Although most fetal disorders can be treated after birth, a few conditions that predictably lead to fetal or neonatal death or that progress before birth and cause significant infant morbidity are ideally treated prenatally .
Three significantly different approaches are currently used to treat the fetus before birth, including medical transplacental therapy, minimally invasive (needle-based or fetoscopic) procedures and open fetal surgery , all of which have their specific risks and benefits. With an increasing number of fetal interventions being performed worldwide, it is of utmost importance that caregivers understand the potential maternal adverse events related to such therapies. The latter is even more important as these interventions have no direct physical benefit to the mother and the risk to her is for a purely altruistic purpose .
In this manuscript, we will not only review the immediate maternal side effects of medical and surgical fetal therapy but also discuss the implications of these interventions for later fertility and reproductive outcomes. Our aim is to provide the reader with information that may help in counseling women and couples considering fetal therapy.
MEDICAL TRANSPLACENTAL THERAPY
Fetal treatment by transplacental passage of maternally administered medications is one of the best known forms of fetal therapy. This intervention is basically the extension of fetal transplacental preventive interventions, such as the administration of folic acid for the prevention of spina bifida , intrapartum antibiotic prophylaxis of group B streptococcal disease or the administration of steroids for prevention of neonatal lung disease. The most commonly used medications for transplacental therapy include corticosteroids, antiarrhythmic drugs and intravenous immunoglobulins (IVIg).
In contrast to hydrocortisone and prednisolone, fluorinated corticosteroids, such as betamethasone and dexamethasone, are not metabolized by the placenta and therefore rapidly reach the fetus. These highly potent steroids are primarily used in the prevention of female genital virilization in congenital adrenal hyperplasia (CAH)  and, more experimentally, in the treatment of anti-Ro/La antibody-mediated fetal heart block . For the treatment of CAH, a daily dexamethasone dose of 20 μg/kg maternal bodyweight, and not exceeding 1.5 mg/day, is used . Even though this medication is administered long term throughout the pregnancy, tolerance is usually good, and a large French study on more than 250 pregnancies at risk for CAH shows that the incidence of typical steroid-mediated side effects such as hypertension, striae, cushingoid appearance and gestational diabetes is low . In pregnancies complicated by fetal immune-mediated heart block, the starting dose of dexamethasone is typically 8 mg/day, which is then gradually tapered. Maternal steroid-induced psychosis has been reported in this setting [8▪] and is more common in the presence of maternal systemic lupus erythematosus [9▪]. Fortunately, steroid-induced psychosis is reversible upon interruption of the steroids.
Antiarrhythmic therapy is the mainstay treatment for persistent fetal tachyarrhythmia, including supraventricular tachycardia and atrial flutter which, if persistent, lead to fetal hydrops and death . Administration of digoxin, flecainide or sotalol to healthy women has the potential to induce arrhythmia and cause severe maternal damage. Despite this theoretical risk, however, no serious maternal cardiac adverse events have been reported.
The latter is probably thanks to the close maternal medical supervision that takes place when antiarrhythmic therapy is instituted, including a baseline ECG, blood electrolyte levels and serum drug level dosing.
Finally, intravenous maternal administration of IVIg is taking a more prominent position in the treatment of fetal and neonatal alloimmune thrombocytopenia [11▪▪] and in the prevention of recurrence of neonatal hemochromatosis . IVIg doses administered for fetal therapy (1–2 g/kg) are much higher than what is used for other nonobstetric conditions (typically 0.5 g/kg). IVIg is a donor-derived blood product and can cause immediate generalized reactions including myalgia, fever, nausea, back pain, hypotension and tachycardia in up to 30% of cases [13,14▪▪]. Headaches and fatigue are reported in 30–70% [14▪▪,15]. Generally, these reactions are relatively mild and self-limited. More severe reactions such as anaphylaxis, renal and neurologic complications, thrombosis and alopecia are rare . Nevertheless, the repeated infusions and their side effects strongly impact the woman's activity, her ability to work and to care for other children, and up to 75% will describe the treatment as having a negative impact on quality of life [14▪▪].
SURGICAL FETAL THERAPY
In contrast to transplacental drug therapy, invasive fetal therapy requires surgical access to the fetus or the placenta. In terms of maternal side effects, a strong distinction should be made between minimally invasive procedures and ‘open’ fetal surgery. Minimally invasive interventions include needle-based procedures (such as for intrauterine transfusion, shunting and radiofrequency ablation of masses) and fetoscopic procedures [laser ablation of placental vascular anastomoses for twin–twin transfusion syndrome (TTTS), fetal tracheal occlusion for congenital diaphragmatic hernia and experimental fetoscopic repair of spina bifida]. All of these interventions can be done under local anesthesia and require one or more maternal abdominal and uterine incisions of less than 5 mm .
‘Open’ fetal surgery on the other hand involves maternal laparotomy and hysterotomy under general anesthesia to access the fetus. The most common procedure requiring this type of access is fetal spina bifida repair. However, debulking of massive solid sacrococcygeal teratomas and resection of large lung masses causing fetal hydrops have also been described . There have been some reports on fetoscopic procedures assisted by maternal laparotomy to facilitate access to the uterus, but these are rarely performed, even in the larger fetal therapy centers.
When discussing maternal risks of fetal surgery, it is important to understand that some of the therapy-related complications are not due to the surgery itself, but can also be caused by the (necessary) cointerventions, such as the use of tocolytics or anesthesia. As such for example, pulmonary edema observed after fetal surgery under general anesthesia is partially due to generous volume loading during the procedure. A ‘fluid restrictive’ anesthesia policy or a move to surgery under local anesthesia can reduce the incidence of this complication . However, pulmonary edema can also be caused by fluid resorption from the surgical field, especially in open fetal surgery or by physiologic intravascular reabsorption of amniotic fluid as is seen after treatment for TTTS . Finally, pulmonary edema is a common complication of tocolytic use, particularly when different classes of tocolytics are used together in multiple gestations .
In contrast to pulmonary edema, other complications are more specific to the surgery itself (Table 1). As such for example, open fetal surgery for spina bifida repair involves a hysterotomy to expose the fetal spine. Despite a multilayer repair, the uterine scar remains a fragile spot in the uterus and poor healing is often described, with partial or complete scar dehiscence at delivery in 7–11% [21▪,22,23,24▪]. As a consequence, all women who undergo open fetal surgery should deliver the index pregnancy by elective cesarean section to prevent scar rupture. This risk for scar rupture persists in subsequent pregnancies. High rates of scar dehiscence (14%) and uterine rupture (14%) have been reported in a cohort of 47 pregnancies following a previous pregnancy that underwent open fetal surgery [25,26]. These risks are probably higher than those reported after classical cesarean section. As a consequence, elective preterm delivery by cesarean section is recommended in all subsequent pregnancies. An interpregnancy interval of more than 2 years is advised after fetal surgery to allow for optimal healing of the hysterotomy. The high risk of uterine rupture in subsequent pregnancies induces significant anxiety in expecting mothers, and attention for signs of depression is warranted .
Other typical complications of open fetal surgery include placental abruption, chorioamnionitis and need for blood transfusion at delivery (Table 1). A clear surgical ‘learning curve’ can be seen over time, leading to a decreased incidence of these complications in the more recently reported series. Fertility is not decreased after open fetal surgery, and the miscarriage rate in subsequent pregnancies is comparable with baseline [25,27].
Fetoscopic interventions carry much lower maternal complication rates than open fetal surgery. The most common complications of fetoscopic laser ablation of placental anastomoses for TTTS include benign intraperitoneal amniotic fluid leakage (1–7%), placental abruption (1–3%) and chorioamnionitis (2–3%) [28–30]. Histologic chorioamnionitis and funisitis are more common though (13 and 8%, respectively) [31▪]. A systematic review shows that, overall, the incidence of maternal complications after laser for TTTS is 5%, with severe complications (pulmonary edema and placental abruption) occurring in only 1% .
Longer and more complex procedures carry slightly higher complication rates. Indeed, Degenhardt et al. report a 6% risk of chorioamnionitis and 2% risk of pulmonary edema in a cohort of 51 fetuses undergoing experimental fetoscopic spina bifida repair.
If the pregnancy is complicated by fetal hydrops (stage 4 TTTS, fetal arrhythmia, fetal pleural effusions or large fetal chest masses) or if hydrops occurs after the fetal therapy [34▪], caregivers should be aware of the risk of mirror (Ballantyne) syndrome, which presents as maternal edema, hypertension and proteinuria (summarized in ). On the other hand, successful fetal medical or surgical therapy and subsequent resolution of hydrops can sometimes also ‘cure’ preexisting maternal mirror syndrome .
Uterine scar problems have not been identified after fetoscopic procedures, and these patients do not necessarily require cesarean section for delivery, neither in the index pregnancy, nor in subsequent pregnancies. Similar to what has been reported after open fetal surgery, fetoscopy does not induce new fertility problems, nor does it increase the risk of miscarriage in future pregnancies (8%, similar to general population) [37▪▪].
The risk of complication after minimally invasive ultrasound-guided needle procedures (radiofrequency ablation in complicated monochorionic twins) is likely even lower than the risk after fetoscopy [16,38]. Rare cases of chorioamnionitis [39▪] and thigh burns  due to suboptimal application of the grounding pads of the radiofrequency generator have been reported.
The number of centers offering fetal therapeutic procedures is gradually increasing worldwide. Patients and caregivers should be aware of the potential risks of these interventions. For medical and minimally invasive procedures, maternal adverse effects are probably rare, when done in expert centers. Open fetal surgery however carries important risks to the mother, both in the index pregnancy and in subsequent pregnancies.
Financial support and sponsorship
T.V.M. is the recipient of a Junior Faculty Award of the Department of Obstetrics and Gynaecology, Mount Sinai Hospital and the University of Toronto, Toronto, Canada.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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This retrospective review of fetuses with atrioventricular block describes a case of steroid-induced psychosis.
9▪. Shimizu Y, Yasuda S, Kako Y, et al. Poststeroid neuropsychiatric manifestations are significantly more frequent in SLE compared with other systemic autoimmune diseases and predict better prognosis compared with de novo neuropsychiatric SLE. Autoimmun Rev
This retrospective study shows that steroid-induced neuropsychiatric disease is common, especially in women with lupus.
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This article compares standard-dose vs. low-dose intravenous immunoglobulins for the treatment of neonatal alloimmune thrombocytopenia.
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Excellent manuscript on the maternal psychosocial effects of fetal transplacental therapy.
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29. Yamamoto M, El Murr L, Robyr R, et al. Incidence and impact of perioperative complications in 175 fetoscopy-guided laser coagulations of chorionic plate anastomoses in fetofetal transfusion syndrome before 26 weeks of gestation. Am J Obstet Gynecol
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30. Rustico MA, Lanna MM, Faiola S, et al. Fetal and maternal complications after selective fetoscopic laser surgery for twin-to-twin transfusion syndrome: a single-center experience. Fetal Diagn Ther
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Case–control study from the Netherlands showing an increased risk of funisitis and chorioamnionitis after fetoscopic laser.
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Case series documenting maternal mirror syndrome in a monochorionic twin pregnancy complicated by twin anemia-polycythemia sequence.
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Retrospective study comparing reproductive outcomes of women who underwent fetoscopic tracheal occlusion with controls.
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Case series describing a low risk of chorioamnionitis after radiofrequency ablation and cord occlusion.
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