anesthesia and medications used for labor seemed to be safe.  Only three women had mast cell reactions to epidural; of these, two had not take pre-meds.  Premedication at the initiation of labor is recommended.
3 out of 45 newborns were born premature and 4 out of 45 had low birth weights.  One had Down Syndrome; one had respiratory distress; one had jaundice; and one had heart rhythm abnormalities before birth.  There was no correlation between mother’s symptoms and outcome.  There was no correlation between anaphylaxis and outcome.  None of the children had skin lesions at birth, but one developed CM at the age of 5. 
The frequency of spontaneous pregnancy loss during first trimester (10-15), birth by Caesarean section (25%), prematurity (7.6%) and low birth weight (3-5.8%) were comparable to the rates in the general population.  Nonaggressive forms of mastocytosis did not appear to impact pregnancy outcome.
Reference:
Matito, A., et al.  Clinical Impact of Pregnancy in Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) in 45 Cases.  Int Arch Allergy Immunol 2011;156:104-111.