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The Treatment of Illnesses Arising in Pregnancy

Dtsch Arztebl Int 2017; 114(37): 616-26; DOI: 10.3238/arztebl.2017.0616

Bolz, M; Körber, S; Reimer, T; Buchmann, J; Schober, H; Briese, V

Background: The treatment of pregnant women who have illnesses unrelated to pregnancy can cause uncertainty among physicians.

Method: We searched the PubMed database and specialty guidelines from Germany and abroad (the guidelines of the German Society for Gynecology and Obstetrics, the American Congress of Obstetricians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists) over the period 2007–2016 for information on standards for the diagnosis and treatment of five illnesses that can arise in pregnancy: bronchial asthma, migraine, hypothyroidism, hyperthyroidism, and varicose veins.

Results: Any diagnostic tests that are carried out in pregnant women should be simple and goal-directed. The choice of drugs that can be used is limited. For many drugs, no embryotoxic or teratogenic effect is suspected, but the level of evidence is low.

Conclusion: When illnesses unrelated to pregnancy arise in pregnant women, attention must be paid to potential divergences from the typical disease course and to possible drug side effects on the fetus in order to prevent serious complications for both mother and child.

Illnesses unrelated to pregnancy are an important component of the (interdisciplinary) care of pregnant women. Uncertainty often arises about what diagnostic or therapeutic procedures can be performed and about the potential embryotoxic or teratogenic effects of drugs. This article is intended as an overview of five common and important maternal illnesses that can arise during pregnancy. Abnormal conditions that are explicitly linked to pregnancy, some of which are more common than the illnesses we discuss here (e.g., emesis and hyperemesis gravidarum, heartburn/gastroesophageal reflux disease), will not be considered in this review.

Learning objectives

This article is meant to provide the reader with

  • an overview of the treatment of bronchial asthma, hypo- and hyperthyroidism, migraine, and varicose veins in pregnant women and
  • knowledge of the standard treatment for each of these conditions.

Bronchial asthma

Asthma is the most common chronic lung disease among pregnant women, with a prevalence of 4–8% (1). As a rule, the disease remains stable in a third of patients during pregnancy, worsens in a third, and improves in a third (the “one-third rule”). Viral infections of the upper airways, discontinuation of inhaled corticosteroids, and active smoking are held to be risk factors for exacerbations (2).

Bacterial superinfection is common; when it occurs, antibiotic treatment is indicated. (For an overview of the use of antibiotics in pregnancy, see [e1].)

Inadequately controlled asthma that is present even before pregnancy is a major risk factor for the development of pre-eclampsia at some time during pregnancy (relative risk [RR] 1.54 compared to pregnant women without asthma). Asthma is also associated with further complications of pregnancy, including intrauterine growth restriction (RR 1.46), small for gestational age (SGA) (RR 1.22), preterm delivery (RR 1.41), and birth defects (RR 1.11) [e2–e5]. These risks, however, are not a reason for women who want to have children to forego pregnancy.

There is no currently valid German guideline for the treatment of asthma during pregnancy. The national care guideline (Nationale Versorgungsleitlinie, NVL) for asthma, which included a chapter on pregnancy, expired on 31 December 2014; an update is not due to be published until 2018. The guideline of the Global Initiative for Asthma (GINA) can be recommended. A German-language pocket guide to this guideline (current as of 2016) is available.

Particular aspects of asthma in pregnancy

Asthma that is present during pregnancy must be optimally controlled. The treatment that was given before pregnancy should be continued, and marked acute exacerbations must be treated at once. To prevent sudden worsening of asthma, the German Standing Committee on Vaccination (Ständige Impfkommission, STIKO) recommends influenza vaccination from the first trimester onward. In the long-term treatment of the pregnant patient, the physician should periodically check the patient’s need for and compliance with prescribed medication, and provide asthma education as needed. Any comorbidities that may arise, e.g., rhinitis or reflux, should be treated as necessary. Delays in diagnosis and treatment should be avoided. Patients who smoke should be encouraged to quit. The pregnant asthmatic patient should also undergo pulmonary function testing once per month. The initiation of desensitization treatment during pregnancy is contraindicated (3).

In a Cochrane analysis carried out in 2014, eight randomized trials on the treatment of asthma in pregnancy, involving a total of 1181 patients, were evaluated (4). No definitive conclusions could be drawn because some trials did not consider current treatment regimens and others were of insufficient power to detect differences in the perinatal status endpoint. Two approaches that were addressed in these trials are nevertheless of interest. One of these involved measurement of the fraction of exhaled nitrous oxide (FeNO) to predict sudden worsening of asthma (e6). A side benefit of this measurement is that it enables a check on the necessary steroid dose and on patient compliance with medication; nonetheless, it is not reimbursed by most statutory health insurance carriers in Germany. Another approach discussed in the reviewed publications was improved asthmatic control through interdisciplinary counseling as part of the MAMMA trial (e7). In particular, counseling was coordinated by pharmacies. No recommendations for routine practice could be extracted from these trials, however, because of their low case numbers (n = 29 per arm).

Clinical features

Shortness of breath and nocturnal coughing are the main manifestations of bronchial asthma. Auscultation reveals signs of obstruction (wheezes, rales, rhonchi). These symptoms and signs are partly or completely reversed after the inhalation of a β2-sympathomimetic agent. Asthma is classically associated with severe intolerance of beta-blockers. The treatment of asthma is essentially the same in pregnant as in non-pregnant patients.

An acute asthma attack in a pregnant woman is always an indication for in-hospital treatment and observation. Pharmacotherapy must be escalated or de-escalated depending on the severity of the attack and the extent of the clinical response (Table 1). Supplemental oxygen should be given at once, the goal being an O2 saturation level above 95%.

Treatment recommendations for asthma attacks during pregnancy*1 *
Table 1
Treatment recommendations for asthma attacks during pregnancy*1 *

The risk of birth defects, pre-eclampsia, preterm birth, or intrauterine growth retardation is not increased by the use of inhaled corticosteroids, theophylline, or short-acting β2-mimetic drugs such as salbutamol (6). The doses of these drugs need not be adjusted in pregnancy.

Oral glucocorticoids given in the first trimester increase the risk of fetal cleft lip or palate (0.3% versus 0.1%) (2). Systemic glucocorticoids increase the risk of diabetes but are nevertheless indispensable in the treatment of severe asthma and the life-threatening situations associated with it.

Inhaled corticosteroids are the cornerstone of the treatment of persistent asthma. They can be used safely in pregnancy; the largest body of evidence is available for budenoside (7). Only scant data are now available for the combination of inhaled corticosteroids with long-acting β2-agonists (formoterol) (e8). Inhaled anticholinergic drugs such as tiotropium bromide are increasingly used as an alternative. They should be given in pregnancy only for strict indications, as valid data on their use are currently still unavailable.

Theophylline in the recommended dose is not dangerous during pregnancy, but its role in the treatment of asthma is now only secondary (it is a weak bronchodilator with a very high side-effect potential, and its use necessitates measurement of serum levels). H1-antihistamines can be taken during pregnancy without any special restrictions (e9). Montelukast, a leukotriene receptor antagonist, has anti-inflammatory properties and can be used as an alternative to inhaled corticosteroids. The current recommendation is that montelukast treatment should not be started during pregnancy but should not be stopped during pregnancy either, if it was initiated beforehand and has met with therapeutic success (1).

The newer biological agents are coming into increasing use as additional treatments for severe bronchial asthma (step 5 in the treatment algorithm of the current GINA guideline). The monoclonal antibody omalizumab binds free human IgE in the blood and is used to treat severe allergic asthma. This drug was given to 191 women around the time of conception, or during pregnancy, without any observed increase in the rate of birth defects or intrauterine growth retardation (e10). Two further antibodies, mepolizumab and reslizumab, are new options for the treatment of severe eosinophilic asthma; both of them bind to the cytokine interleukin-5. No clinical data on their use in pregnancy are available.

Mode of delivery

Spontaneous delivery is to be preferred. Endogenous cortisol secretion during delivery makes asthma attacks during delivery very rare (5).

Special aspects of delivery in asthmatic mothers

During delivery, anti-asthmatic medication must be continued; short-acting β2-agonists with or without corticosteroids should be given. Intravenous fluid replacement is beneficial as well. Peridural anesthesia enables the optimal treatment of pain and may help reduce bronchospasm. The patient’s pulmonary function and oxygen saturation should be evaluated as necessary. To prevent acute adrenal failure during delivery, the patient should be given a stress dose of glucocorticoid (20 mg of methylprednisolone every 8 hours for 1–2 days), especially if she has already been taking systemic glucocorticoids in the last few months (8).

If labor needs to be induced (e.g., with prostaglandin administration after post-partum bleeding), bronchoconstrictors must be avoided. Prostaglandin F2α has not been approved in Germany, but prostaglandin E2 or E1 may be given. The administration of fenoterol or oxytocin during delivery is not contraindicated (3).

Clinical experience has shown that asthma returns to the same level of severity as before pregnancy within 3 months of delivery (e11). Most anti-asthmatic medications can be safely taken during the breastfeeding period. The breast-fed newborn infants of mothers who take theophylline or antihistamines may become sleepy or irritable.

Migraine

Migraine is characterized by recurrent bouts of headache, often of a pulsating character, usually unilateral, and of variable intensity. Associated symptoms included nausea, vomiting, photo- and phonophobia, and a general feeling of being unwell. Women are more commonly affected than men; 14% of women have migraine at some time in their lives. The prevalence of migraine is highest between the ages of 35 and 45 (e12, e13). A migraine attack that lasts longer than 72 hours is called status migrainosus (e14). In some 15% of patients, the headache is preceded by an aura.

The most important differential diagnoses of migraine in pregnancy are pre-eclampsia (pregnancy-induced hypertension and proteinuria) and eclampsia (pregnancy-induced epileptic seizures). Women with migraine typically suffer from less frequent and less intense attacks when they are pregnant (9). Women who have their first-ever migraine attack when pregnant (pregnancy-associated migraine) have an increased risk of stroke and myocardial infarction during pregnancy (10, 11) and should therefore be seen in consultation by a neurologist (12).

Treatment

Non-pharmacological interventions are preferred for the treatment of migraine during pregnancy. Multimodal approaches to the prevention and treatment of migraine are useful for pregnant women as for other sufferers. These include avoiding triggering factors, learning relaxation techniques, and making use of manual therapy and acupuncture (13, 14). The pharmacological prevention of migraine attacks with beta-blockers can be maintained during pregnancy, if necessary. There is good evidence for the efficacy of metoprolol (initially 50 mg/day, maintenance dose 100–150[200] mg/day), propranolol (initially 40 mg/day, maintenance dose 120–160 mg/day), and bisoprolol (5 mg/day).

When a pregnant woman is treated with a beta-blocker, there must be surveillance for the possible development of intrauterine growth retardation. Neonatal bradycardia may arise, and the newborn infant must therefore be kept under close observation for the first 24 hours after birth.

Further options for the pharmacological prevention of migraine attacks include analgesic drugs, magnesium, and non-steroidal anti-inflammatory drugs. These, however, should be given no later than the end of the 32nd week of gestation, as otherwise there is a danger of premature closure of the fetal ductus arteriosus. There is little evidence to support the administration of acetylsalicylic acid (100 mg/day) to prevent migraine attacks, which is an off-label use of this drug. Likewise, there is little evidence to support the administration of magnesium (200 mg bid) for this purpose.

Anticonvulsant drugs such as topiramate and valproic acid are associated with a higher risk of birth defects. The indications for their use should, therefore, be critically evaluated even before conception (15, e12e16).

80% of migraine sufferers use non-prescription pain relievers to treat their acute migraine attacks, often without consulting a physician. The non-prescription drug of first choice to treat acute migraine attacks during pregnancy is acetaminophen (1000 mg/day up to a maximum of 3 g/day for 10–14 days). The evidence available to date indicates that acetaminophen is not teratogenic. There is evidence, however, of a higher likelihood of bronchial asthma after maternal use of acetaminophen during pregnancy (e17, e18). The non-prescription drugs of second choice to treat acute migraine attacks during pregnancy are ibuprofen and acetylsalicylic acid. Ibuprofen should be given in single doses of 200–600 mg, up to a daily maximum of 1200 mg. Ibuprofen should not be given during the third trimester due to the associated risk of premature closure of the ductus arteriosus in the fetus.

Triptans are the drugs of first choice for patients who are not pregnant but are not approved for use by pregnant women, even though there is no evidence that they cause birth defects. For sumatriptan in particular, there exists a large registry of pregnant women among whom no increase in the rate of complications in the first trimester can be seen (16). Sumatriptan is, therefore, the drug of third choice to treat acute migraine attacks (in a single dose of 50–100 mg p. o.).

Mode of delivery

Migraine per se is not an indication either for the induction of delivery or for cesarean section.

Thyroid dysfunction

Thyroid hormones make it possible to meet the increased energy requirement during pregnancy. They are extraordinarily important for fetal growth and development. An absolute deficiency of thyroid hormones during pregnancy leads to the syndrome of cretinism in the infant (17). Nearly 50% of pregnant women have a moderate iodine deficiency. The avoidance of iodine deficiency through daily supplementation with 100–150 µg of iodide compensates for the thyroid gland’s elevated demand for iodine (25–50% higher than normal) and thus ensures adequate thyroid hormone synthesis and the avoidance of hypothyroidism and goiter.

Both latent and overt hypothyroidism during pregnancy confer higher risks of spontaneous abortion (16.7%), intrauterine growth restriction, preterm birth (odds ratio [OR] 1.19), and intrauterine fetal death (0.65%) (18, e19, e20). Impaired neurocognitive development of the child due to hypothyroidism is irreversible (19). (Unrecognized) hypothyroidism elevates the risk of sterility.

Untreated maternal hyperthyroidism is associated with multiple risks for embryonal/fetal development, including pre-eclampsia, thyrotoxic crisis, spontaneous abortion (17.2%), intrauterine growth retardation, preterm birth (RR 1.24), and intrauterine fetal death (0.82%) (e19, e20). The treatment that is needed to lower maternal thyroid hormone levels promotes the development of hypothyroidism in the fetus (18).

The secretion of thyroid hormones is stimulated by the influence of TSH (thyroid-stimulating hormone); in the bloodstream, thyroid hormones are coupled with thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin. Only the free (unbound) thyroid hormones are biologically effective. The ratio of free to bound thyroid hormone is roughly 1:1000 (Figure, Table 2).

The passage across the placenta of thyroid hormones and related substances (21).
Figure
The passage across the placenta of thyroid hormones and related substances (21).
Clinical manifestations of thyroid diseases
Table 2
Clinical manifestations of thyroid diseases

Diagnostic evaluation

The diagnostic tests that can be applied during pregnancy are limited. fT3, fT4, TSH, anti-thyroperoxidase (anti-TPO) antibodies, anti-thyroglobulin antibodies (TAB), anti-TSH-receptor antibodies (TRAB), and thyroxine-binding globulin (TBG) can be measured in the laboratory (Tables 3 and 4), and ultrasonography, color-Doppler ultrasonography, and fine-needle biopsy of the thyroid gland can be considered as well. Radionuclide scintigraphy of the thyroid gland is contraindicated during pregnancy and breastfeeding, as is the thyrotropin releasing hormone (TRH) test. Nonetheless, if scintigraphy is performed during the first semester because of unawareness of pregnancy, there is no medical indication for a termination of pregnancy.

Refrence ranges for thyroid laboratory values in pregnancy (modified from [20])
Table 3
Refrence ranges for thyroid laboratory values in pregnancy (modified from [20])
Typical laboratory constellations in selected thyroid diseases during pregnancy (modified from [20])
Table 4
Typical laboratory constellations in selected thyroid diseases during pregnancy (modified from [20])

HyperthyroidismHyperthyroidism arises in 0.1–1.0% of pregnancies (e21, e22). Its most common cause is Graves disease, i.e., autoimmune-mediated overstimulation of the thyroid gland by anti-TSH-receptor antibodies (TRAB). The manifestations can be expected to improve during the second and third trimesters; after delivery, however, the immunological condition generally reverts to the state that prevailed before pregnancy. Rare causes of hyperthyroidism include toxic adenoma, toxic nodular goiter, carcinoma, subacute thyroiditis, and drugs (amiodarone, lithium).

The differential diagnosis of hyperthyroidism during pregnancy includes pregnancy-induced hyperthyroidism triggered by human chorionic gonadotropin (HCG) in the first and second trimester. This condition is caused by very high HCG levels (maximum in gestational week 12, ca. 210 000 mU/mL). HCG stimulates the TSH receptor, often resulting in (marked) intractable vomiting during pregnancy (hyperemesis gravidarum). In this situation, the laboratory test for anti-TSH-receptor antibodies (TRAB) is negative. The condition is self-limiting: from about the 17th gestational week onward, its manifestations disappear, and no treatment is needed to lower the thyroid hormone level (e23).

Untreated maternal hyperthyroidism may worsen into a thyrotoxic crisis in the setting of infection, stress around the time of delivery, or operative delivery (cesarean section). The manifestations of thyrotoxic crisis include fever, confusion, and cardiac decompensation (21).

Antithyroid antibodies cross the placenta and cause neonatal or fetal hyperthyroidism in about 10% of cases. Their half-life is three weeks, which explains the occurrence of (transient) hyperthyroidism in the neonate. Pregnant women with a known history of Graves disease must therefore be checked for the presence of antithyroid antibodies in the third trimester of pregnancy as well. Maternal hyperthyroidism is a clear indication for treatment. The lowest effective dose should be given, and laboratory checks should be repeated every four to six weeks. The administration of iodide is contraindicated in women with florid hyperthyroidism.

The drug of first choice is propylthiouracil (PTU) (50–100 mg/day). Under treatment, the fT4 value should revert to the upper normal range. Laboratory checks should be repeated every two to four weeks as needed. The liver enzymes should be regularly measured as well, as PTU is hepatotoxic.

The drug of second choice is thiamazole (5–20 mg/day). It should be borne in mind that thiamazole is embryotoxic if given during the first trimester. Approximately 1 in 100 to 1000 exposed children is affected. Some 200 cases of birth defects of various kinds have been reported, including choanal atresia, tracheo-esophageal fistula, aplasia cutis, hypoplasia of the nipples, and mental retardation; the link between these defects and the specific substance remains unclear. Thiamazole can, however, be given during the second and third trimesters.

Beta-blockers can be given in individual cases to inhibit the conversion of T4 to T3, e.g., propranolol in a dose of 20–40 mg every 6–8 hours. Thyroidectomy is indicated only in exceptional cases of treatment failure or suspected cancer. Radioiodine therapy is contraindicated during pregnancy (2225).

Breastfeeding is allowed while the mother is taking thyrostatic drugs, as long as they are taken in the following doses:

  • PTU, no more than 150 mg/day (first choice);
  • Thiamazole, no more than 20 mg/day.

HypothyroidismSubclinical hypothyroidism (TSH ≥ 4.0 mU/L) is present in roughly 3% of all pregnancies, and 0.3–0.5% of pregnant women suffer from clinically overt hypothyroidism. In 5.1–12.4% of cases, the cause is an autoimmune disorder called Hashimoto’s thyroiditis (e21, e22). Other causes include atrophic thyroiditis, congenital thyroid aplasia, iatrogenic hypothyroidism (status post thyroidectomy), drugs (thyrostatic agents), and, rarely, hypopituitarism.

The condition is usually recognized and treated before conception. If an increased dose of levothyroxine is needed during pregnancy, it is usually because the dose before conception was already insufficient.

The target value for TSH before conception should be between 2.5 and 4.0 mU/L. Targets ≤ 2.5 mU/L are not absolutely necessary (e24, e25). The euthyroid state is a prerequisite for a normal course of pregnancy. Thyroid hormones are substituted with L-thyroxine at a dose of 1.2–2.0 µg per kilogram of body weight daily, including during the breastfeeding phase. The necessary initiation and titration of treatment must take place before the 8th gestational week, as it has been found that the initiation of treatment between the 8th and 20th gestational week does not result in any improvement of the children’s cognitive abilities at age 5 (e26).

Pregnant women with antithyroid antibodies are at elevated risk (up to 40%) of post-partum thyroiditis (PPT). It is therefore recommended that their TSH values should be checked 3 and 6 months after delivery (e27, e28).

Screening for thyroid disease during pregnancy

There have not been any studies indicating the benefit of universal screening for thyroid disease during pregnancy. Situations in which individuals may be advised to undergo testing are listed in the Box.

Individualized recommendations for screening for thyroid diseases during pregnancy (e23)
Box
Individualized recommendations for screening for thyroid diseases during pregnancy (e23)

Mode of delivery

Women with thyroid disease can give birth normally. For women with large goiters, a prepartal anesthesiological consultation is recommended in order to determine whether there is any impediment to intubation.

Varicose veins (chronic venous insufficiency)

Varicose veins are a component of the syndrome of chronic venous insufficiency (primary varicosis). They are not an obligatory manifestation of the syndrome. The main symptoms are heavy and tired legs, ankle edema, a feeling of restlessness in the legs, and nocturnal leg cramps. The prevalence of varicosis is 20–30% in primiparae and 50% in multiparae (e29). Obesity markedly increases the tendency of varicose veins to become thrombosed. The greater saphenous vein is most commonly affected. Intradermal telangiectasiae are visible on the skin surface; if they are present in a network-like pattern, they are called reticular varices. Varicosis arising after venous thrombosis is called secondary varicosis. Complications of varicosis that can arise during pregnancy include thrombophlebitis, thrombosis, and pulmonary embolism. The risk of thrombosis and pulmonary embolism in pregnancy is 0.2 % (26). Thrombophlebitis is a superficial inflammation of epifascial veins with the secondary development of thromboses. Small, possibly subclinical pulmonary emboli may result. The skin changes that accompany varicosis include stasis dermatitis, induration, white atrophy, and ulcerations.

The following sites of involvement are important in pregnancy because of the possibility of hemorrhagic complications: suprapubic varicosis, varicosis vulvae (differential diagnosis, Klippel-Trenaunay-Weber syndrome), uterine and ovarian varicosis (spontaneous hemoperitoneum!), and hemorrhoids (2730). The alarm signs for superficial thrombophlebitis include sudden pain and swelling or a persistent ”charley-horse” of the legs. Clinical signs of thrombosis that can be seen during pregnancy also include the following:

  • Livid discoloration; patchy skin pigmentation; atrophic, tense, and shiny skin
  • Pain in the groin, over the adductor canal, in the popliteal fossa, the calf, the ankle, or the sole of the foot
  • Calf pain on plantar flexion (Homans sign)
  • Pratt’s warning veins (dilated pretibial veins)
  • Painful pretibial Meyer pressure points
  • Pain in the sole of the foot: Payr sign elicited by simultaneous pressure and plantar flexion.

Any suspicion of thrombosis during pregnancy calls for immediate diagnostic evaluation. No diagnostic algorithm for thrombosis during pregnancy and the postpartum period has yet been tested. Duplex ultrasonography of the femoral and pelvic veins is the diagnostic test of first choice. The D-dimer test cannot be interpreted accurately during pregnancy because of the physiologic rise in D-dimers. Echocardiography additionally enables the detection of pulmonary emboli. Magnetic resonance imaging (MRI) is a further diagnostic alternative during pregnancy. The treatment of deep vein thrombosis (DVT) and/or pulmonary embolism during pregnancy is with low-molecular-weight heparin, which should be given until 6 weeks postpartum. Vitamin K antagonists are contraindicated during pregnancy. There have not yet been any systematic studies of non-vitamin-K-dependent oral anticoagulants during pregnancy (26).

According to a recent meta-analysis, among women with superficial thrombophlebitis during pregnancy, 18% will develop a deep vein thrombosis and 7% will have a pulmonary embolism (31). For comparison, the overall prevalence of deep vein thrombosis in pregnancy is only 0.08–0.29%, or 1.56% among pregnant women with more than three days of bedrest (32). Obese pregnant women with thrombophlebitis are at particularly high risk. Further risk factors for deep vein thrombosis include maternal age over 35, multiple pregnancy, pre-eclampsia, trauma, emergency cesarean section, and high peripartal blood loss.

No treatment for chronic venous insufficiency is supported by high-level evidence. The most important therapeutic measure is to stabilize the connective tissue from outside with compressive stockings. In addition, mobilization and intermittent positioning of the legs above the torso are recommended.

There is only low-level evidence for various pharmacological and physical treatments to relieve the symptoms of venous insufficiency during pregnancy. These include rutoside, reflex-zone massage, and Kneipp therapy in the form of “alternating showers” (thermal conditioning) (32). The supplementary local application of botanical ointments, including horse-chestnut and yarrow extract, may be helpful as well.

Patient education and prevention are important. Pregnant women should not sit for more than one hour at a time without taking a 5–10 minute mobilization break. In the physical therapy department, aquajogging and bicycling in the supine position are indicated. Nicotine, alcohol, hot baths, prolonged sun exposure, leg massages, and long journeys should be prophylactically avoided. Brush massages of the legs promote the development of telangiectasiae.

Horváth et al. (33) recommend the prophylactic treatment of women at high risk with low-molecular-weight heparin (exoxaparin) in a dose of 1 to 1.5 mg/kg body weight, twice per day; the target parameter is an anti-factor-Xa activity of 0.5 four hours after the injection.

For women with marked varicosis vulvae (i.e., varicosis affecting the labia and/or vagina), a cesarean section can be considered in individual cases. However, the risk of thrombosis is markedly higher (by a factor of 5 to 10) in the postpartum period (26). The term “varicosis” refers to the entire syndrome of chronic venous insufficiency. Obese pregnant women with superficial thrombophlebitis are at especially high risk and need thrombosis prophylaxis with low-molecular-weight heparin.

Conflict of interest statement
Prof. Buchmann has received honoraria from Allergan for preparing scientific presentations.

The remaining authors state that they have no conflict of interest.

Manuscript dates
Manuscript received on 24 January 2017; revised version accepted on 31 July 2017.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Dr. med. Michael Bolz

Universitätsfrauenklinik, Klinikum Südstadt Rostock

Südring 81, D-18059 Rostock, Germany

michael.bolz@kliniksued-rostock.de

Supplementary material
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Kawata E, Kondoh E, Kawasaki K, et al.: Utero-ovarian varices and absent inferior vena cava in pregnancy. J Obstet Gynaecol Res 2015; 41: 631–4 CrossRef MEDLINE
30.
Yara N, Masamoto H, Iraha Y, et al.: Diffuse venous malformation of the uterus in a pregnant woman with Klippel-Trénaunay Syndrome diagnosed by DCE-MRI. Case Rep Obstet Gynecol 2016; 2016: 4328450 CrossRef
31.
Di Minno MN, Ambrosino P, Ambrosini F, Tremoli E, Di Minno G, Dentali F: Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2016; 14: 964–72 CrossRef MEDLINE
32.
Smyth RM, Aflaifel N, Bamigboye AA: Interventions for varicose veins and leg oedema in pregnancy. Cochrane Database Syst Rev 2015; 10: CD001066 CrossRef
33.
Horváth B, Skrapits J, Bódis J: Obstetrical management of an extremely overweight pregnant woman (184kg bw) with special attention on thromboprophylaxis. Case Rep Obstet Gynecol 2013; 2013: 689549.
e1.
Schaefer C: Medikamentöse Therapie in Schwangerschaft und Stillzeit – aktueller Kenntnisstand und Empfehlungen. Frauenheilkunde up2date 2015; 9: 2–8 CrossRef
e2.
Murphy VE, Namazy JA, Powell H, et al.: A meta-analysis of adverse perinatal outcomes in women with asthma. BJOG 2011; 118: 1314–23 CrossRef MEDLINE
e3.
Murphy VE, Wang G, Namazy JA, et al.: The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis. BJOG 2013; 120: 812–22 CrossRef MEDLINE
e4.
Namazy JA, Murphy VE, Powell H, Gibson PG, Chambers C, Schatz M: Effects of asthma severity, exacerbations and oral corticosteroids on perinatal outcomes. Eur Respir J 2013; 41: 1082–90 CrossRef MEDLINE
e5.
Wang G, Murphy VE, Namazy J, et al.: The risk of maternal and placental complications in pregnant women with asthma: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2014; 27: 934–42 CrossRef MEDLINE
e6.
Powell H, Murphy VE, Taylor DR, et al.; Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomized controlled trial. Lancet 2011; 378: 983–90 CrossRef
e7.
Lim AS, Stewart K, Abramson MJ, Walker SP, Smith CL, George J: Multidisciplinary approach to management of maternal asthma (MAMMA): a randomized controlled trial. Chest 2014; 145: 1046–54.
e8.
Eltonsy S, Kettani FZ, Blais L: Beta2-agonists use during pregnancy and perinatal outcomes: a systematic review. Resp Med 2014; 108: 9–33 CrossRef MEDLINE
e9.
Etwel F, Faught LH, Rieder MJ, Koren G: The risk of adverse pregnancy outcome after first trimester exposure to H1 antihistamines: a systematic review and meta-analysis. Drug Saf 2017; 40: 121–32 CrossRef MEDLINE
e10.
Namazy JA, Schatz M: The treatment of allergic respiratory disease during pregnancy. J Investig Allergol Clin Immunol 2016; 26: 1–7 CrossRef
e11.
Schatz M, Harden K, Forsythe A, et al.: The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509–17 CrossRef
e12.
Deutsche Migräne-und Kopfschmerzgesellschaft (DMKG), Deutsche Gesellschaft für Neurologie (DGN), der Berufsverband der Neurologen (BDN), die Deutsche Gesellschaft für Psychologische Schmerztherapie und –Forschung (DGPSF), die Österreichische Kopfschmerzgesellschaft (ÖKSG) und die Schweizer Kopfwehgesellschaft (SKG): Gemeinsame S1-Leitlinie: Kopfschmerz bei Übergebrauch von Schmerz- und Migränemitteln. www.dmkg.de/files/dmkg.de/Empfehlungen/Leitlinie_Kopfschmerz_Medikamentenuebergebrauch_2012.pdf (last accessed on 24 August 2017).
e13.
Briese V, Bolz M, Reimer T: Krankheiten in der Schwangerschaft. Handbuch der Diagnosen von A–Z. Berlin, Boston 2010: De Gruyter.
e14.
Gaul C: Migräne: Diagnose, Therapie, Prophylaxe. Frauenarzt 2015; 56: 132–7.
e15.
Embryotox: Valproinsäure. www.embryotox.de/valproinsaeure.html, (last accessed on 18 December 2016).
e16.
Silberstein SD: Topiramate in migraine prevention: A 2016 perspective. Headache 2017; 57: 165–78 CrossRef MEDLINE
e17.
Eyers S, Weatherall M, Jefferies S, Beasley R: Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review an meta-analysis. Clin Exp Allergy 2011; 41: 482–9. CrossRef MEDLINE
e18.
Liew Z, Bach CC, Asarnow RF, Ritz B, Olsen J: Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. Int J Epidemiol 2016; 45: 2009–17.
e19.
Sheepan PM, Nankervis A, Araujo Junior E, et al.: Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol and Metab 2015; 100: 4325–31 CrossRef MEDLINE
e20.
Andersen SL, Olsen J, Laurberg P: Hypothyroidism and pregnancy loss: comparison with hyperthyroidism and diabetes in a Danish population based study. Clin Endocrinol 2016; 85: 962–70 CrossRef MEDLINE
e21.
Springer D, Jiskra J, Limanova Z, et al.: Thyroid in pregnancy: from physiology to screening. Crit Rev Clin Lab 2017; 54: 102–16 CrossRef MEDLINE
e22.
Führer D: Schilddrüsenerkrankungen und Schwangerschaft. Internist 2011; 52; 1158–66 CrossRef MEDLINE
e23.
Stagnaro-Green A: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21: 1081–125 CrossRef MEDLINE PubMed Central
e24.
Cai YY, Zhong L, Guan J, et al.: Outcome of in vitrofertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol 2017; 15: 39 CrossRef MEDLINE
e25.
Plowden TC, Schisterman EF, Sjaarda LA, et al.: Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab 2016; 101: 2358–65 PubMed Central CrossRef CrossRef MEDLINE
e26.
Casey BM, Thom EA, Peaceman AM, et al.: Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017; 376: 815–25 CrossRef MEDLINE
e27.
Argatska A, Nonchev B, Orbetzova M, et al.: Postpartum thyroid dysfunction in women with autoimmune thyroiditis. Gynecol Endocrinol 2016; 32: 379–82 CrossRef MEDLINE
e28.
Heufelder AE, Hofbauer LC: Die Thyreotitiden. Dtsch Arztebl 1998; 95: A-466–76 VOLLTEXT
e29.
Dindelli M, Basellini A, Rabaiotti E, et al.: Epidemiological analysis of the incidence of varicose pathology in pregnancy. Ann Obstet Gincol Med Perinat 1990; 111: 257–64 MEDLINE
Department of Obstetrics and Gynecology, Klinikum Südstadt Rostock:
Dr. med. Bolz, Dr. med. Körber, Prof. Dr. med. Reimer, Prof. Dr. med. Briese
Department of Internal Medicine I, Klinikum Südstadt Rostock: Prof. Dr. med. Schober
Department of Child and Adolescent Psychiatry, Neurology, Psychosomatics and Psychotherapy, University Medicine Rostock and Clinic and Policlinic for Psychiatry and Psychotherapy, Health Care Center for Neurology, University of Rostock: Prof. Dr. med. Buchmann
Individualized recommendations for screening for thyroid diseases during pregnancy (e23)
Box
Individualized recommendations for screening for thyroid diseases during pregnancy (e23)
The passage across the placenta of thyroid hormones and related substances (21).
Figure
The passage across the placenta of thyroid hormones and related substances (21).
Treatment recommendations for asthma attacks during pregnancy*1 *
Table 1
Treatment recommendations for asthma attacks during pregnancy*1 *
Clinical manifestations of thyroid diseases
Table 2
Clinical manifestations of thyroid diseases
Refrence ranges for thyroid laboratory values in pregnancy (modified from [20])
Table 3
Refrence ranges for thyroid laboratory values in pregnancy (modified from [20])
Typical laboratory constellations in selected thyroid diseases during pregnancy (modified from [20])
Table 4
Typical laboratory constellations in selected thyroid diseases during pregnancy (modified from [20])
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19.Bolz M, Körber S, Schober HC, Briese V: Schilddrüsenerkrankungen in der Schwangerschaft und im Wochenbett. Arztebl Mecklenburg-Vorpommern 2012; 22: 168–73.
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27.Díaz-Murillo R, Tobías-González P, López-Magallón S, Magdaleno-Dans F, Bartha JL: Spontaneous hemoperitoneum due to rupture of uterine varicose veins during labor successfully treated by percutaneous embolization. Case Rep Obstet Gynecol 2014; 2014: 580384.
28.Haynes MC, Lu BY, Winkel AF: Ovarian vein thrombophlebitis related to large uterine myoma. Obstet Gynecol 2014; 123(2 Pt 2 Suppl 2): 450–3 CrossRef MEDLINE
29.Kawata E, Kondoh E, Kawasaki K, et al.: Utero-ovarian varices and absent inferior vena cava in pregnancy. J Obstet Gynaecol Res 2015; 41: 631–4 CrossRef MEDLINE
30.Yara N, Masamoto H, Iraha Y, et al.: Diffuse venous malformation of the uterus in a pregnant woman with Klippel-Trénaunay Syndrome diagnosed by DCE-MRI. Case Rep Obstet Gynecol 2016; 2016: 4328450 CrossRef
31.Di Minno MN, Ambrosino P, Ambrosini F, Tremoli E, Di Minno G, Dentali F: Prevalence of deep vein thrombosis and pulmonary embolism in patients with superficial vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2016; 14: 964–72 CrossRef MEDLINE
32.Smyth RM, Aflaifel N, Bamigboye AA: Interventions for varicose veins and leg oedema in pregnancy. Cochrane Database Syst Rev 2015; 10: CD001066 CrossRef
33.Horváth B, Skrapits J, Bódis J: Obstetrical management of an extremely overweight pregnant woman (184kg bw) with special attention on thromboprophylaxis. Case Rep Obstet Gynecol 2013; 2013: 689549.
e1.Schaefer C: Medikamentöse Therapie in Schwangerschaft und Stillzeit – aktueller Kenntnisstand und Empfehlungen. Frauenheilkunde up2date 2015; 9: 2–8 CrossRef
e2.Murphy VE, Namazy JA, Powell H, et al.: A meta-analysis of adverse perinatal outcomes in women with asthma. BJOG 2011; 118: 1314–23 CrossRef MEDLINE
e3.Murphy VE, Wang G, Namazy JA, et al.: The risk of congenital malformations, perinatal mortality and neonatal hospitalisation among pregnant women with asthma: a systematic review and meta-analysis. BJOG 2013; 120: 812–22 CrossRef MEDLINE
e4.Namazy JA, Murphy VE, Powell H, Gibson PG, Chambers C, Schatz M: Effects of asthma severity, exacerbations and oral corticosteroids on perinatal outcomes. Eur Respir J 2013; 41: 1082–90 CrossRef MEDLINE
e5.Wang G, Murphy VE, Namazy J, et al.: The risk of maternal and placental complications in pregnant women with asthma: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2014; 27: 934–42 CrossRef MEDLINE
e6.Powell H, Murphy VE, Taylor DR, et al.; Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomized controlled trial. Lancet 2011; 378: 983–90 CrossRef
e7.Lim AS, Stewart K, Abramson MJ, Walker SP, Smith CL, George J: Multidisciplinary approach to management of maternal asthma (MAMMA): a randomized controlled trial. Chest 2014; 145: 1046–54.
e8.Eltonsy S, Kettani FZ, Blais L: Beta2-agonists use during pregnancy and perinatal outcomes: a systematic review. Resp Med 2014; 108: 9–33 CrossRef MEDLINE
e9.Etwel F, Faught LH, Rieder MJ, Koren G: The risk of adverse pregnancy outcome after first trimester exposure to H1 antihistamines: a systematic review and meta-analysis. Drug Saf 2017; 40: 121–32 CrossRef MEDLINE
e10.Namazy JA, Schatz M: The treatment of allergic respiratory disease during pregnancy. J Investig Allergol Clin Immunol 2016; 26: 1–7 CrossRef
e11.Schatz M, Harden K, Forsythe A, et al.: The course of asthma during pregnancy, post partum, and with successive pregnancies: a prospective analysis. J Allergy Clin Immunol 1988; 81: 509–17 CrossRef
e12.Deutsche Migräne-und Kopfschmerzgesellschaft (DMKG), Deutsche Gesellschaft für Neurologie (DGN), der Berufsverband der Neurologen (BDN), die Deutsche Gesellschaft für Psychologische Schmerztherapie und –Forschung (DGPSF), die Österreichische Kopfschmerzgesellschaft (ÖKSG) und die Schweizer Kopfwehgesellschaft (SKG): Gemeinsame S1-Leitlinie: Kopfschmerz bei Übergebrauch von Schmerz- und Migränemitteln. www.dmkg.de/files/dmkg.de/Empfehlungen/Leitlinie_Kopfschmerz_Medikamentenuebergebrauch_2012.pdf (last accessed on 24 August 2017).
e13.Briese V, Bolz M, Reimer T: Krankheiten in der Schwangerschaft. Handbuch der Diagnosen von A–Z. Berlin, Boston 2010: De Gruyter.
e14.Gaul C: Migräne: Diagnose, Therapie, Prophylaxe. Frauenarzt 2015; 56: 132–7.
e15.Embryotox: Valproinsäure. www.embryotox.de/valproinsaeure.html, (last accessed on 18 December 2016).
e16.Silberstein SD: Topiramate in migraine prevention: A 2016 perspective. Headache 2017; 57: 165–78 CrossRef MEDLINE
e17.Eyers S, Weatherall M, Jefferies S, Beasley R: Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review an meta-analysis. Clin Exp Allergy 2011; 41: 482–9. CrossRef MEDLINE
e18.Liew Z, Bach CC, Asarnow RF, Ritz B, Olsen J: Paracetamol use during pregnancy and attention and executive function in offspring at age 5 years. Int J Epidemiol 2016; 45: 2009–17.
e19.Sheepan PM, Nankervis A, Araujo Junior E, et al.: Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol and Metab 2015; 100: 4325–31 CrossRef MEDLINE
e20.Andersen SL, Olsen J, Laurberg P: Hypothyroidism and pregnancy loss: comparison with hyperthyroidism and diabetes in a Danish population based study. Clin Endocrinol 2016; 85: 962–70 CrossRef MEDLINE
e21.Springer D, Jiskra J, Limanova Z, et al.: Thyroid in pregnancy: from physiology to screening. Crit Rev Clin Lab 2017; 54: 102–16 CrossRef MEDLINE
e22.Führer D: Schilddrüsenerkrankungen und Schwangerschaft. Internist 2011; 52; 1158–66 CrossRef MEDLINE
e23.Stagnaro-Green A: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21: 1081–125 CrossRef MEDLINE PubMed Central
e24.Cai YY, Zhong L, Guan J, et al.: Outcome of in vitrofertilization in women with subclinical hypothyroidism. Reprod Biol Endocrinol 2017; 15: 39 CrossRef MEDLINE
e25.Plowden TC, Schisterman EF, Sjaarda LA, et al.: Subclinical hypothyroidism and thyroid autoimmunity are not associated with fecundity, pregnancy loss, or live birth. J Clin Endocrinol Metab 2016; 101: 2358–65 PubMed Central CrossRef CrossRef MEDLINE
e26.Casey BM, Thom EA, Peaceman AM, et al.: Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017; 376: 815–25 CrossRef MEDLINE
e27.Argatska A, Nonchev B, Orbetzova M, et al.: Postpartum thyroid dysfunction in women with autoimmune thyroiditis. Gynecol Endocrinol 2016; 32: 379–82 CrossRef MEDLINE
e28.Heufelder AE, Hofbauer LC: Die Thyreotitiden. Dtsch Arztebl 1998; 95: A-466–76 VOLLTEXT
e29.Dindelli M, Basellini A, Rabaiotti E, et al.: Epidemiological analysis of the incidence of varicose pathology in pregnancy. Ann Obstet Gincol Med Perinat 1990; 111: 257–64 MEDLINE

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