Most of the patients are not suitable and difficult to receive surgery and 131 I treatment, and drug treatment is not easy to ensure the health of mother and child during pregnancy and lactation.
In this paper, we observe the changes of thyroid function during pregnancy and lactation, and study the dispersion pattern of different antithyroid drugs (ATDs) through the placenta and mammary glands. Combined with data from prospective clinical studies, we suggest the proper use of ATDs in these two periods.
Effects of hyperthyroidism on pregnancy
Effects on the mother
(1) During pregnancy, maternal T cell and B cell reactivity is altered
Auxiliary T cells (Th) change from Th1 (mediated by Υ interferon and IL-2 products, with potential cytotoxic and cytolytic effects) to Th2 (mediated by IL-4, IL-5 and IL-10 products, with relative immune tolerance and immunosuppressive effects), and inflammatory cytokine formation decreases
The above changes often result in a state of immunosuppression during pregnancy, where T cells and antibodies are regulated in a highly recognizable manner, and the titer of thyroid autoantibodies in the blood circulation decreases and GD is reduced
(2) Due to the immunosuppressed state, the degree of rejection of the growing fetus with paternal antigens is minimized and the degree of tolerance is maximized
(3) If left untreated, complications increase
Congestive heart failure occurs in 62% (5/8) of pregnant women with untreated hyperthyroidism, compared to 3% (1/36) of treated women.
Effects on fetus
(1) Increased rates of low birth weight, preterm delivery and stillbirth
Analysis of a retrospective study of 181 hyperthyroid pregnancies
Group 1: 34 cases with a recent history of hyperthyroidism but normal prenatal nail function that remained normal throughout the pregnancy
Results: the rate of low birth weight in normal pregnancies was the same as that in normal pregnancies
Group 2: 90 cases with prenatal hyperthyroidism, but controlled with medication
Results: The rate of low birth weight in normal babies was 2.4 times higher than normal; the rate of preterm birth was 2.8 times higher than that of group 1
Low group 3: 57 cases with untreated or uncontrolled hyperthyroidism
Results: The rate of low birth weight was 9.2 times higher than normal; the rate of preterm birth was 16.5 times higher than that of group 1; the rate of eclampsia was also 3.7 times higher; and the incidence of stillbirth was about 50%.
(2) Increased rate of congenital malformations
A Japanese group reported
Hyperthyroidism in the first 3 months of pregnancy: 6% of fetuses had malformations (3/50, anal atresia, anencephaly and cleft lip, respectively)
In treated cases, the incidence of malformations was 1.7% (2/111, respectively, external ear malformation and umbilical protrusion)
Those whose nail function was always normal after treatment: no 1 case of malformation (1/126)
The above observations have attracted the attention of endocrinologists, obstetricians and gynecologists and geneticists
However, a group of reports from the United States did not confirm
In the first trimester of pregnancy
The difference in the eventual occurrence of fetal malformations in pregnant women with controlled versus uncontrolled hyperthyroidism
A number of manifestations similar to hyperthyroidism may occur during pregnancy.
Increased metabolism: increased appetite, excessive sweating, increased heart rate
Enlarged thyroid gland, increased blood flow to the thyroid gland
Amenorrhea
Slight decrease in serum TSH (increase in HCG, which stimulates the thyroid and leads to suppression of pituitary TSH secretion, especially in the 8th-14th weeks of pregnancy)
Increased serum TT4 (estrogen increases TBG and increases binding to T4)
In addition, severe pregnancy reactions (severe vomiting) can increase TT3 and TT4
The above two should be differentiated
Diagnosis of hyperthyroidism in pregnancy
Increased FT3 and FT4
TSH less than 0.1 mU / L
Ocular signs, significant goiter and positive TSAb or TRAb may help in the differential diagnosis
Since thyroid-stimulating antibodies can pass through the placenta, persistent positivity during pregnancy
often indicates the possibility of neonatal hyperthyroidism
A mild decrease in TSH (0.1-0.5 mU/L) during pregnancy alone is not diagnostic of hyperthyroidism or subclinical hyperthyroidism.
is not diagnostic of hyperthyroidism or subclinical hyperthyroidism
Choice of anti-thyroid medication
Currently used antithyroid drugs
Propylthiouracil (PTU)
Methimazol (MMI, tabazol)
Carbimazol (Carbamazol)
The first two are especially used
All of the above drugs can enter the fetal blood circulation through the placenta
Higher doses can cause fetal goiter and hypothyroidism
MMI can also cause congenital scalp hypoplasia in the fetus
The placental passage rate of MMI is very high, 0.72-1
In other words, 72%-100% of the maternal MMI can enter the fetal blood circulation
In contrast, the passage rate of PTU is 27%-35%.
Reason: The binding rate of PTU to albumin is much higher than that of MMI, and it is fat-soluble.
It is also related to the different metabolism and excretion rates of the two drugs
Therefore, PTU is recommended for clinical practice instead of MMI.
However, in recent years, some in vitro tests and clinical observations have failed to confirm
The significant difference between PTU and MMI on the fetus
Mild cases can be left untreated
Although PTU is less likely to pass through the placenta
However, the concentration in the fetus can be more than 1/4 of that in the mother, which still has some effect.
Therefore, mild cases can be closely observed and not treated.
What is a mild case?
There is no precise definition
It is generally accepted that if the pregnancy is progressing well and FT4 is only around 2.5ng/dl (if the normal high limit is 2.0ng/dl)
It can be monitored closely with monthly monitoring of nail function
Keep in mind that
The effect of hyperthyroidism on the fetus depends on the concentration of thyroid hormones in the mother’s blood
It does not depend on the maternal blood levels of thyroid hormones, but on the maternal symptoms and signs
As pregnancy progresses, hyperthyroidism may resolve on its own
ATD treatment for moderate to severe hyperthyroidism
Diagnosis established, if patient is on MMI, pregnant or preparing for pregnancy, should be changed to PTU
The starting dose of PTU is 100 mg, 1/8h (instead of 100 mg, 3/day)
Some literature recommends the following regimen
Start with a moderate dose (i.e., 200-300 mg/day) of PTU
to normalize the patient’s thyroid function as soon as possible
Then reduce the dose to 50-100mg/day
When thyroid function gradually improves and the drug is reduced to 50-100mg/day
Thyroid function indicators are still satisfactory, especially TSH is normalized
At this point, the low dose of PTU is no longer meaningful
It can be stopped completely
During the treatment period, thyroid function should be monitored once a month
Adjust the dose to maintain FT4 at or slightly above the upper limit of normal value (TT4 is not used as an indicator)
In very severe hyperthyroidism
PTU dose should be increased to 450mg-600mg/day without hesitation
The literature even mentions 800mg/day
Usually works quickly
If the condition worsens during pregnancy and high doses of PTU are necessary
Thyroidectomy is often required eventually
Combination of levothyroxine is not recommended
Reason: L-T4 has a low placental passage rate and is not protective for the fetus
The combination with L-T4 may increase the dosage of PTU, which is detrimental to the fetus
A strategy of direct PTU dose adjustment and complete discontinuation of PTU at the right time is more appropriate
No combined use of β-blockers
There is a risk of intrauterine asphyxia
Transmammary dispersion of ATD
The conventional wisdom is that treatment with ATD should not be breast-feeding
However, there is no evidence from trials
Mothers treated with PTU
Researchers in the 1980s observed
9 women (7 without thyroid disease, 2 with hyperthyroidism already treated with PTU)
Administered PTU 200 mg
The amount of PTU eliminated from breast milk was measured and calculated
Results
The concentration of PTU in breast milk was 10% of that in serum
The amount of PTU excreted from breast milk was 0.025% of the amount ingested.
Using these data, it was calculated that
If the mother uses 200 mg of PTU, 3/day
The amount of PTU transferred from breast milk to the infant is 149ug per day
If the infant weighs 4 kg
The dose ingested is equivalent to 3mg of PTU for a 70kg adult
This is equivalent to 1/17th tablet of PTU
Mothers treated with MMI
The situation is very different
The excretion rate of MMI from breast milk is about 4-7 times higher than that of PTU
If the mother takes 40mg of MMI daily
The infant can consume 70ug of MMI from breast milk
This dose is equivalent to 1.2mg of MMI for a 70kg adult
This is equivalent to ¼ tablet of MMI
Application of ATD during lactation
If the patient has stopped using ATD in the second trimester and has a normal thyroid function
After delivery, the patient should be treated as a normal mother breastfeeding
However, after delivery, as the immunosuppression during pregnancy is eliminated
If the original hyperthyroidism has been controlled, the condition may worsen and the dosage of ATD may be increased.
It has been traditionally believed that
If the patient is treated with ATD, she should be persuaded to stop breastfeeding
If ATD therapy is needed
PTU should be chosen over MMI or CA
A recent 7-year prospective follow-up study showed that
women with hyperthyroidism on PTU or MMI who were breastfeeding
No adverse effects on the nail function of their offspring
No difference in IQ between children of the same age
When ATD is taken during breastfeeding
Increased TSH and decreased T4 can be measured in the blood of newborns
These abnormalities are usually seen with high doses of ATD (e.g., PTU 600-750 mg/day)
and may persist during the first week
but may return to normal after one month
Some literature suggests that
If a mother on ATD must be breastfeeding
PTU dose should be less than 450mg/day
and should be breastfed before taking the drug
The next breastfeeding should be at least 3-4h apart from the dose
This is not the best treatment option
Large-scale, multicenter, long-term
randomized, double-blind, placebo-controlled
clinical trials to further confirm
Summary.
(1) Hyperthyroidism is associated with a maternal immunosuppressed state in pregnancy
(2) The main effects of hyperthyroidism on the fetus are low birth weight, preterm delivery, stillbirth and fetal malformations
(3) Placental and breast milk passage rates are higher in MMI than in PTU
(4) Although there is no strong evidence to confirm the difference in the effects of PTU and MMI on the fetus and newborn
However, PTU is routinely recommended over MMI for hyperthyroidism in pregnancy and lactation
(5) Mild cases of hyperthyroidism may be left untreated
(6) Moderate doses should be used to adjust the thyroid function at or slightly above the upper limit of normal for treatment.
(7) Combination of L-T4 and β-blockers is not recommended.