Skin in Pregnancy

Abstract

Pregnancy gives rise to a myriad of physiological changes in the skin and its appendages through the different stages. Cutaneous and appendageal alterations are mostly reversed postpartum. These changes can sometimes cause substantial distress to the prospective mother. Awareness, understanding, and the genesis of these normal physiological variations will help differentiate them from pathological ones, and needless interventions can be avoided. It is important for dermatologists to be familiar with the safety profile of different drugs used during pregnancy as some drugs are known to cause adverse effects in the fetus. This chapter describes the various physiological changes in pregnancy and the safety of dermatologic drugs in pregnancy. It also gives a broad overview of the new US FDA (Food and drug administration) pregnancy and lactation labeling rule (PLLR).

1 Physiological Skin Changes in Pregnancy

1.1 Introduction

Pregnancy or gravid state is associated with a temporary shift of hormonal, endocrinological, immunological, metabolic, and vascular factors leading to multitudinous systemic and cutaneous changes [1]. Physiological alterations in the skin and its appendages frequently appear in the early stages of gestation, causing significant impact on quality of life [2]. It is also imperative to distinguish the physiological changes from specific pregnancy dermatoses as some of the latter can cause serious risk to both the mother and the fetus or either of them [3]. Majority of the physiological skin changes resolve after child birth or require only conservative management [4]. Early recognition and accurate diagnosis of these changes are thus essential to improve the outcome in pregnant women while avoiding unnecessary treatment [5].

1.2 Pigmentation

Skin hyperpigmentation is one of the most common physiological changes seen during pregnancy and is observed in some form and intensity in all pregnant women, usually in discrete areas or patterns [6]. The new hormonal milieu of pregnancy with increased pituitary, ovarian, and placental hormones, i.e., melanocyte-stimulating hormone, β-endorphins, estrogen, progesterone along with bioactive sphingolipids enhanced tyrosinase activity is chiefly responsible for stimulating melanin production [1, 7]. These physiological pigmentary changes are more marked in skin of color; the intensity and distribution, however, is largely determined by genetic predisposition, environmental factors, and ultraviolet exposure [2].

Pigment accentuation of normally hyperpigmented anatomic sites is observed in almost all pregnant women and is among the first manifestations seen in pregnancy. This accentuated pigmentation is the result of an increase in number and sensitivity of melanocytes to hormonal stimulation in these regions.

It is most often appreciated in the nipple and areolar region [8] (Fig. 3.1). This hyperpigmented area gradually enlarges as pregnancy progresses, leading to the development of a new outer zone of pigmentation which is termed as secondary areola [9]. Genitals, perineum, axillae, inner thighs, and periumbilical skin also get affected. Skin folds and intertriginous sites can also become dark and pigmented.

Fig. 3.1

Pigmentation of areola in pregnancy

Pigmentation fades postpartum; however, prepregnancy color may not be attained [1].

Acanthosis nigricans can occur de novo in some pregnant women or there can be an exacerbation of pre-existing lesions when there is concomitant insulin resistance or gestational diabetes (Fig. 3.2).

Fig. 3.2

Acanthosis nigricans in pregnancy

Linea nigra refers to the hyperpigmentation of linea alba, a blended aponeurosis that runs vertically down the midline of the abdomen from the symphysis pubis to the xiphisternum with the umbilicus at or below its center [10]. The darkening and hyperpigmentation is generally more notable below the level of umbilicus; however it may also extend around and above it [8] (Fig. 3.3). There is frequent displacement of the umbilicus to the right, and this shift is known as the “ligamentum teres sign” [10]. Longitudinal melanonychia, benign linear pigmentation of the nail plate, may affect multiple fingers and/or toenails in pregnancy and is thought to result from the activation of nail matrix melanocytes. Pigmentation may fade or persist postpartum, sometimes recurring in following pregnancies. Irregular pigmentation or cuticular involvement warrants a thorough examination [11].

Fig. 3.3

Linea nigra, pigmentation of umbilicus and striae gravidarum

Pigmentary demarcation lines also known as Futcher’s lines and Voigt’s lines are sharp physiological lines demarcating areas of hyperpigmentation from normal skin [12]. Type B pigmentary demarcation lines are seen along the posterior aspect of lower limbs. They generally appear in the third trimester and regress after delivery [13]. The hormonal alterations, neurogenic inflammation secondary to trapping of cutaneous nerves by the enlarging uterus, genetic factors, and differential distribution of melanocytes on dorsal and ventral sides for better sun protection are possible factors that are likely to be involved in their development [14].

Freckles and scars that are fairly new also tend to darken during pregnancy. There are contradictory reports on the enlargement and darkening of melanocytic nevus in the gestation period and this area requires further research [15]. Any lesion with changes suspicious of melanoma should be immediately biopsied and assessed regardless of the site or gestational age [16].

Generalized mild hyperpigmentation occurs in pregnant women with Fitzpatrick skin type 1 or 2 [6].

1.2.1 Melasma

Pregnancy-related melasma commonly described as chloasma is characterized by light to dark brown, blotchy, irregular patches present symmetrically on photoexposed areas, especially face [17]. It usually starts to develop in the second trimester and reportedly affects 65–75% of pregnant women. It can occur on the malar, mandibular, or centrofacial regions of the face.

Nose and cheeks are the most frequently involved areas followed by the forehead, upper lip, and chin (Fig. 3.4). Forearms and other photoexposed areas can also sometimes get involved. Increased sun exposure, genetic predisposition, cosmetic usage, and elevated melanocyte-stimulating hormone, estrogen, and progesterone are the underlying causative factors [17]. Chloasma usually resolves completely after treatment within one year after delivery. Occasionally, spontaneous and complete remission may occur.

Fig. 3.4

Melasma in pregnancy

Some pigmentary sequelae are reported in about 30% of women. Pigmentation is found to be more persistent in dermal melasma and in women on oral contraceptives and may cause considerable impact on cosmetic appearance leading to psychosocial and emotional distress [18]. Melasma often tends to recur in subsequent pregnancies. Multiple pregnancies increase the possibility of melasma developing for the first time during pregnancy [17]. Sunscreen usage and prevention of photoexposure are strongly recommended during pregnancy to prevent the development or worsening of melasma [19]. Hydroquinone and topical tretinoin, though effective in treating melasma, are pregnancy category C drugs and better deferred during this period. Corticosteroids, chemical peels, and microdermabrasion can be tried after delivery. There is scarcity of literature on the usage of lasers during pregnancy [20].

1.3 Vascular Changes

Vascular changes are congruent with pregnant state and arise in almost all pregnant women. Majority of these vascular changes resolve within few months after delivery. However, in some women these changes can lead to significant cosmetic consequences [21].

1.3.1 Varicosities

The physiological vascular adaptions of pregnancy secondary to elevated hormones and angiogenic factors lead to high circulating blood volume, increased proliferation and dilatation of cutaneous blood vessels, congestion, and hyperemia. These changes, together with progesterone-induced reduction of venous return secondary to partial compression of the inferior vena cava by enlarging the uterus, reduced plasma colloid osmotic pressure, and a hereditary predisposition are all responsible for the development of venous insufficiency, varicosities, and edema during pregnancy [21].

Varicosities involving the saphenous system, hemorrhoidal, vulvar, and vaginal networks occur in about 40% of pregnant women (Figs. 3.5 and 3.6). Of these, Varicosities of the lower limbs are the most frequent to occur and they characteristically present as edema, heaviness of legs, pain, night cramps, and paresthesias [22]. The skin surrounding the varicosities may also become hyperpigmented, itchy, and over a period of time develop eczematous changes resulting in varicose or gravitational eczema [23]. These symptoms tend to worsen with standing and with subsequent pregnancies.

Fig. 3.5

Varicosities around ankle in pregnancy

Fig. 3.6

Vulvar and vaginal varicosities in pregnancy

Hemorrhoidal varicosities can bleed, become painful, and also commonly undergo thrombosis during pregnancy [24]. (Although uncommon in pregnancy, complications that can arise from varicose veins include venous ulcer, bleeding from the vein, inflammation or thrombophlebitis, deep vein thrombosis, and pulmonary embolism [25]) Varicosities improve three to four months post-delivery. Conservative measures like leg elevation, elastic compression stockings, and avoidance of prolonged standing suffice during pregnancy. Medical management with rutoside trihydrate has shown to alleviate the symptoms in severe cases. Sclerotherapy is hazardous and has to be strictly avoided during pregnancy [26]. Vein stripping and vascular surgery can be done postpartum [25].

1.3.2 Edema of Pregnancy

Nonpitting edema is found in 80% of pregnancies and occurs due to hormone-induced retention of salt and water, enhanced vascularity, and capillary permeability. Caval compression by the enlarging the uterus further exacerbates it [25]. It is usually noted during the third trimester and continues to progress with pregnancy. The edema is most conspicuous in the lower extremities and during early morning; however, edema may also manifest in periorbital area, hands, and face (Fig. 3.7). This edema is benign in nature and can be reduced by taking rest, leg elevation, use of compression stockings, and by sleeping in the left lateral decubitus position. The edema can also manifest in the complication of carpal tunnel syndrome.

Fig. 3.7

Pitting edema, both legs in pregnancy

Persistent edema along with high blood pressure and proteinuria can be a sign of cardiac, renal, and preeclamptic edema and calls for further examination [27].

1.3.3 Spider Angioma

Spider angioma (syn: vascular spider, spider nevus, arterial spiders, nevi aranei) is the most common vascular change in pregnancy. It consists of a central, small, flat/raised, blanchable, faintly pulsating arteriolar telangiectatic puncta, surrounding erythema and extensions of fine thin-walled vessels that radiate outward like a spider’s web. They commonly arise in the vascular territory of the superior vena cava such as the neck, face, throat, and arms during second and fifth months of pregnancy and continue to increase in number and size throughout pregnancy. Circulating plasma estrogen-induced anomalous dilatation of end vasculature is the main pathomechanism for their occurrence [28]. About 75% of these regress, although not completely by three months post-delivery. Recurrences in subsequent pregnancies are also reported. For the lesions that tend to persist, low voltage electrodessication at the center of the punctum gives good cosmetic outcome [29].

1.3.4 Palmar Erythema

Palmar erythema occurs commonly in the first trimester of pregnancy. It is often seen occurring together with spider angioma in the same patient. Increased estrogen, increased blood volume and flow, and genetic predisposition are all the possible underlying factors. It can either present as a localized area of erythema strictly confined to the thenar and hypothenar eminences or as mottled erythema involving the entire palm. Palmar erythema resolves quickly within a week post-delivery [30].

Multiple telangiectasias and unilateral nevoid telangiectasias may also develop secondary to increased estrogen levels [6]. Hemangiomas, subcutaneous hemangioendotheliomas, glomangiomas, petechiae and purpura may have an onset during pregnancy or already pre-existing lesions can exacerbate [4].

Cutis marmorata, a transient bluish mottling of the skin on cold exposure, can manifest on the legs in pregnancy due to elevated estrogen-induced vasomotor instability (Fig. 3.8). If cutis marmorata persists post-delivery, it is advisable to investigate for any underlying blood dyscrasia, collagen vascular disorder, or neoplastic disease [2]. Flushing, pallor, and paresthesias are other manifestations of vasomotor instability. Increased permeability and fragility of capillaries can result in purpura on the lower extremities in the latter half of pregnancy [21].

Fig. 3.8

Cutis marmorata in pregnancy

1.4 Connective Tissue Changes

1.4.1 Striae Distensae

Striae gravidarum is the most frequently noticed change affecting the connective tissue and is seen in 55% to 90% of women during the late second and early third trimester. They first appear as flat/raised pink to violet-red (striae rubra) bands along skin tension lines on the abdomen, breast, hips, and thighs [31]. They enlarge and become longer and wider with the progression of pregnancy, and over a period of months to years postpartum they gradually fade away forming atrophic, hypopigmented linear scars (striae alba).

Hormonal factors, increased maternal weight gain, genetic predisposition, and mechanical stress on the connective tissue are the causative factors of the abnormalities (Fig. 3.9) of elastic fibers, collagen, and other extracellular matrix components [32, 33]. Histologically, there is decreased adhesiveness between the collagen fibrils, increased ground substance, rupture, and retraction of elastic fibers within the reticular dermis [34]. Although mostly asymptomatic except for occasional itching and burning reported in a few, they can still be a substantial cause of cosmetic concern and decreased quality of life. Preventive measures such as application of almond oil, olive oil, and hyaluronic acid have all been reportedly tried with limited success. Post-delivery treatment with topical tretinoin, glycolic acid, ascorbic acid or microneedling, microdermabrasion, radiofrequency ablation, fractional nonablative and nonfractional lasers can result in some improvement [35, 36].

Fig. 3.9

Striae distensae

Molluscum fibrosum gravidarum are benign, small, pedunculated, tan-to-brown, fleshy skin tags that develop on the face and in intertriginous areas during the second trimester [37].

Pregnancy leads to an increase in size and number of pre-existing neurofibromas. Also, eruptive neurofibromas appearing during pregnancy may be seen as an initial presentation of neurofibromatosis. Increased hypertensive and cerebrovascular complications are known to be associated with neurofibromatosis in pregnancy. In majority of cases, only partial regression of neurofibromas is seen postpartum. Complete resolution is not reported [38]. Increased estrogen levels cause worsening of keloids, cellulite, leiomyoma, and dermatofibroma during pregnancy [39].

1.5 Glandular Activity

The modifications of maternal immune functions and glandular functions by pregnancy have its repercussions on glandular skin diseases. Glandular dermatoses of sebaceous and eccrine origin are usually aggravated while those involving the apocrine glands are reported to improve during gestation [40].

1.5.1 Eccrine Glands

Increased thyroid activity and relative iodine deficiency in pregnancy give rise to increased eccrine gland activity in later stages of pregnancy. In addition, increased vasomotor activity due to altered functioning of the autonomic system and abnormal weight gain leads to excessive sweating leading to an increased development of hyperhidrosis, pompholyx, and miliaria. However, the adrenocortical activity results in increased suppression of palmar digital sweating [41]. These physiological adaptations do not have any definitive treatment and if they are too troublesome, aluminum chloride hexahydrate 20% solution in ethyl alcohol can be applied on sweaty areas every night for one to two weeks [1].

1.5.2 Sebaceous Glands

The nature of acne during pregnancy is highly unpredictable; it often improves during the first trimester but is known to exacerbate during the third trimester under the influence of elevated androgens in the pregnant mother and the resultant heightened sebum production [42,43,44] (Fig. 3.10). Pregnancy-related hormonal and immunologic changes lead to the development of more inflammatory lesions often involving the trunk [42]. Women with prior acne have more propensity to manifest acne during pregnancy. Mild acne is treated with topical therapies such as benzoyl peroxide, azelaic acid, and topical antibiotics (clindamycin and erythromycin).

Fig. 3.10

Acne aggravated in pregnancy

Oral erythromycin base or ethylsuccinate may be required to treat moderate to severe cases. Comedone extraction, mild superficial alpha-hydroxy acid peels, and microdermabrasion have been reported to cause no adverse effects. Salicylic acid is best avoided as systemic absorption is reported to occur. Safety data for laser modalities is inadequate [2].

1.5.3 Apocrine Glands

Fox-Fordyce disease and hidradenitis suppurativa are two apocrine disorders that were reported to have good remissions during pregnancy with chances of rebound post-delivery [45]. Apocrine glands are commonly found in the resting state and secrete less during pregnancy, and this effect on the functional activity of apocrine glands is the key reason behind the amelioration of apocrine gland disease in pregnancy.

1.6 Hair Changes

There can be increased or decreased hair growth under the influence of pregnancy hormonal changes. About 80% of scalp hairs are generally in the anagen phase of hair cycle. In pregnancy there is an even more increase in this number of anagen hairs because of decreased conversion of hairs from anagen to telogen phase [46]. Thus, hair is thicker and denser with increased shaft diameter throughout pregnancy [47]. Post-delivery, hormonal alterations cause all these anagen hairs to enter into the telogen phase simultaneously. Subsequently, shedding of this telogen hair causes diffuse hair loss (telogen effluvium) starting one to five months postpartum and may continue up to one to two years [48]. Mostly, there is excellent recovery with complete regrowth and reassurance is all that is required. Some women may rarely experience frontoparietal recession or male-pattern alopecia in late pregnancy. Complete regrowth of the shed hair does not usually happen in this minor group of patients [2].

1.6.1 Hirsutism

Male-pattern terminal and vellus hair growth involving the face, chest, lower abdomen, arms, and legs is seen in many pregnant women, particularly in women with darker hair [46]. Elevated ovarian and placental androgens influencing the pilosebaceous unit are thought to be responsible for the patterned hair growth. The terminal hairs are mostly permanent whereas the soft fine hairs regress to some extent within six months postpartum. Laser can be used to remove the persistent hair postpartum [49].

1.7 Nail Changes

Nail changes in pregnancy are seen in 2% to 40% of gravid women. Leukonychia, white spots on the nails, is the most common nail alteration reported and it can present as punctate, striate, partial, or total forms. Onychocryptosis (ingrown toenail), the second commonest nail change encountered, occurs due to increased weight gain. It causes paronychia with granulation tissue formation and tenderness of the involved digit. Onychoschizia (splitting of distal free end of nails), onycholysis, and brittleness of nail may arise due to accelerated growth and softening of the nail plate. Subungual hyperkeratosis, Beau’s lines (transverse grooves on nail plate), and onychomycosis have also been reported. Koilonychia (spoon nail) is seen in anemic pregnant women with iron deficiency. Uniform, symmetrical melanonychia (pigmented nails) is often known to occur during pregnancy and it fades postpartum [50]. However, irregular pigmentation with cuticle involvement warrants a thorough dermatological examination for evaluation of possible melanoma. Some studies have reported an increase in nail plate thickening rather than an increase in the nail growth [11].

1.8 Breast

The mammary gland/breast undergoes extensive anatomical and physiological changes to prepare for lactation. In early pregnancy, under the influence of elevated estrogen, vascular proliferation, increased blood flow, new duct formation and branching occur. Increased progesterone during the latter half of pregnancy induces lobular hyperplasia, involution of the breast’s fibrofatty tissue, and distension of acini with colostrum. All these changes present clinically as progressive increase in the volume, firmness, nodularity of the breast tissue, tenderness, prominence of veins, striae, areolar and nipple enlargement, with/without nipple sensitivity [1] (Fig. 3.11).

Fig. 3.11

Enlargement of nipple and areola

Hyperkeratosis of the nipple and areola appears as bilateral, brown, pigmented, hyperkeratotic, hard warty crusts/plaques mostly involving the tip of the nipple (Fig. 3.12). These lesions tend to improve after delivery and can at times be persistent postpartum causing difficulty in breast feeding. Recurrence and worsening of the condition in subsequent pregnancies is also reported. In severe cases the treatment is challenging and unsatisfactory [51].

Fig. 3.12

Severe nipple hyperkeratosis with fissuring

As discussed earlier, the nipple and areola may darken along with the formation of secondary areola and Montgomery’s tubercles. Montgomery’s tubercles represent hypertrophic sebaceous glands and are seen as circularly arranged small yellowish papules near the peripheral border of the areola (Fig. 3.13). Their secretions help lubricate the nipple-areolar complex and also serve as olfactory stimulus for the newborn to breast feed [10].

Fig. 3.13

Montgomery tubercles with nipple hyperkeratosis

1.9 Mucosa

Bluish-purple discoloration of the vaginal or cervical mucosa, known as the Chadwick’s sign, is among the earliest signs observed during pregnancy. It occurs as a result of increased blood supply to the area [52].

Gingivitis is very common in pregnancy, affecting 30 to 100 percent of pregnant women. It usually first appears during the second month, increases through the eighth month, and disappears postpartum. Its development is initiated by dental plaque and exacerbated by endogenous steroid hormones. Significant worsening of pre-existing gingivitis or periodontitis is also known to occur in pregnancy [40]. The fluctuation in estrogen and progesterone levels exerts an influence on subgingival microbiota and ensues a spectrum of inflammatory response through alterations in chemotaxis, cytokine profile, release of proinflammatory enzymes and antioxidants from neutrophils, periodontal ligament cells, and gingival fibroblasts. Bleeding upon probing or mechanical stimulation, severe hyperplasia, increased periodontal probing depths, and gingival crevicular fluid flow are all the characteristic features of pregnancy gingivitis [6].

Pyogenic granuloma of the nasal or oral mucosa, a reactive inflammatory lesion, occurs in up to 5% of pregnancies and is therefore commonly referred to as “pregnancy tumor” and “granuloma gravidarum.” Pregnancy hormonal fluctuations and exposure to low-grade irritants are the possible pathomechanisms behind its development. It has a potential for rapid growth and spontaneous bleeding. Expectant management is possible as it resolves after delivery. Maintenance of good oral hygiene and periodical dental check-ups during pregnancy are highly effective in combating this condition [53].

Hemangiomas, benign tumors of thin-walled blood vessels, have an increased incidence during pregnancy and can affect any organ or system. The increased estrogen levels aid in vascular proliferation and hemangioma formation [40]. Although most of these do not pose serious problems, hemangiomas of the central nervous system and abdominal viscera are reported to cause dangerous complications like severe blood loss, shock, and very rarely even maternal death [29].

Raised abdominal pressure and hormonal changes of pregnancy lead to the swelling and enlargement of external hemorrhoidal veins [29]. About 25% to 35% of pregnant women develop hemorrhoids and the incidence rises further up to 85% in the third trimester. Pruritus, burning, painful swellings at the anus, dyschezia, and bleeding are the symptoms associated with hemorrhoids. Spontaneous resolution of most of hemorrhoids occurs soon after delivery. Postpartum interventions such as vein stripping, hemorrhoidectomy, and sclerotherapy will be needed only for serious cases. Conservative measures will help relieve most symptoms during pregnancy and include administration of stool softeners and increasing the intake of liquids and fiber content of the diet. Proper bowel habits, hot sitz baths, astringent compresses, laxatives, suppositories, and topical anesthetic creams will also provide symptomatic relief. Appropriate management is however crucial to prevent more grave complications such as thrombosis and prolapse [54].

Nasal physiology is altered by hormonal changes during pregnancy; increased estrogen levels cause edema of the nasal mucosa, vascular congestion, and recurrent rhinitis (rhinitis of pregnancy) in 20% of pregnant females [55].

Tear film physiology is disturbed by pregnancy leading to the development of dry eye. Prolactin, epidermal growth factor, and transforming growth factor beta-1 induced direct destruction of acinar cells and immune reaction in the lacrimal duct cells are the hypothesized pathomechanisms responsible for dry eye. Dryness can be further exacerbated by dehydration [56]. Dry mouth from decreased salivary secretion may also develop [52].

2 Dermatologic Drugs in Pregnancy

During pregnancy drug prescriptions have to be personalized according to individual needs taking into consideration maternal and fetal risks. A thorough risk-benefit analysis is essential.

Factors affecting use of drugs in pregnancy:

• Timing of drug usage: Before conception, 1st/2nd/3rd trimester

• Essentiality to treat the dermatological disease

• Nature of the drug and adverse effects

• Risk assessment

In 2014: The US Food and Drug Administration (US FDA) issued the pregnancy and lactation labeling rule (PLLR) replacing the earlier guidelines with pregnancy categories W.E.F June 30, 2015. The older pregnancy categorization and new PLLR rule are depicted in Tables 3.1 and 3.2 respectively.

Table 3.1 Pregnancy categories according to the FDA

Table 3.2 New pregnancy and lactation labeling rule (PLLR)

The new rule contains descriptive subsections for usage of drugs during pregnancy and lactation. In addition the new rule contains a summary of the risks involved with using different drugs and supporting data that enables physicians to make informed prescribing choices during pregnancy and lactation [57, 58].

2.1 Topical Dermatology Drugs in Pregnancy

During pregnancy, topical medications are often preferred over oral medications keeping in view the lesser risk of systemic side effects. However the safety of topical drugs should also be considered especially when higher concentrations are used or in cases of usage over long durations [59]. Safety of topical drugs in pregnancy is described in Table 3.3 including original FDA categories and risk description (PLLR).

Table 3.3 Topical dermatology drugs in pregnancy

3 Systemic Dermatologic Drugs in Pregnancy

3.1 Safety of Systemic Drugs in Pregnancy is Described in Table 3.4

3.1.1 Biologicals in Pregnancy (Table 3.5)

The existing evidence recommends the use of biologicals to treat psoriasis in pregnancy to circumvent any possible psoriasis-associated adverse outcomes. There is more data available on anti-TNF alpha agents compared to IL-12/23 and IL-17 inhibitors and hence anti-TNF alpha agents are preferred over the latter. The use of anti-TNF alpha agents is restricted in the first half of pregnancy, and these drugs should not be used during the last trimester because of the risk of disseminated infections in infants following live vaccinations during that period [61].

Table 3.4 Systemic dermatology drugs in pregnancy

Table 3.5 Biologicals in pregnancy [65,66,67,68,69,70,71,72,73,74]

Anti-TNF alpha agents (excluding certolizumab) are IgG1 antibodies or receptors attached to an Fc portion of an IgG1. IgG1 placental transfer is substantially increased in the third trimester [62].

Unlike adalimumab and infliximab, etanercept is a fusion protein and has minimal transfer across the placenta. Certolizumab is an Fc-free PEGylated TNF alpha inhibitor with negligible transfer across the placenta. The routine use of TNF alpha inhibitors during pregnancy is not recommended. They can nevertheless be used in severe and recalcitrant disease with caution.

Rituximab has been found to cause an increased risk of neonatal hematological abnormalities and is therefore not recommended for use in pregnancy. Transplacental passage of the drug gradually increases with due course of pregnancy and is minimal in the first trimester. It steadily increases by the second trimester and is maximum by the third trimester and may also affect B-cell development in the fetus. Pregnancy should be avoided for at least a year post rituximab exposure.

It is recommended to avoid pregnancy for at least 12 months after rituximab exposure [63].

Ghalandari N et al. in a systematic review concluded that the risk of congenital fetal malformations with the use of infliximab, certolizumab pegol, and adalimumab in pregnancy is not significantly increased compared to the risk in general population. The risk in general population is about 2–5.5% [64]. The European Medical Agencies recently issued their conditional approval for the use of these drugs and etanercept during pregnancy based on the data obtained from pregnancy registries maintained by pharmaceutical companies.

Table 3.5 Depicts comments, Evidence, and EULAR (European League Against Rheumatism) Recommendations [64, 65]

3.2 Cosmetic Procedures in Pregnancy: Table 3.6 [76]

There is a relative dearth of data on the safety of cosmetic procedures in pregnancy. Thus procedures are often deferred until after delivery unless there is a strong therapeutic indication. Procedures are better performed with the patient lying in the left lateral decubitus position in order to avoid vascular compromise caused by pressure on the inferior vena cava.

Table 3.6 Cosmetic and surgical procedures in pregnancy

Routine procedures such as biopsies and electrocautery can be performed in pregnant women.

With regard to cosmetic procedures, chemical peels, glycolic and lactic acid peels are considered safe whereas trichloroacetic and salicylic acid peels are recommended to be best avoided or used with caution.

There is scarcity of safety data on botulinum toxin A. Systemic absorption and transfer across placenta has been found to be minimal. Botulinum toxin A has been used for medical indications such as spasticity in pregnancy without any adverse effects.

Sclerotherapy is considered safe during pregnancy; however it should be avoided during the first trimester and late in pregnancy after 36 weeks. Laser therapy has been performed for patients with genital warts without adverse effects. Laser epilation may be avoided during pregnancy and other options such as waxing and shaving may be preferred.